Table of Contents:
When we think about aging, one of the first thoughts that comes to mind is wrinkled and sagging skin as well as the greying and loss of hair – simply put, the physical changes to appearance that we associated with advancing age. These changes are the most striking reflection of the underlying molecular aging processes that are happening inside our bodies.
The current size of the cosmetic industry alone highlights that physical appearance is important to people. As we continue developing strategies to improve longevity allowing us to live longer and in far better health, people will inevitably want a “youthful appearance” to match their newfound “youthful state”. Furthermore, as this report explains in more detail, aesthetic aging plays a significant and grossly underappreciated role in influencing the rate of biological aging.
It is fair to say that the cosmetic industry alone might not be enough to address aesthetic aging from a longevity point of view, as cosmetic products work to conceal the signs of aging. We need tactics that can address the underlying causes of skin and hair aging to achieve long-term benefits and halt the fine interlink between aesthetic aging and biological aging. This is where advanced aesthetics comes in.
Longevity.Technology defines advanced aesthetics as any therapeutics and technologies that address aesthetics aging by using evidence-based products that target hallmarks of aging, in other words targeting the root cause of skin and hair aging.
One of the most striking aspects of this report is the very large surge of advanced aesthetics companies since 2013, the very year López-Otín et al, published “The Hallmarks of Aging” paper. Since 2013, we have seen steady growth in both the number of advanced aesthetic companies and the number of investments, emphasising the very potential of this relatively new market. This should inspire confidence that the market will continue to grow. However, as it is still relatively unsaturated, it is the perfect time to jump on the advanced aesthetic tide whether as an investor or a developer.
Our Longevity.Technology report provides key insight into the opportunities within the Advanced Aesthetic market for scientists, developers, and investors. We hope you will find it interesting and informative.
The population aged 60 or above is growing faster than all younger age groups and this development is impacting skin disease morbidity and mortality, as well as reflecting in the incidence of several other chronic diseases of aging. The number of older persons in the world is projected to be 1.4 billion in 2030, 2.1 billion in 2050 and even 3.1 billion in 2100 (Strnadova, 2019). A harbinger of the future promise, potential investment opportunity and intense need for therapeutics that extend healthy longevity.
Figure 1. The projected number of elderly is set to reach 3.1 billion by 2100
The most visually striking and apparent features of the aging process is wrinkled and sagging skin as well as the greying and loss of hair. Although there are other features of aging that are more detrimental to quality of life and imminent to mortality (such as muscle loss and cognitive decline), the cosmetics industry currently garners a larger net worth and market size than the longevity industry as a whole (Allied Market Research, 2022).
How we look impacts our health and well-being
There is substantial evidence that the burden from a remarkable number of skin conditions and diseases is greater in the elderly. As such, aging of the skin had classically been thought of as an innocuous byproduct of getting older, but this could not be further from the truth. Skin aging involves a major disease component and not all individuals are similarly affected. The majority of senior adults have at least one treatable skin complaint, and many have more (Farage, 2013). On one level, skin aging reflects the process of biological aging going on throughout the body. On another level, skin aging itself can accelerate aging of our internal organs and tissues (Franco, 2022). Regardless, skin aging has a significant impact on quality of life and the fitness of an organism.
In recent years, the field of BioAge diagnostics has revealed the truly intimate link between skin aging and overall longevity by demonstrating that individuals that are older looking are more likely to have a higher incidence of morbidity and mortality, regardless of chronological age (Coma, 2014). Take, for example, SuperAger centenarians (and their SuperAger children) that live 100 and beyond in good health and look decades younger than their chronological age.
In this sense, the skin can be thought of as a canvas on which a large part of our interior world is painted.
Aging of the skin and hair also takes a physiological and psychological toll on an individual. This (psychological) aspect of aging is often overlooked or ignored. The association between how we feel about ourselves and our health goes even deeper than this. In 2020, Deep Longevity developed a tool that measures the rate of biological aging called the subjective age test (SAT). The SAT uses psycho-social questionnaires to assess various parameters of mental and emotional health, personal experiences, personality traits, cultural values and lifestyle parameters that reflect an individual’s perception of their age (Zhavoronkov, 2020).
Surprisingly, this tool proved more accurate at predicting morbidity and mortality than our chronological age. Perceived self-image is a major component of the SAT, hence a major driver of the biological aging process (Zhavoronkov, 2020). This is not entirely surprising as it is well known that our psychological state controls several physiological factors that influence longevity (Thyagarajan, 2019).
Aesthetic aging therefore plays a significant and grossly underappreciated role in influencing the rate of biological aging.
Unfortunately, the field of cosmetics is built on a shaky foundation that is characterised by charlatans, snake oil and a lack of rigorous scientific evidence (Rubin, 2019). This has left the fundamental geroscience nature of skin/hair aging largely unrecognised. This highlights an immense opportunity for the longevity field.
Advanced Aesthetics: using a geroscience approach to go beyond the cosmetic
The term “antiaging” is over-used within the cosmetic field to capture the attention and emotions of its market. Antiaging is commonly used to encompass any product that conceals or even temporarily mitigates downstream mechanisms of aging while upstream “root causes” of aging continue to accrue (Mohiuddin, 2019).
This can be detrimental to health as it not only does not address root issues, it allows them to accumulate behind the veil of visually pleasing and superficial changes. For this reason, it is imperative to take a moment to redefine antiaging within the context of Advances Aesthetics (AAs). AAs uses the terms “antiaging” and “longevity” to characterise evidence-based products that are strategically developed to target hallmarks of aging and have quantifiable effects on cellular, physiological and aesthetic levels.
Cosmetics vs Advanced Aesthetics
Conceal the byproduct of aging process
– wrinkles, hair loss, skin discoloration
Address the root cause of aging
– aging drivers
AAs operate with the strategy that developing longevity therapeutics that target early hallmarks of aging will ultimately address phenotypes of skin aging, improve aesthetic appeal and most importantly – help individuals age healthier, longer. As AAs are technically purposed towards improving beauty and aesthetics, while not explicitly targeting diseases, the preclinical data is quickly translated to human trials and then to the consumer, therefore bypassing the rigours of the clinical trial process required for drug validation. Technically, with enough scientific evidence and a robust safety profile, AAs do not need to go through clinical trials at all. Although we will argue that this should be the rare case as the value of human clinical data is immense for the longevity of AAs companies. Information gathered from AAs can help drive the longevity economy
Difference between cosmetic, drug and advanced aesthetics
|Cosmetic||Cosmetics are any products that are applied to the body with the intent of improving appearance.|
Cosmetics regulatory process does not require clinical calibre data to be collected at all – beyond ingredients within the product being GRAS (generally recognised as safe).
Products can travel directly from conception to the consumer. Because of this, only a small fraction of cosmetic companies actually have products that are backed by preclinical and clinical evidence
|Drug||Pharmaceutical grade intervention that is purposed towards treating a skin disease.|
Governed by stringent regulatory standards
Drugs are more expensive and time consuming to develop, appeal to a narrower demographic of individuals (afflicted with disease), have a higher risk/benefit ratio.
|Advanced Aesthetic||AAs are therapeutics and technologies that preserve and/or rejuvenate the parts of our body that we associate with vitality and beauty (skin, hair, &c). The AAs approach sets the stage for longevity products that not only revitalise aesthetic appearance at a cellular level, but also rewind the clock of aging to improve systemic health|
As AAs are technically purposed towards improving beauty and aesthetics, while not explicitly targeting diseases, the preclinical data is quickly translated to human trials and then to the consumer, therefore bypassing the rigours of the clinical trial process required for drug validation.
The major barriers within the longevity field has been conveying to the public the real and immediate nature of the aging process and the potential of therapeutics to slow it down. Taking the intangible and making it not only tangible, but imminent. AAs offer a gateway opportunity to improve appearance by slowing down the process of aging throughout the body – starting with aesthetic organs (Prescott, 2017) . In doing so, AAs will reach market segments and demographics that the longevity field never had access to before.
Furthermore, the skin is one of the first organs to externalise signs of aging and one of the few organs from which it is relatively easy to obtain samples for analysis. This makes the skin a fantastic model for studying the various factors that drive the aging process. These studies have already revealed a plethora of cellular hallmarks and biological pathways through which internal and external factors conspire to drive aging of skin and hair. Unsurprisingly, many of these aging pathways are common to all the other cells and organs within our body (Zouboulis, 2019). Therapeutics that prove to target these underlying “aging drivers” within preclinical studies have privileged access to human cohorts within the marketplace. Therefore, AAs serve as a translational platform upon which we can accelerate our understanding of the aging process and demonstrate the potential of rejuvenating other tissues throughout the body.
But AAs have an even more direct effect on longevity than this. The field of geroscience has revealed that organ systems are intimately interconnected and networked with one another. Inflammation, senescence, and cellular trash from one part of the body gets transmitted to distant organs via the circulatory system. This means that the health of skin and hair influences the health of all the other organs in the body – including the brain (Castellani, 2015). Addressing the root drivers of aging within these tissues not only improves aesthetic appeal, it also improves overall systemic health, functionality and performance.
This report dissects the different aspects of skin and hair aging with an emphasis on the cellular and molecular drivers brewing beneath the surface. With this geroscience framework in place, the report presents an unprecedented classification system that highlights the different types of AAs, their strengths and weaknesses and the aging drivers they target. This classification system serves to highlight the utility and investment potential of each AA intervention within the context of its relative impact on skin and hair aging. The final section of the report provides a breakdown and analysis of the market potential and investment landscape within the AAs field. This section highlights key opportunities and challenges that will determine the fate of companies within this prospective, multi-billion dollar industry.
What is skin?
The skin (integumentary system) is the largest organ in the human body, accounting for 10-15% of total body weight. In fact, it can be considered the body’s most extensive sensory receptor and critical protective barrier as it shields from physical, chemical and infectious insults. The skin is also an essential organ of the immune system (with its own immune cells) and is involved in constant surveillance to intercept and destroy toxins and microbes in our immediate external environment. Due to the stressors imposed on it, the skin undergoes constant changes and has a high capacity for repair and regeneration (Russell-Goldman, 2020).
Other important roles of the skin include thermoregulation, fluid and electrolyte balance, toxin excretion, wound healing as well as systemic immunomodulatory and neuromodulatory functions (Russell-Goldman, 2020).
How is it composed?
The integumentary system includes the epidermis, dermis, subcutaneous tissue (hypodermis), associated glands (sebaceous and sweat) and appendages (hair and nails). The health and functioning of these layers give rise to healthy, youthful skin and skin aging is characterised by their degeneration. Compromised functioning of any one of these layers can drive the aging process, but as you will see the dermis plays the most central role in skin aging (Strnadova, 2019). The epidermis serves as the window through which we can visually observe the aging process of the skin unfolding beneath the surface.
Figure 5. Structure of the skin.
A) The epidermis is is the most superficial part of the skin that prevents water loss from the body and protects against abrasions, chemicals, ultraviolet light and pathogenic microorganisms. It host the majority of the skin microbiota and also gives rise to appendages and glands.
B) The dermis is the deep part of the skin and is responsible for structural strength and flexibility. Importantly, it is also a critical signalling hub that provides blood vessels to the epidermis that allows exchange of gases, nutrients, regulatory factors and waste products (dermal-epidermal junction).
C) Subcutaneous tissue resides under the dermis and is loose connective tissue with abundant deposits of fat (adipose tissue) that attach the dermis to underlying structures. Adipose tissue provides energy storage, insulation and padding for the skin (Russell-Goldman, 2020)
How does the skin age?
Skin aging determinants
Our biological rate of aging has two principal determinants that interact together to dictate how we age throughout our lifespan (Gragnani, 2014).
- Intrinsic disposition includes genetic makeup, cellular metabolic signatures and capacity and hormonal balance.
- Extrinsic factors include environmental influences, nutrition and lifestyle
Skin aging is a by-product of the interplay between intrinsic and extrinsic factors that influence cellular functioning and metabolism of cells both within the layers of the skin as well as the microbes on top of the skin. The way in which extrinsic factors (like UVR) affect skin aging depends on intrinsic factors such as endogenous protection systems present in human skin like pigmentation (melanin content), DNA repair machinery and antioxidant defence capacity, &c. Therefore, a decline in DNA repair capacity and melanin leads to an increased sensitivity to UV radiation and increased risk of photoaging induced carcinogenesis. These intrinsic factors may differ between different ethnic groups, age groups and because of genetic differences within these groups (Krutmann, 2016). Each individual’s skin ages in a unique way based on their specific intrinsic vulnerabilities to aging drivers and extrinsic exposures to aging determinants. This “aging trajectory” can be characterised as an individual’s distinct “ageotype”. Understanding intrinsic/extrinsic interactions in skin aging will help identify susceptible subgroups and provide a scientific basis for the development of personalised cosmetics to combat skin aging.
Skin aging drivers
Intrinsic and extrinsic factors influence drivers of skin aging which eventually accumulate damage that presents as cellular dysfunction and the emergence of skin aging phenotypes such as: eczema, dermatitis, psoriasis, autoimmune disorders, skin cancer (basal cell carcinoma (76%), squamous cell carcinoma (19%) and melanoma (5%)) (Vandiver, 2020).
A key feature of AAs is that it targets drivers of skin aging and the cellular manifestations that occur due to the damage. The following model illustrates how the process of aging unfolds within the skin, as well as where cosmetics, drugs, and AAs play a role.
The pathways by which accumulating effects of extrinsic and intrinsic factors lead to accumulation of hallmarks or aging and contributing to skin aging and systemic disease.
Skin aging drivers – the main targets of advanced aesthetics
The role of oxidative stress in skin aging
Reactive oxygen species (ROS) are highly reactive chemicals that are formed as a metabolic byproduct of oxygen containing molecules (H2O2, O2, OH, lipid oxides, &c). In the skin, approximately 1.5∼5% of oxygen consumption is converted to ROS by intrinsic processes. The occurrence of photoaging, pollution, smoking and other extrinsic factors further accelerate its production (Gu, 2020).
ROS play a beneficial signalling role in the body when they are present for short periods of time and at levels that can be regulated by our cell’s antioxidant enzymes. In this context, ROS signals serve to boost mitochondrial health, antioxidant capacity and the expression of several longevity genes (Shields, 2021).
Figure 7. Increasing age leads to loss of defences against oxidative stress. An increase in uncontrolled oxidative stress in older people leads to an increase in Reactive oxygen species (ROS) production. As ROS accumulates further it causes damage to organelles such as mitochondria and increases the number of mutations (Gu, 2020).
But when ROS is chronically present at unmanageable levels it creates oxidative stress that damages DNA, extracellular matrix (ECM) proteins, lipids and organelles (such as mitochondria) of cells in the skin, compromising their function. Further, oxidative stress drives the process of cellular senescence – a major driver of skin aging. Aberrant ROS signalling is a byproduct of both intrinsic and extrinsic factors that drive skin aging. Therefore, boosting the skin’s ability to deal with ROS is a powerful preventative approach to address skin aging – regardless of the initial insult. Reducing oxidative stress is necessary, but not sufficient, to mitigate skin aging (Ho, 2021).
The role of inflammation in skin aging
Chronic inflammation can arise from several factors including repeated exposure to extrinsic factors of aging, poor lifestyle habits, oxidative stress, increased senescent burden, hormonal imbalances, mechanical stressors, mitochondrial dysfunction and intrinsic insults. Chronic inflammation initiates a “self-perpetuating loop” of damage and dysfunction that aggravates all other hallmarks of aging. The presence of chronic inflammation is such a profoundly progeronic factor (common denominator of all chronic diseases) that it has earned itself its own theory of aging – Inflammaging (Pilkington, 2021).
Inflammaging leads to increased production and circulation of cytotoxic factors (cytokines, ROS) that damage healthy cells and tissues. It also involves the release of enzymes that degrade ECM proteins and change the tissue microenvironment. The innate cause of ECM degradation is to allow immune cells access to a given stressor; once the stressor is resolved, the ECM is then repaired. However, the chronic presence of inflammation does not allow resolution of ECM structure once the stressor is eliminated. Chronic inflammation within the skin wreaks havoc on dermal fibroblasts, ECM components and melanocytes that are more vulnerable to aging drivers (Lee, 2021).
Chronic inflammation also disturbs signalling in the stem cell niche, inhibiting the proliferation of stem cells and stifling their regenerative capacity. This is an important point because with aging, stem cells may still hold significant regenerative capacity, but are actively inhibited from performing their regenerative roles. Chronic inflammation is an extremely energy demanding process that disproportionately consumes NAD, depriving other cells of its important roles in signalling, DNA repair and epigenetic maintenance. Because inflammation disturbs the intercellular signalling environment, it can accelerate aging both within the skin as well as in other organs and tissues of the body and even influences the skin microbiome (Franceschi, 2018).
The role of senescence in skin aging
The size of the skin, its proliferative capacity (vulnerability to tumorigenesis) and its role as the first line of defence against extrinsic stressors makes it vulnerable to premature senescence and aging. Senescence is the process in which cells stop replicating, become death resistant and secrete an array of factors called the senescent associated secretory phenotype (SASP) that promote inflammation, growth and ECM remodelling. In younger adults, senescence serves as a repair mechanism, as SASP factors recruit the immune system to the site of damage. This facilitates the ability to repair the damage and/or clear away any tumorigenic cells. However, with increasing age this defence mechanism becomes less efficient. As senescent cells accumulate, they secrete factors that trigger inflammation and senescence in neighbouring cells. Once the rate of senescent cell accumulation exceeds a certain threshold, inflammaging ensues and this compromises the immune system’s ability to clear senescent cells away (Ho, 2021).
Figure 8 Senescence is the process in which cells stop replicating, become death resistant and secrete an array of factors called the senescent associated secretory phenotype (SASP). In younger adults, senescence serves as a repair mechanism, as SASP factors recruit the immune system to the site of damage leading to repair. In older adults, this defence mechanism becomes less efficient. As senescent cells accumulate, they secrete factors that trigger inflammation and senescence in neighbouring cells leading to accumulating damage (Gruber, 2019).
The most damaging aspect of senescent cells is their ability to alter the skin microenvironment by releasing an array of SASP molecules which includes immune system regulators called cytokines. One of these cytokines (colony stimulating factor) transforms inert monocytes into aggressive macrophages that release factors which wreak havoc on the surrounding microenvironment. These factors include ROS that cause oxidative stress and matrix metalloproteinases (MMPs) that break down critical components of the ECM, including collagen and elastin. Impaired functioning of key ECM proteins significantly impairs the dermal response to UVR, leading to photoaging (Lee, 2021).
The toxic environment created by the SASP also initiates a senescence cascade that is propagated through tissue layers via a phenomenon called “bystander senescence” – the spreading of senescence features to cells in spatial proximity of senescent cells. As senescence burden increases in the skin, the integrity of the epidermal barrier is compromised and SASP factors leak into the circulatory system. This can spread senescence and further inflammation throughout the body system, driving diseases in organs throughout the body (Gruber, 2019).
The role of mitochondrial dysfunction in skin aging
As we age and encounter stressors, our mitochondria absorb damage. This is because mitochondria are at the centre of cellular metabolism and are constantly exposed to toxic metabolic by-products. Eventually, these damaged mitochondria need to be degraded and/or replaced through the production of new mitochondria (a process known as mitochondrial biogenesis) (Vandiver, 2020).
Mitochondrial dysfunction has been shown to be one of the most prominent drivers of intrinsic aging and senescence within dermal fibroblasts. AA interventions that boost the efficiency and health of mitochondria within dermal fibroblasts can serve both a preventative and rejuvenative role by (Krutmann, 2021)(Vandiver, 2020):
- Reducing oxidative stress and senescent cell burden
- Improving intracellular signalling and NAD levels
- Promoting expression of genes that restore the ECM matrix
- Restore intercellular signalling involving GFs to promote stem cell regeneration and reduce cell death
Despite the profound promise of targeting mitochondria to achieve skin rejuvenation it remains severely understudied and under-implemented within the cosmetic realm. Hence, the development of mitochondrial therapeutics for both prevention and rejuvenation of skin aging represents an opportunity for the field of AAs.
The role of stem cells in skin aging
Interestingly, epidermal stem cells are considered unique in comparison with other adult stem cells in their ability to resist aging. Age-related changes within epidermal stem cells seems to be largely dependent on the signalling factors and communication going on within their microenvironment, the so-called niche. The epidermal niche is defined as the interplay of cell-extrinsic factors (ECM composition, growth factors, cell-cell interactions) with cell-intrinsic factors like the epigenetic and metabolic state of the stem cells (Gruber, 2019). A growing body of data suggests that stem cells retain their regenerative capibilities with aging, but are living in a prohibitive environment (Vandiver, 2020). Understanding and modulating the stem cell niche signalling environment is a next generation therapeutic strategy that has great potential to enhance regeneration and repair of the skin throughout the aging process.
The role of autophagy
Autophagy, which literally means “self-eating”, is the process in which cells selectively clear out old and damaged components (ECM proteins, mitochondria, protein aggregates) and recycle them to make new and improved machinery. The process of breaking down and recycling “garbage” in the cell is called proteostasis. Autophagy has been shown to be a critical process for the removal of molecules damaged by oxidative stress including proteins, lipids and organelles (such as mitochondria). (Mohiuddin, 2019).
In humans, loss of proteostasis has been observed in dermal fibroblasts upon intrinsic aging and UV exposure. The loss of capacity to remove oxidised and misfolded protein can lead to the activation of DNA damage response (DDR) pathways that result in induction of cellular senescence and release of the infamous SASP (Eckhart, 2019).
Of particular interest is the role of autophagy in clearing out damaged ECM components that accumulate with age. High levels of blood sugar, UVR, pollutants and byproducts of cellular metabolism can cause damage to ECM proteins, many of which are known to be irreversible (Zhang, 2018). AA’s that “boost autophagy” hold great promise for skin rejuvenation.
Enhancing autophagy is one of the most well supported strategies for slowing down the biological aging process. In the skin, activation of autophagy by topically applied rapamycin has been shown to prevent UVB-induced photoaging and senescence of dermal fibroblasts by reducing the production of ROS (Vandiver, 2020).
The role of epigenetics in skin aging
Epigenetic dysregulation is another major hallmark of skin aging and encompasses changes in the types and arrangement of molecules (such as methylation and acetylation) on top of DNA that regulate the expression of genes. With aging, the marks on our DNA get scrambled and this gradually causes our cells to lose their identity and compromise function (Russell-Goldman, 2020).
Research suggests that exposome factors, either singly or in combination, may have the potential to conspire in a manner to “reprogram” the epigenome with age. This process modifies the epigenetic landscape of skin cells, causing dysfunctional gene expression (Vandiver, 2020).
UVR in particular has been shown to trigger high levels of ROS that induces an imbalance between methylation and acetylation of DNA. This leads to low-level expression of unnecessary genes in dermal fibroblasts which interferes with cellular function. Further, aged skin exhibits specific epigenetic signatures (senescence associated heterochromatin foci) that may play a causative role in skin senescence (Ho, 2021).
The role of cell regulators and signalling in skin aging
Cell regulators are molecules that regulate the genetic expression, energy metabolism, growth and behaviour of cells. This includes growth factors, hormones, retinols (Vitamin A derivatives), peptides and metabolites (most popular of which is NAD+) that serve an important signalling role (Mohiuddin, 2019).
Skin aging is characterised by shifts in cellular signalling that stray from youthful signalling patterns. Multiple small trials show clinical benefit with topical formulations of growth factors (such as FGF and PDGF) for reducing fine lines, wrinkles and increasing dermal collagen (de Araújo, 2019).
Main cellular and structural changes in skin aging
Because the skin is an extremely complex organ consisting of epidermal, dermal and subcutaneous layers – each of which contains distinct cellular populations – the different layers and cell types of the skin show distinct vulnerabilities to aging drivers which influences the process of skin aging (Table X) (Eckhart, 2019). Understanding the aging signatures of these cell types can be extremely useful for making sense of the utility of various AAs therapeutic strategies based on their delivery modality, cellular target and mechanism of action.
Preservation of the ECM in skin aging
The ECM provides the skin with structural integrity and resilience to stressors. It also allows communication between cells by creating and maintaining a signalling environment that promotes continuous regeneration and repair. The most popular targets of AAs, and critical components of ECM structure and function, are collagen, elastin and proteoglycans (particularly hyaluronic acid (HA)) (Lupu, 2020).
Dermal fibroblasts are a key influencer to skin aging
Research within the realm of skin aging points towards a compelling theory: the health status of dermal fibroblasts may be the most influential factor in the longevity and health of our skin. An abundance of data suggests that their high metabolic rate, long lives, and limited proliferative potential make them extremely vulnerable to hallmarks of aging (Eckhart, 2019).
Once dermal fibroblasts accumulate age-related damage, this leads to senescence and dysfunctional intercellular signalling which leads to degeneration of surrounding cells and ECM. This is further exacerbated as the ECM components (collagen and elastin) that the dermal fibroblasts make are stable proteins with a half-life measured in years (for skin collagen is approximately 15 years) and hence are predisposed to experiencing the long-term cellular stressors of aging without faithful replacement (Lupu, 2020).
Figure 9 Collagen and Fibroblast: Fibroblasts in the skin are responsible for the synthesis of collagen important for providing structural support to the skin
Table 1. Cellular and Structural Changes in Aging Skin: The epidermal and dermal layers of the skin consist of several cell types and components that decline in structure and function with age. This decline is caused by cellular and molecular aging drivers that accumulate and lead to dysfunction over time. These age-related changes lead to the visible changes in skin appearance we observe with age (wrinkles, sagging discoloration) (Gruber, 2019), (Reilly, 2021), (Ho, 2021), (Strnadova, 2019)
|COMPONENT||NORMAL FUNCTION||CHANGE WITH AGE|
|Keratinocytes (~95%)||Production of keratin, a major structural protein that provides strength to the skin. As keratinocytes die they creates a lipid rich matrix that aids in forming the physical barrier of the skin. Eventually, dead keratinocytes are shed and replaced by new keratinocytes.||The entire epidermis of the skin is replaced every 28 days in young individuals, whereas this process slows down considerably in the elderly and varies between 40 and 60 days.|
|Epidermal stem cells||These stem cells are tasked with regenerating the epidermis as cells get damaged and die. After they detach from the basement membrane, they differentiate into keratinocytes and traverse across different maturation states as they migrate across the 5 layers of the epidermis until they reach the outermost layer (called the stratum corneum).||Epidermal stem cells are absolutely critical for regeneration and repair of the skin. Stem cell dysfunction is a hallmark of aging.|
|Stratum corneum||First line defense against external threats from ultraviolet radiation and other environmental toxins, allergens and pathogens. Supporting the skins endogenous antioxidant system, production of antimicrobial peptides, activation of the host innate immune responses.||The stratum corneum shows age related changes in permeability to factors as well as impaired recovery in the face of mechanical stress. This is associated with a decreased concentration of lipids, changes to the types of lipids present on the membrane and increased stiffness. Many of these changes are driven by DNA damage in epidermal and dermal cells that lead to compromised intercellular signalling. Both genomic instability and compromised intercellular signalling are hallmark of aging.|
|These are cells that are scattered throughout the basement membrane of the epidermis that produce a photoprotective pigment called melanin which gives our skin its unique colour.||With aging, these highly metabolic cells accumulate damage from years of oxidative stress and mitochondrial dysfunction. This leads to impaired melanin production and transfer to keratinocytes, leading to pigmentation disorders. Mitochondrial dysfunction and associated increased oxidative stress is another hallmark of aging.|
|The epidermis houses immune cells (Langerhans cells) that are the sentinel protectors of the body from foreign invaders||These cells show compromised migration with aging which results in suboptimal T-cell function, reduced immunity, reduced beta-defensin-3 (antimicrobial), decreased immune barrier function and vulnerability to extrinsic aging stressors that cause chronic inflammation. Chronic inflammation is another hallmark of aging.|
(The ecosystem on our skin)
|Integral ecosystem of microbes that are in constant exchange with our environments and influences skin metabolism, inflammation, immunity and overall systemic health||With aging, the content and activity of our skin microbiome exhibits marked changes that lead to microbial dysbiosis. This is another hallmark of aging. Microbial dysbiosis in the skin typically involves an increase in pathogenic and decrease in commensal microbial species. Metabolically, it is characterised by a pro-inflammatory metabolic profile.|
(Sweat and Oil)
|The sweat gland provides thermoregulation, anti-bacterial, antiinflammatory properties and even participates in hormone metabolism. The sebaceous gland produces natural oils that retain moisture in the body and in doing so, provides essential conditions that promote the health of the skin structure, has antimicrobial properties and creates niche environments across that skin to promote the health of the skin’s microbial ecosystem.|
|COMPONENT||NORMAL FUNCTION||CHANGE WITH AGE|
|Dermal fibroblasts||These critical cells produce a collagen-rich extracellular matrix (ECM) |
Fibroblasts are activated by both physical tension and biochemical signalling (growth factors and cytokines) from the ECM. In healthy skin these signals typically result in increased production of the proteins collagen (28 different forms) and elastin, as well as associated glycosoaminoglycans (chains of sugars) like hyaluronic acid (HA).
Healthy skin relies on continuous production of these ECM components to support the structure and integrity of the skin and to keep up with the significant demand for skin cell replacement.
|Dysfunctions in turnover and replacement of damaged ECM is often driven by an insidious process that dermal fibroblasts are extremely vulnerable to called cellular senescence. Both ECM dysfunction and cellular senescence are hallmarks of skin aging. |
Dermal fibroblasts do not represent a uniform population because they can take on at least two phenotypes – papillary and reticular. During skin aging, the balance between these two fibroblast types shifts toward the reticular phenotype. This transition in cell type is driven by another hallmark of aging called epigenetic dysregulation
|The ECM (Structure of youth)||Key EMC components |
1. COLLAGEN Types I (predominantly) and Ill collagen constitute 90% of the dermis and provide mechanical resistance and elasticity to the skin.
2. ELASTIN Elastin gives skin the flexibility to stretch by facilitating a long-range deformability, followed by a recoil to allow tissues to return to their original conformation.
3. GLYCOSOAMINOGLYCANS Glycosoaminoglycans such as hyaluronic acid (HA).fills the space around collagen and elastin fibres, holding them in a matrix. HA is essential for water retention and skin hydration, elasticity, as well as augmenting softness, firmness and volume of skin layers. HA is also critical for maintaining a “youthful” signalling environment that mediates communication between, and activity of, different cells in the skin.
4. OTHER Other key components of the ECM include fibrin and fibronectin which are critical for wound healing through the formation of blood clots that prevent the loss of blood and help with tissue repair.
|These are essential for skin maintenance and critical for delaying skin aging. Loss and damage to collagen fibres with age leads to wrinkles, sagging and thinning skin. The loss of elastin with age leads to sagging skin and wrinkles.|
|The Dermal Epidermal Junction: Critical crosstalk||The DEJ is interface between the dermis and epidermis and a critical signalling hub that allows the various layers of the skin to communicate in order to maintain a youthful phenotype. Through the DEJ, the dermis exchanges growth factors, immune factors (cytokines) / cells and other metabolites to provide instructions that are critical for maintaining the health of epidermal stem cells, modulating inflammation and repair of skin cells.||Impaired structure and an imbalance of signalling factors at the DEJ drives dysfunctional intercellular signalling which is a hallmark of skin aging.|
There are four criteria that interventions must meet in order to be classified as an Advanced Aesthetic.
- The end goal of any AA must be improved appearance
- AAs must achieve this goal by targeting the hallmarks of aging, ideally within the framework of a geroscience model
- AAs based on conventional cosmetic solutions must exhibit enhanced features that aid in targeting aging mechanisms
- AAs are purposed towards prevention or rejuvenation but not treatment of disease or disease symptoms.
Regarding the last point, this does not exclude AAs from being adjuvants for drugs to enhance their efficacy.
There are four modalities of AA technologies that we will highlight in this report: molecules, hormesis technologies, cellular and microbes.
Oral, tropical, injectable compounds
Laser/VL stimulation, chemical peel, micro-needling
Stem cell and platelet rich plasma (PRP)
Targeting aging drivers using AAs
AAs can take a role as preventative, rejuvenative, or partially rejuventative intervention by targeting the various hallmarks of aging. AA modalities that target multiple different hallmarks hold the most potential, but targeting certain hallmarks are more impactful than others based on the hierarchy of primary, antagonistic and integrative hallmarks (see Table 2)(Vandiver, 2020). In Table 3 we have summarised how these modalities can target each aging driver described in “how the skin ages”.
Table 2. The impact of AAs depends on the number and type of “hallmarks of aging” targeted. Targeting primary hallmarks serves a preventative role, targeting integrative hallmarks serve a therapeutic or partially rejuvenative role, targeting antagonistic hallmarks hold promise for skin rejuvenation
|Primary hallmarks||Antagonistic hallmarks||Integrative hallmarks|
|Definition||Are the primary cause of cellular damage.|
DNA and telomere damage.
Loss of proteostasis.
|Are the antagonistic or compensatory responses to the manifestation of primary hallmarks. |
Antagonistic hallmarks accelerate damage accumulation through feedforward effects and initiation of “self-perpetuating loops”.
Senescence and mitochondrial dysfunction.
|Are the response to the preceding hallmarks that lead to further operational deterioration of aging that characterise aging phenotype.|
Stem cell dysfunction.
Altered intercellular communication
|Treatment Potential||AAs targeting primary hallmarks of aging are better suited as preventative interventions.||AAs that target antagonistic hallmarks are rejuvenative.||AAs that target integrative hallmarks are partially rejuvenative or therapeutic.|
Table 3. Summary of the different AA modalities and the “aging drivers” they target
Anti-oxidants (phytochemicals, vitamins)
|Inflammaging||Stem cell therapy|
Media, exosomes, molecules
Peptides and phytochemicals (i.e. Oneskin Peptide 14)
High power, ablative
Antioxidants, Collagen, Hyaluronic Acid
Low power, non ablative
Low power, non ablative
|Stem Cell Dysfunction||Stem cell therapy|
Stem cells (cells, media, exosomes, molecules)
High power, ablative
|Dysfunctional Cellular Signalling||Molecules|
Growth factors (such as FGF)
|Loss of Proteostasis||Molecules|
Combinatorial (such as phytochemicals)
|Microbial Dysbiosis||Microbe therapeutics|
Molecular based advanced aesthetics
A wide range of molecules can influence the health and functioning of epidermal and dermal cells, including bioactive peptides, antioxidants, collagen, retinoids, vitamins, ω6- and ω3-fatty acids, growth factors and an array of botanical extracts (Reilly, 2021). Since there are multiple delivery routes to the skin, it is a very tractable target. Even orally ingested compounds can travel to the skin where they exert their function. The efficacy of AA molecules depends on their purity, potency, chemical properties and resulting mechanism of action. One of the biggest hurdles for molecule-based AAs is efficacious delivery (Katta, 2020).
Getting molecules through the stratum corneum (SC) of the skin is no easy task. Therefore, delivery formulations require strategic design, considering features of the skin barrier in conjunction with the molecule. For example, small molecules that are hydrophobic (unlike most peptides) are better able to get through the SC. They don’t require as much investment into delivery formulation, but there are other variables to consider. This includes age, the integrity of the skin, presence of proteolytic (protein degrading) enzymes, skin thickness, cutaneous metabolism, microbial flora content and skin type (particularly in the case of dry, sebaceous, or moist skin). All these factors vary significantly between individuals and heavily influence optimal delivery strategy (Rizzi, 2021).
A particularly powerful methodology for AA delivery is nanosized delivery systems (NDS). NDS are vehicles that are typically a few hundred nanometers in size, currently in use for sustained and enhanced delivery of plant derived and synthetic bioactive compounds. Many NDS are derived from lipids as this is the most effective way to get insoluble molecules through the stratum corneum. In this vein, liposomes derived from skin epithelial lipids are particularly effective delivery vehicles due to compatibility with the skin (Ganesan, 2016).
Oral and topical molecules
Most topical or oral AA products contain multiple molecules which exert synergistic interactions that enhance the efficacy of the product, often by targeting multiple hallmarks of aging at once. Since this is a nascent field that is rapidly expanding, much more rigorous science needs to be done to ensure robust skin longevity benefits.
Specific factors that must be taken into consideration for oral therapies include (Rizzi, 2021):
- Resilience within the digestive tract
- Metabolism by the liver
- Efficacious delivery of intact molecules to the skin in high enough concentration to exert effect.
- The potential for neutralising (or adverse) effects of metabolic byproducts produced during transition to the skin
- Specific factors that must be taken into consideration for topical therapies include (Rizzi, 2021):
- sun exposure level
- sebaceous gland activity
- microbial composition
Example of an oral molecule AA: There are few molecules that directly target mitochondria to rejuvenate skin health. Accordingly, this is an intense area of research and discovery for the realm of AAs. Topical and oral CoQ10 is one such molecule that has shown promise for improving skin health. CoQ10 is used by mitochondria to increase the efficiency of ATP production, the primary energy source used for skin maintenance and repair (Oresajo, 2009). Human skin cells treated with CoQ10 show increases in energy metabolism and decreased senescence. In a preclinical study, CoQ10 promoted the healthy proliferation and ECM homeostasis of aged fibroblasts. A drawback of CoQ10 is its size often makes it too large to enter the mitochondria (Mohiuddin, 2019). MitoQ have developed a unique version of CoQ10 where the size is reduced and a positive charged ion is added to convert CoQ10 to Mitoquinol Mesylate. Mitoquinol Mesylate can penetrate the mitochondrial wall up to 1000 times more effectively than any other CoQ10 supplement (Gottwald, 2018).
Bioactive peptides – also known as biomimetic peptides – are compounds that have an identical amino acid sequence to physiological peptides but are frequently synthesised biotechnologically. Peptides are extremely versatile and potent at targeting various hallmarks of aging (senescence, mitochondrial dysfunction, inflammation), especially since many have naturally evolved to play this regulatory role. Although the process is not complicated or difficult to perform, peptide synthesis, with a defined sequence and high purity (> 90%), can be expensive. In this regard, however, it should be noted that the high efficacy compensates for the cost (Rizzi, 2021).
Specific factors that must be taken into consideration for peptide delivery include (Rizzi, 2021):
- Due to the chemical structure of peptides, they typically have more difficulty traversing the cutaneous membrane.
- Even if they can get through the defences of the SC, they must avoid degradation by proteolytic enzymes.
Example of AA peptide: A company called OneSkin has transformed the skin aging space by targeting cellular senescence using a peptide. They have developed a senotherapeutic called Peptide 14 that is able to block the formation of senescent cells (senoblocker) and alter the SASP of pre-existing senescent cells (senomodulator) (Zonari, 2020).
This is a crucial aspect of Peptide 14 as simply killing senescent cells (with senolytics) may interfere with their beneficial role or simply deplete cellular mass of organs. The senomodulator approach to targeting senescent cells is gaining increased traction as biotechnological advances allow us to better characterise the effects of specific SASP molecules on pathology (Pils, 2021).
The AAs field has shifted towards natural, plant derived polyphenols to soak up oxidative stress, reduce inflammation, target senescence, influence signalling environments and confer resilience to intrinsic and extrinsic aging. Panels including hundreds or thousands of (identified and unidentified) natural compounds are being tested with high throughput screens for their ability to target the hallmarks of aging (Faria-Silva, 2019).
Although these phytochemicals hold much promise, a distinction must be made between single isolated molecules and plant extracts. While the precise mechanisms of single molecules can be more easily elucidated to aid precision targeting, extracts have the advantage of preserving the natural synergy of several different phytochemicals interacting together to exert their benefit (Katta, 2020) .
Example of phytochemical AA: Application of phytochemicals has been shown to play a preventative role in mitigating photoaging related damage to the ECM. Topical antioxidants can inhibit ROS accumulation and MMP expression, preserving the integrity of the ECM. Further, antioxidants have been shown to inhibit IL-1 alpha activity. Given its role in bystander senescence, suppressing IL-1 alpha expression has the potential to inhibit feed forward loops of ECM destruction caused by inflammation and senescence (Boyajian, 2021).
Injectables classically used in cosmetics include ECM proteins, including collagen and proteoglycans (such as hyaluronic acid (HA)). Formulations are most commonly delivered as fillers. Although subdermal injections help these molecules avoid primary layers of the epidermis, their size still matters as larger molecules have more trouble getting to their intended location. For this reason, molecules like collagen and HA are typically fragmented before injecting into the skin (Ganceviciene, 2012). Interestingly, successful seeding of healthy ECM proteins into the dermal layer of the skin has been shown to have positive signalling roles and effects on gene expression of dermal fibroblasts. This in turn prompts dermal fibroblasts to reinforce the extracellular matrix, reduce wrinkles and improve overall skin health (Mohiuddin, 2019).
Example of an AA injectable: HA has been used in various forms such as hydrogel, dermal filler, intradermal injection, scaffolds, creams, films, foams and gels for treatment of different types of diseases. HA has shown a wide range of pharmacological activities including anti-inflammatory, wound healing and tissue regenerating, immunomodulatory, anticancer, anti-diabetic, skin repairing and anti-aging cosmetic properties (Bukhari, 2018).
HA is a relatively large molecule, so one of the key factors that influences its efficacy in the body is its delivery. Absorption and bioavailability of HA can be optimized by fragmenting the large molecule into shorter fragments that can be pieced back together once absorbed by the skin (Bukhari, 2018).
Bioxis Pharmaceuticals is working on the next generation of dermal filler by developing Cytosial, a proprietary technology based on chitosan and hyaluronic acid. The Cytosial range uses a new way of stabilising hyaluronic acid to provide long lasting effects, improve the rheological performance and ensure high safety.
Hormesis technologies for advanced aesthetics
When skin cells are challenged by a certain amount of acute stress or damage – below a “harmful threshold” – they typically respond by modulating gene expression to activate cellular processes that effectively resolve the stress/damage and make them more resilient and robust than they were before. This biological process is called hormesis and it is a target of several AAs technologies designed to rejuvenate the skin (Calabrese, 2017).
Skin hormesis technologies induce physical, chemical, or thermal stress to temporarily trigger an immune response, stem cell activation, mitochondrial biogenesis, upregulation of genes (antioxidants, DNA repair, autophagy), as well as ECM turnover and repair. The response to an effective hormesis stimuli goes beyond addressing the acute stressor and actively repairs and rejuvenates age-related damage that has accumulated in the skin. Further, the post-hormesis state of the cell is more “primed” to face future stressors and age-related insults (Suresh, 2013). A particularly intriguing application for hormesis technologies is as an adjuvant for PRP, stem cell and topical therapies.
One of the major challenges of hormesis technologies is that they are typically less specific in function, less precise in terms of cellular targets and elicited cellular responses and have greater risk of adverse side effects. This is especially true for aged individuals that may not be able to mount significantly robust cellular responses to recover from the stressor (Ganceviciene, 2012). For this reason, the AAs field must carefully personalise hormesis technologies based on an individuals age, genetics and health status.
Microneedling in AA
Microneedling creates tiny pores within the skin that stimulate regenerative functions. Although microneedling is not a particularly strong rejuvenative technology, one extremely promising use of microneedling is to get molecular therapeutics through the deep dermis and delivered to dermal fibroblasts (Iriarte, 2017). Effective methodologies to enhance delivery of therapeutics to dermal fibroblasts hold great promise for rejuvenation due to their regulatory role in overall skin health and aging (Strnadova, 2019).
Chemical peels in AA
Chemical peels are procedures in which an acidic solution (alpha or beta hydroxy acid, trichloroacetic acid) is applied to the skin to chemically ablate (remove) epidermal and dermal layers. When layers of the skin are damaged, a hormesis response kicks in. This causes neighbouring cells to activate inflammatory pathways, regeneration and repair mechanisms. One of the most striking effects of chemical peels is restructuring and repair of the ECM. This includes a notable increase in type I collagen and elastin – leaving the skin firm, even and wrinkle-free (Mohiuddin, 2019).
Chemical peels are not as precise as lasers as they seem to be more broadly destructive. Treating the skin with strong acids come with risk of infection as well as lasting pigmentation and ECM damage – especially if the skin is not healed properly (Ganceviciene, 2012). There is significantly less wiggle room to modulate and iterate on this intervention in a way that would make it fit nicely in the AAs realm.
Laser/VL (resurfacing) therapies in AA
During laser resurfacing, an intense beam of light energy (laser) is directed to precise locations on the skin (Heidari, 2020). Laser resurfacing works by inducing “hormesis” in skin cells and associated regeneration and repair.
In ablative laser resurfacing, the laser beam selectively destroys tissues in the epidermis which subsequently stimulates regeneration and repair. Ablative laser resurfacing also heats the dermis. Stressing out dermal fibroblasts with precise amounts of heat has been shown to stimulate collagen production. Over time, this results in fewer wrinkles, better skin tone (depigmentation) and smooth texture. Non-ablative laser resurfacing uses lower intensity IR light to penetrate the dermis, heating up dermal fibroblasts but leaving epidermal cells intact (Heidari, 2020).
While high power lasers have immense regenerative potential, there is a tenuous line between hormesis and pathological damage. Laser therapies have significant heterogeneity in terms of efficacy due to differences in the laser system used, device settings, skin type, genetics, health status and other demographic variables (Heidari, 2020). The field of AAs is focused on optimising precision and personalised application of these therapies to improve safety profile and efficacy. For example, Exocel Bio is a company that provides skincare post laser or microneedling treatment through the development of its product evovex, which contains exosomes with growth factors and mRNA. This product aids the regeneration process after the damage occurred by hormesis technologies by providing the nutrients and resources necessary to facilitate the repair of cells (Ha, 2020).
Photodynamic therapy / visible light devices in AA
Another milder, non-invasive variation on laser therapy is photodynamic therapy using visual light devices. These interventions are typically short duration and do not disrupt the epidermis at all. Photodynamic therapy uses different frequencies of visual light to address mitochondrial dysfunction by activating proteins in the mitochondria (called chromophores) of dermal fibroblasts. This effectively “supercharges” mitochondria so they can more efficiently generate ATP, providing more energy for skin cells to perform their functions. Photolight therapy has been shown to stimulate new collagen production and reduce wrinkles (Ganceviciene, 2012).
In some, more extreme forms of photodynamic therapy, a photoactive molecule (i.e. aminolevulinic acid) is injected into the epi.dermis and visible light is used to activate the molecule and destroy damaged and senescent cells in the epidermis. This has been shown to accelerate regeneration and repair of the epidermal layer of the skin and improve “clinical photoaging grade” – a metric used to quantify the extent of photoaging (Linda Stocum, 2021).
Cellular therapies in AA
Platelets are a component of blood that play a crucial role in blood clotting, serving as the “first responders” in wound healing. Due to their role in tissue growth and repair, platelets contain many critical cell regulatory and signalling factors that promote healing, regeneration and rejuvenation of tissues (Maisel-Campbell, 2019).
PRP therapy is an autologous (from self) blood product of platelets concentrated at “supraphysiological levels” that are delivered via injection into the skin. The super concentrated nature of PRP supports its therapeutic benefit as it is thought to contain over 800 bioactive molecules derived from platelet granules, including TGF-beta, epidermal growth factor, PDGF, FGF, IGF and other notable “youth factors” (Maisel-Campbell, 2019).
These factors are thought to impact tissue rejuvenation and repair in the skin through stimulating (Elghblawi, 2017):
- Proliferation of epidermal stem cells
- Differentiation and migration of keratinocytes
- Angiogenesis at the DEJ
- Activation of fibroblasts to promote ECM synthesis and restoration of a “youthful” signalling environment.
In doing so, it has been shown to temporarily improve skin appearance, texture, tone and reduce wrinkles. Notably, leukocyte-rich PRP (L-PRP) is a variation of PRP that is gaining increasing attention because it has been shown to induce greater skin volumisation and wrinkle reduction. Some data suggests that including leukocytes in the concentrated PRP mixture can propagate an undesirable inflammatory response. This must be carefully looked into and appropriately addressed to refine the potential of L-PRP (White, 2021).
Important factors that may affect clinical outcomes include (White, 2021):
- PRP preparation method (centrifuge speed, time and repetitions, addition of activators)
- Concentration of platelets
- Quantity and quality of growth factors in patient sample
- Other cells in final product that may induce inflammation (leukocytes, erythrocytes)
- Administration technique (ie, depth of injection)
- Regimen (number and timing of treatments)
In many aspects, PRP is still a relatively new and understudied technology that suffers from inconsistent methods of extraction, preparation and treatment regimen. Due to a lack of scientific rigour, poor characterisation of protocols and lack of standardisation in outcome measures – the immense potential of PRP is diluted. More high-quality trials with sufficient follow-up are needed to rigorously characterise the effects of PRP and optimise treatment protocols and regimens (Emer, 2020).
Interestingly, most of the “magic” of PRP resides within the first 10 minutes after platelets are extracted. These first minutes are crucial because this is when platelets are most actively secreting growth and cell regulatory factors. Clinical studies reveal that platelets remain active for about 8 hours after the procedure, although biological effects beyond this point are not well characterised. Typically, PRP is applied every 4-6 months in the first year, then yearly for maintenance (Maisel-Campbell, 2019).
Stem Cell Therapy for AA
Stem cells have been of central focus to the longevity field since its conception. In fact, some would argue that the longevity field was built on the foundation of our understanding of stem cells and their regenerative potential. Certainly, stem cell dysfunction has a profound role to play in aging of the skin. AA interventions that restore youthful function to epidermal stem cells is a major component of achieving skin rejuvenation.
Stem cell therapies come in many different variations depending on how the stem cells are used. Mesenchymal stem cells (MSCs) are the most popular source of stem cell therapy in the AAs field to date. This is because of their ability to efficiently repair the epidermis and secretion of several growth factors necessary for skin regeneration (Wang, 2020).
MSCs are multipotent stem cells derived from adult stem cells and can be obtained from diverse sources including bone marrow, adipose tissue and umbilical cord blood. We will focus on MSCs that are derived from adipose tissue (AMSCs) because they are multipotent (can turn into many types of cells), have better engraftment success and have an increased proliferation capacity compared to other MSCs. Further, they are by far the most popular stem cell type deployed in the AA field (Jo, 2021).
Challenges for MSC therapy include a poor rate of engraftment into target skin tissue (less than 3%) and limited in vitro expansion capacity (Jo, 2021).
Table 10 Describing the different stem cell therapy variations and the advantages of each one (Wang, 2020) (Surowiecka, 2022) (Jo, 2021)
|Stem cell Therapy Variations||Advantages|
|Stem cell media||This is particularly promising as matrix fluid is very accessible and has regenerative capacity, even when used on its own. Companies have also focused on using stem cell conditioned media, that is stem cells exposed to various stressors to induce secretion of specific factors.|
|Exosomes released from stem cells||Nanosized packets of information that are a major form of communication between cells. Exosomes are easily obtained, free from safety issues of tumorigenic potential and can be produced as an off-the-shelf product. Subcutaneous injection of exosomes has been shown to have anti-photoaging potential (similar to AMSC injection).|
|Molecules that activate dormant stem cells||Epidermal stem cells are- not typically irrevocably damaged or lost with aging, rather they are inhibited by their surrounding stem cell niche and enter a state of quiescence (inactivity). Research suggests that specific ADSC-associated growth factors re-activate otherwise quiescent stem cells to drive reversal of age-related changes.|
|Personalized stem cell populations||Recent research has revealed that a specific population of stem cells characterised by an Lgr6+ biomarker are quiescent and more shielded from UV radiation than non Lgr6+ stem cells. This means that Lgr6+ stem cells are less susceptible to oxidative stress and damage than other epidermal stem cells, increasing their rejuvenative potential and long term effects|
|Autologous, adipose stem cells combined with PRP||PRP has shown a remarkable induction effect on the skin as it stimulates proliferation of dermal fibroblast and AMSCs leading to increased epidermal and dermal thickness. Accordingly, administration of autologous adipose stem cells combined with PRP has been shown to enhance and sustain the effects of stem cell treatment over longer periods of time|
The above stem cell therapy modalities have shown a significant decrease in skin wrinkles, enhanced skin volume and tone, as well as improvement in skin elasticity and skin barrier function. Most data suggests that sustained rejuvenation of skin requires multiple injections a year (Jo, 2021). For this reason, less invasive and safer stem cell methodologies including cell conditioned media and exosomes are favourable.
Microbial therapies in AA
The health of the skin and its microbiome depends on a delicately balanced ecosystem of commensals and pathogenic bacteria. Tipping of this delicate balance towards the pathogenic end of the spectrum accelerates aging of the skin and can lead to a number of skin related (and even systemic) pathologies (Boxberger, 2021).
Skin aging is characterised by a decrease in sebum (sebaceous gland activity) and hydration levels as well as immune dysfunction, which results in significant alterations in skin physiology. These physiological changes also imply changes in the skin ecology, inducing a disbalance of skin microbiota (Abadías-Granado, 2021).
It is unclear whether changes to the skin microbiome precede other hallmarks of aging within the skin or vice versa. It is likely the case that both scenarios are true and which changes occur first is dependent on each individual’s unique ageotype. The field of AAs is focused on developing diagnostic tools to characterise age-related changes to the skin microbiome (and the metabolites they produce) and restore balance.
Examples of microbial therapies AAs
Topical probiotics (various Lactobacillus, Bifidobacterium, Staphylococcus strains) have been shown to interact with dermal fibroblasts in a photoprotective manner by (Prescott, 2017)(Khmaladze, 2020):
- Releasing metabolites that protect the skin from UVB induced inflammatory damage
- Inhibiting NFKB expression to reduce oxidative stress and prevent impaired pigmentation
- Improve skin hydration to reduce sunburns
- Decrease the expression of MMP’s that break down ECM in response to UVR
- Secrete tumour suppressor molecules (6-HAP) that protect against skin cancer (melanoma) induced by UVR
There are several longevity skin products that combine emollients (skin softener) with probiotics (such as Vitreoscilla filiformis) to rejuvenate a youthful skin microbiome and reduce eczema flares (Prescott, 2017). Interestingly, oral probiotics have also been shown to exert many similar effects as topical probiotics, suggesting an intimate connection and communication between the gut and skin microbiome. The research and scientific findings on topical probiotics is more numerous and efficacious than oral delivery (Boxberger, 2021). An exciting and powerful new field of microbial therapeutics involves transferring live microbes derived from healthy human skin tissue to rejuvenate multiple aspects of skin aging. Interestingly, research has revealed that microbes can even jump from one person to another during close contact encounters in a process called horizontal transfer. The horizontal transfer of microbes due to dense social networks and intimate connections is positively associated with longevity. The emerging field of donor skin microbiome transplantation holds the most promise of all as it preserves dense networks of youthful microbes in physiologically relevant configurations which increases the probability of efficacy and is amenable to personalisation (Prescott, 2017).
With today’s increasing “life-expectations” (think Instagram and other social media) and quality of life, the desire for beautiful, healthy-looking hair plays a bigger role than ever. This attention is reflected in a hair care market that is a multibillion-dollar enterprise worldwide (Trüeb, 2018).
Conventionally, the study of hair aging has focused on two main streams of attention (Trüeb, 2018):
- The aesthetic problem of aging hair and its management – in other words, everything that happens outside of the skin.
- The biological problem of hair aging – or the microscopic, biochemical and molecular changes that occur within hair follicles and in the depths of the scalp. These are the changes that encompass the hallmarks of aging and this is the major focus of AA companies.
Studying the molecular mechanisms through which our scalp and hair follicles age – and which lead to grey hair, hair thinning and hair loss – facilitates the development of therapeutics that directly target these hallmarks of aging. The preventive and regenerative potential is clear.
Anatomy of hair
A hair follicle (HF) is a tunnel-shaped structure that stretches from the dermis through the epidermis of the skin. Although it may seem like a single thing, the hair follicle is actually a complex structure consisting of 20 different cell types (Williams, 2020).
How is it composed?
The root of the hair follicle is called the hair bulb and it is made up of dermal papilla cells and matrix cells. Matrix cells consist of keratinocytes that produce keratin which makes up the visible part of the hair fibre and melanocytes that produce melanin that gives hair its colour. The hair bulb is nourished by a rich supply of blood vessels and fat cells lying directly beneath the follicle (Williams, 2020).
The different stem cell populations of the hair and scalp reside in the bulge of the hair follicles (slightly above the bulb). Proliferating (dividing) hair follicle stem cells (HFSCs) migrate down to the hair bulb to grow the hair follicle or migrate to the upper part of the hair follicle to generate sebaceous gland and epidermis (Williams, 2020).
The hair follicle bulb is one of the most integral components of the HF as it regulates the HF cycle and and how the HF ages. The “master regulator” cells within the hair follicle bulb are the dermal papilla cells (DPCs). DPCs are essentially the “control centre” for hair cycling. The DPCs determine follicle and hair fibre characteristics through the secretion of mediators that regulate HFSC activity in the hair fibre (Williams, 2020).
Understanding the Hair cycle
Hair follicle cycling is a dynamic and complex process involving continued renewal by transitioning through four phases:
1. Anagen phase
Remodelling of lower part of the follicle and rapid growth of new hair fibres.
2. Catagen phase
Regression of the lower part of the follicle and death of old hair follicle
3. Telogen phase
Maintenance of follicular cells and machinery to prepare for new follicle
4. Exogen phase
Shedding of old hair
The progression of the hair cycle is dependent on the signalling environment within and around each hair follicle which plays an essential role in regulating healthy growth, decay and renewal of HFs (Sadick, 2017).
Characteristics of hair aging
Aging of the hair affects hair colour (greying), hair production (alopecia) and structural properties of the hair fibre including diameter, volume, curvature, stretching, bending, torsional rigidity, lustre, texture and lipid composition. These attributes all converge to determine how hair looks, feels,= and ages. Hair loss is quite prevalent throughout the aging process, significantly and steadily increasing with age. The general heuristic is 20% of men in their 20s, 30% of men in their 30s, 40% of men in their 40s, have visible signs of hair loss. Socio-culturally, this takes a significant psychological toll, especially when the loss arises earlier on in life. This is because hair is an attribute that is considered aesthetically pleasing, a sign of good health and virility (Trüeb, 2018).
To successfully characterise hallmarks that are driving hair aging, we must look beneath the hair fibre as well – to the scalp. The scalp around an area of hair loss typically shows classic signs of reduced blood flow, lower sebaceous gland activity, skin photoaging (particularly solar elastosis) and microinflammation with age (Trüeb, 2018).
Hair aging drivers
One of the prevailing factors that drives age-related changes in hair is an individual’s genetic makeup. In fact, there are over 200 genes that influence how hair looks and ages, while hair loss itself has a heritability of well over 90% (Hagenaars, 2017).
Nonetheless, the reasons for hair loss are numerous and span a multitude of both intrinsic and extrinsic factors. These include hormonal imbalances, vitamin D and iron deficiency, poor sleep, psychological stress, microbiome imbalances, toxins and UVR in the environment, intrinsically and extrinsically generated oxidative stress and chronic inflammation (Trüeb, 2018).
What makes hair ever more susceptible to these intrinsic and extrinsic factors is the fact that hair follicles are one of the most highly metabolic cell populations and fastest growing tissues in the human body. This high metabolic activity makes hair follicles sensitive to poor nutrition, sleep, inflammation and the intrinsic damages of aging (Williams, 2020). Any lapse in meeting the metabolic demands of HFs can interfere with cycling and topple over the initial domino that drives the “hair aging cascade”.
The average hair follicle goes through 10-30 growth cycles in a lifetime before succumbing to age-related degeneration (Williams, 2020). DPCs are the “conductors” of hair follicle cycling throughout an individual’s life. Hence, DPCs are extremely sensitive to extrinsic and intrinsic stressors that compromise their signalling and metabolism (Sadick, 2017).
Cellular dysfunction and manifestations from aging drivers
The intrinsic and extrinsic stressors impair hair follicle’s “youthful” regulatory circuitry over time by inducing damage accumulation in DPCs . In the absence of strategies to counterbalance this damage accumulation, the net accumulation of aging drivers within DPCs can ultimately override the internal control mechanisms that maintain youthful hair cycling. In other words, DPCs exhibit increased oxidative stress, DNA damage, epigenetic dysregulation and loss of functional identity. This accumulative damage in DPCs also leads to impaired function in other cells within close vicinity, including stem cells (Sadick, 2017).
Accumulation of hallmarks of aging within DPCs compromise their ability to support proliferation of HFSCs. Stem cells are governed by sensory integration of both local factors from DPCs and distant signalling factors from other organs and tissues (Chen, 2020). Understanding the complexity and nuances of HFSC regulation is absolutely critical for the field of AAs to achieve rejuvenation of youthful hair follicle cycling.
Molecular pathways of hair aging
Overall, oxidative stress, senescence and inflammation are three major nodes that create a feedforward cycle that drives aging of hair follicles and cells across the scalp. When these three hallmarks accumulate past a certain threshold, they induce HFSC dysfunction, hair follicle miniaturisation and hair loss. Therefore, uses AAs to intervene (at any node) within this vicious cycle offers tremendous opportunity for hair rejuvenation. Table 5 describes the molecular pathways and hallmarks of aging that lead to hair aging phenotypes and highlight the impact AA interventions can offer.
Table 13 Hair aging drivers and the potential impact of of AA on hair rejuvenation. (Trueb, 2018) (Sadick, 2017) (Gentile, 2019) (Wadstein, 2020) (Trueb, 2021)
|Senescence: the most prominent hallmark of HF aging||Cellular senescence of dermal fibroblasts within the hair follicle and scalp are major drivers of hair thinning, loss, changes in pigmentation and, potentially, even systemic consequences of hair aging.||Dermal fibroblasts within the hair follicle bulb (as well as the inter-follicular zones) accumulate oxidative damage that drives cellular senescence. This in turn is associated with increased release of pro-inflammatory SASP, an increase in ECM degrading MMPs and ultimately-impaired HFSC activity and HF cycling.||Senotherapeutics hold special importance within the field of AAs due to their potential for hair rejuvenation.|
|Microinflammation: a common thread||Microinflammation is inflammation that is confined to areas of the scalp associated with individual HFs or groups of HFs. Microinflammation appears to be a common thread in all types of hair loss and aging.||There are a diverse range of factors that can trigger microinflammation including: toxins in the environment, UVR, microbial dysbiosis, hormonal signalling changes, senescent cells and metabolic byproducts produced from intrinsic aging.||Anti-inflammatory molecules as well as those that protect against oxidative stress, toxins and cellular senescence have great potential for mitigating microinflammation. HRT and Microbial therapeutics also hold great potential, especially as adjuvant therapies.|
|Compromised immune privilege||Inflammation contributes to hair loss and greying. Hair follicles and the scalp microenvironment are unique in that they are known as “immune privileged (IP) sites”. IP means that the cells of the scalp do not readily mount an immune response and “reject” foreign tissue.||IP has been observed to collapse with aging and this is linked to age related damage and loss to proteoglycans in the ECM. Once IP collapses, T-cells become reactive and mount attacks against HFs – leading to hair loss and graying. IP collapse is driven by a multitude of factors including hormonal imbalances (excess androgen stimulation), chronic toxin exposure, excess fungi (dysbiosis), senescence, mechanical injury and extrinsic/intrinsic factors that induce oxidative stress.||Research suggests that the majority of cases (71%) of male and female pattern hair loss are accompanied by compromised IP and microinflammation at compromised HFs. Administration of proteoglycans have been shown to help preserve IP with aging.|
|Inflammaging of the scalp/hair||A deleterious and self-sustained inflammatory cascade that becomes chronic. The presence of inflammatory signalling factors damages neighbouring cells, induces cellular senescence and microbial dysbiosis.||In the event of chronic inflammation, overproduced cytokines like IL-1 and enzymes that disfigure the ECM, cause apoptosis and further propagate inflammation. Furthermore, emerging evidence suggests that chronic inflammation alters biochemical signalling in the HFSC niche, causing stem cell dysfunction. Ultimately, this leads to fibrosis and follicle miniaturisation.||Data shows that lymphocytes and mast cells aggregated around the miniaturising follicle in individuals with androgenic alopecia. Molecules and cellular therapies that target these immune cells can mitigate inflammaging|
|Extracellular Matrix: Importance of proteoglycans||Another hallmark of hair aging is dysfunction of the ECM surrounding the dermal fibroblasts in the scalp. One of the most important changes that drive aging of the scalp ECM is the loss of critical proteoglycans, particularly versican and decorin, which leads to a dry and rigid scalp environment. As proteoglycans are lost with aging, the scalp environment becomes more rigid.||Proteoglycans serve as bridges between ECM proteins and cells, are involved in the recruitment of stem cells and fibroblasts and serve to bind and configure HA in a way that promotes elasticity and hydration. |
Rigidity results in new anagen hair follicles that are unable to penetrate as deeply into the dermis, impeding their growth and causing them to sit higher in the dermis. Ultimately, mis-localisation of the HF bulb impairs tissue cross talk and stimulation of stem cells which results in smaller HFS with each cycle – a process called follicle miniaturisation.
|Supplementation with proteoglycans and laser therapy have been shown to preserve the structural integrity of the scalp ECM with aging.|
|HFSC Dysfunction||HFSC dysfunction is associated with hair loss||Aged HFSCs exhibit enhanced resting and abbreviated growth phases and are delayed in response to tissue-regenerating cues. As follicles spend more time in catagen/telogen and less time in anagen, they weaken and demand less blood flow. This compromised blood flow affects other hair follicles in the neighbouring area which then initiates a vicious cycle of hair loss.||This cycle can be mitigated by cultivating hair growth with laser, PRP, stem cell and molecular therapies – redemanding blood flow once more.|
|Microbiome||The oily nature of the scalp creates a unique microenvironment for microbes as sebaceous areas of skin typically have greater species richness than dry ones. Specifically, the scalp commensal yeast Malassezia makes up about 45% of the microflora and has a particularly impactful and unique role to play in hair health and aging.||There is an imbalance of Malassezia in patients with dandruff and seborrheic dermatitis where it makes up 75 and 85% of the microflora, respectively. Notably, an overabundance of this strain of fungi is associated with senescence and inflammation. Pro-inflammatory factors released at the site then travel through the bloodstream to influence gut and brain health.||The field of AAs recognises the significant endocrine and immunomodulatory role of the skin microbiome, giving rise to a renewed paradigm called the gut-brain-skin axis. Conversely, emerging studies have demonstrated that intestinal dysbiosis is involved in the pathophysiology of alopecia and probiotics may counteract the anagen-shortening effects of stress and reduce apoptosis in the hair epidermis.|
|Oxidative stress||Aging of the hair and scalp is characterized by altered expression and capacity of antioxidant enzymes as well as accumulation of oxidised proteins and lipids. These changes in oxidative stress load and tolerance are largely due to photoaging, toxin exposure, mitochondrial dysfunction, microbial dysbiosis and the effects of microinflammation. Melanocytes are particularly vulnerable to oxidative stress and this imbalance between ROS and antioxidative enzymes are a major contributing factors for hair greying.||With time, the amount of ROS produced exceeds the antioxidant defence threshold and initiates cellular senescence. The SASP contains specific MMPs that degrade type XVII collagen (COL17A1) which is abundant in the HFSC niche. Reduction of COL17A1 in turn compromises hair follicle stem cell function and ability to meet the demands of growth and differentiation factors released in the anagen phase of HF cycling. The pathophysiology of hair graying has also been related to inflammaging of the hair follicle, further aggravating its ability to handle oxidative stress and loss of follicular melanocyte activity.||This represents an opportunity for AAs to develop interventions that reduce oxidative stress before it reaches this detrimental threshold. The development of timely and efficacious interventions will be greatly aided by the development of precision biomarkers for oxidative stress in the scalp.|
The hallmarks of aging approach to hair aging and rejuvenation
Currently, pharmaceutical formulations mainly target one aspect of the signalling cascade that drives hair loss – androgens. However, androgen signalling is just one significant trigger for accelerated hair aging (Chen, 2020).
The goal of AAs is to therapeutically intervene to rebalance the biochemical environment that drives hair loss by targeting the most impactful hallmarks of hair aging, mainly inflammation, senescence, mitochondrial dysfunction, stem cell dysfunction and oxidative damage.
PRP (platelet-rich plasma) therapy for hair loss is a three-step medical treatment in which a person’s blood is drawn, processed and then injected into the scalp (Mercuri, 2021).
A special collection tube is used to draw your blood and is placed into a centrifuge.
After 10 minutes of centrifugation, the platelets are concentrated and drawn up into a syringe.
Using a small needle, the platelets are then injected strategically into your scalp in the areas that need improvement.
PRP has been shown to create an environment that promotes regeneration and improves blood flow. Both these factors stimulate and support HFSCs and prolong the anagen cycle of hair follicles. Although PRP is not effective in hair follicle depleted areas, it has shown remarkable promise in causing miniaturised follicles to grow thicker, stronger and denser. This is due to improvements in the number of hair follicles, follicle density and diameter, reduced shedding and increased pigmentation (Gupta, 2019).
Although the field of PRP holds a lot of promise, its potential will not be realised until several factors are optimised. There is still an incredible amount of heterogeneity in terms of clinical protocols and the scientific literature still does not account for conflicting results. To date, there are no double blind, randomised, placebo-controlled trials conducted on a large sample size to comprise high quality evidence for PRP. The efficacy of PRP for hair rejuvenation highly depends on patient selection and product formulation. Specifically, PRP is not for severe issues, such as baldness, but has significant potential as a preventative therapy that can help mitigate future loss of hair (Bano, 2021).
The main factors that influence PRP success include:
Platelet count in PRP formulation (Elghblawi, 2017):
- Emerging clinical evidence suggests that platelet count has a “sweet spot” and affects patient outcomes.
- Somewhere between 1.4-1.5 million platelets per uL is most significantly associated with vascularization and stem cell activation
Frequency of injections (Kelm, 2021):
- In clinical studies, PRP is most commonly delivered once a month for 3-4 months for patients seeking rejuvenative results, with a booster treatment every 4-6 months.
- For those seeking preventative hair loss, the frequency of treatment can be reduced to once every 3-4 months.
- Depending on the protocol, some research indicates that a single PRP injection can have lasting effects for 10-14 months.
Patient demographics (Kelm, 2021):
- Younger patients experiencing hair related issues for a shorter period of time (5 years or less) seem to have better results in hair regrowth than older patients with longer standing, severe disease.
For the advancement of the field, accurate biomarkers to measure the quality of PRP products are required. This will help create a framework to assess results and lead to standardisation of PRP preparation and application. There are several different variations of PRP to be explored. Each can be optimised towards a given patient demographic and goal.
Finally, as hair aging is a multifactorial process and PRP is revealing itself to be an excellent adjuvant tool, a combinatorial approach will likely be most efficacious. Recent research has shown that a combination of PRP, minoxidil and microneedling is significantly more effective at reversing the effects of hair aging than either monotherapy (Elghblawi, 2017).
Stem cell therapy
Stem cell therapy is a non-surgical therapy that stimulates and regrows the hair follicles by activating the already existing stem cells on the scalp. Adipose (fat) cells are harvested typically from the waist area. The stem cells are then separated from the adipose cells and activated. These activated stem cells are then injected into the scalp. These activated stem cells may give off the chemical signals to the nearby follicle cells that have shrunk during the aging process. The follicle cells then respond to the signals by regenerating and restoring youthful hair reference (Lockhart, 2016).
A small amount of fat – 50-100cc is taken from your waist area.
Stem cells are separated from fat cells.
Your stem cells are activated with natural proteins.
The activated stem cells are injected into the scalp.
Rejuvenate and repair hair follicle.
Advances in understanding the role of intercellular signalling in stem cell dysfunction has led to the optimisation of regenerative protocols. To date, autologous injection of adipose derived stem cells, their conditioned media and/or their vascular fraction have shown the greatest benefit in hair density and growth (Stefanis, 2019). This suggests that the benefits of stem cell treatment extend beyond direct regenerative effects of stem cells and towards beneficial effects of factors they secrete to influence the follicle signalling environment.
Interestingly, ex vivo exposure of adipose stem cells to hypoxic conditions has been shown to improve the generation of growth factors and chemokines which improves efficacy of treatments. This provides the opportunity to expose stem cells to various stressors/conditions (ex vivo) and guide their secretion milieu to further personalise and increase the efficacy of the final product (Fukuoka, 2019).
The field of AAs seeks to optimise stem cell therapies for hair rejuvenation through (Gentile, 2019):
- elucidating specific factors that stimulate and inhibit HFSC proliferation
- characterising the various microenvironments across the scalp zones and their receptivity to treatment
- developing new strategies for more accurate imaging and high-resolution data captures
- and adopting biomarker-based diagnostics to assess if stem cell therapy is the right AA strategy
Optimisation of administration protocols will require larger, randomized, double-blinded, controlled trials that confirm the early promise of observed clinical effects.
Topical compounds and phytochemicals
There is an expanding array of compounds that target various hallmarks of aging within the scalp and balance the biochemical signalling milieu at the hair follicle.
Many of these factors are being researched and discovered through means of artificial intelligence and machine learning analysis, as well as high throughput screens, for the identification of geroscience mechanisms and factors that target them. Due to the nature and complexity of hair aging, combinatorial approaches that include multiple phytochemicals/compounds that act in synergy to target several hallmarks of aging in a synchronized manner have the most potential for hair rejuvenation (Sadgrove, 2021).
Due to the nature and complexity of hair aging, combinatorial approaches have the most potential for hair rejuvenation. Some therapeutic avenues currently being explored are (Sadgrove, 2021):
- Topical application of a combination of caffeine, niacinamide, panthenol, dimethicone, and an acrylate polymer has demonstrated benefits for improving hair follicle diameter by inducing maintenance of anagen hair follicles
- Topical and oral application of NAD, resveratrol, mallate, senolytic peptides and growth factors have also shown early promise in targeting multiple molecular hallmarks of hair aging and rejuvenating aspects of hair growth
- Cannabinoids are another class of compounds that have been shown to promote proliferation of HFSC, induce anti-inflammatory effects at the hair follicle and improve health of the interfollicular ECM to support hair growth. But cannabinoids health promoting benefits are contingent upon activation of CB2 receptors and not CB1. This highlights the importance of tailoring therapies – based on mechanistic insights – that optimize benefits while reducing side effects or unintended consequences.
However, there is a need for more clinical studies and systematic approaches to validate compounds that target hair aging and this is exactly what the field of AAs promises to address.
There are several other molecular pathways that can be targeted with molecules for rejuvenation, we have listed a few below (Trueb, 2018) (Wadsetein, 2020) (Sadick, 2017):
Molecular Pathways that can be targeted with molecules for rejuvenation
|Epigenetic Dysfunction||With aging, HFSCS may lose function through epigenetic changes that result in reduced proliferation and self renewal and enhanced periods of dormancy mediated by senescent cells and the presence of microinflammation.|
|Mitochondrial Dysfunction||As hair follicle cells are extremely metabolically active and oxidative stress is clearly a significant driver of aging, mitochondrial health is a sensitive node that plays a central role in triggering the aging cascade.|
|Microbiome Therapeutics||Developing prebiotic, probiotic and post-biotic formulations that restore youthful balance to the scalp microbiome hold potential to have senotherapeutic, anti-inflammatory, antioxidant and HF rejuvenating properties.|
|Targeting inflammation||Most HFs aren’t lost during the process of microinflammation, rather suppressed in a catagen state. Accordingly, removal of pathogenic T (immune) cells can reverse hair loss and restore hair growth.|
|ECM therapeutics||Local injection of proteoglycans can ameliorate microinflammation, induce HFSC proliferation and growth of DP cells and initiate entry into the anagen phase of HF cycle.|
Low laser therapy
Low-level laser therapy is a safe, non-invasive and clinically proven treatment for stimulating hair follicles to grow fuller and thicker hair (Pillai, 2021).
Laser therapy is one of the most powerful AAs modalities as it targets a root mechanism of hair aging: “energy deficiency in highly metabolic cells”. Photons of light from laser therapy interact with “photo-activated” proteins (cytochrome c oxidase) in the mitochondria of DPCs, melanocytes and HFSCs.
This in turn charges mitochondria (like a battery) and induces a surge of ATP to boost mitochondrial efficiency and promote intracellular signalling (e.g. NF-kB) to facilitate entry and maintenance of anagen follicles. Laser therapy provides a temporary boost to mitochondria yet signalling changes that result from this intervention have been shown to cause longer lasting changes in DPC signalling, the ECM and HF cycling dynamics (Gentile, 2019).
Laser therapy isn’t a “one time fix”; it requires a regular regimen that is personalized towards given demographics of individuals based on genetics, hair type and the health state of hair follicles and scalp (defined by presence of various hallmarks of aging). Laser therapy can be administered using state-of-the-art devices within clinics or through the commercial sale of spot or cap therapy. The latter methodology is a simple cap that contains lasers and light stimulation mechanics that allow for the construction of a daily treatment regimen that serves both prevention and rejuvenation purposes (Egger, 2020).
Low-level laser treatment is being used to enhance hair growth in individuals with androgenic alopecia and for individuals with non-androgenic hair loss issues. From initial clinical studies, low level laser treatment has been found to be most effective at stimulating hair growth, thickness and density when applied 15 days after adipose stem cells and PRP treatment and every three weeks after the last treatment for a period of six months (Gentile, 2019). This early data demonstrates the wave of the future. The ability to effectively use several AAs in a multimodal strategy to target multiple hallmarks at once (including mitochondrial dysfunction, stem cell proliferation, inflammation and intracellular signalling).
Aging has become one of the biggest beauty concerns faced by female and male populations; it is, therefore, fair to predict that the aging population will be the primary factor driving the AA market. Furthermore, the rising consumer consciousness regarding health will likely play a role in the growth of this market in the foreseeable future.
Due to the distressing nature of many dermatological diseases, and the enormous consumer demand for products to reverse the effects of skin photodamage, aging and hair loss, the discovery of novel skin longevity interventions and testing of consumer products in the field of dermatology is a multi-billion-dollar business. According to a report by Goldstein Research, in 2016 the global beauty supplement market was valued at about $3.5 billion, and by the end of 2024 this market is estimated to reach $6.8 billion (Katta, 2020). And this pales in comparison with the global demand for antiaging skincare solutions which is expected to be worth $83.2 billion by the year 2027. The skincare market is also projected to reach $200.25 billion by 2026, with an emphasis on achieving skin health using natural compounds. Several ailments are projected to hold large shares of the future market including ultraviolet radiation (UVR) damage, wrinkle formation and dyspigmentation (Russell-Goldman, 2020). In a recent report published by Deloitte, skincare efficacy was ranked as the top factor driving skincare purchases, above even sales promotions (Deloitte, 2021). This data suggests that the existing cosmetics market is primed to pour into AAs.
Investment by location
Unsurprisingly North America is largely dominating the AA market. An increasing aging population, high standard of living and high per capita spending in the region are likely playing a key role.
The AA products will be priced higher in comparison with cosmetic products available due to presence of highly effective ingredients. In the US, the growing disposable income has already facilitated consumers towards purchasing cosmeceuticals and a similar growth can be expected for the AA market (Mordor Intelligence, 2021). Lastly, the US was the largest contributor to the antiaging market in 2020 due to the rising preference for non-surgical antiaging treatments, increasing awareness about skincare products and growing number of cosmetic procedures being performed in the region (Prescient Strategic Development, 2021). This rising interest and awareness amongst the North American population means companies operating in this region are likely to see excellent growth. Similarly, companies operating elsewhere in the world will could benefit by focusing their marketing efforts to break into the North American market.
Nonetheless, across the world, the Asia-Pacific region is expected to be fastest-growing market for antiaging products, attributed to the increasing urbanisation rate and number of cosmetic procedures being performed. Although, not as high as North America, the number of AA companies in this region is showing promise that the AA market could see substantial growth. The large pool of geriatric people in India and China continues to drive the antiaging market growth, by generating a high demand for antiaging products to address their age-related and aesthetic conditions. According to the World Population Ageing 2019 report, in Asia, the number of people aged 65 years and above is expected to reach 954.7 million by 2050 from 395.3 million in 2019 (Prescient Strategic Development, 2021) . These trends hold promise that the AA market is likely to quickly gain momentum within this region and see a faster growth rate soon.
Formations by year
Advanced Aesthetic companies founded analysis by Longevity.Technology, according to Pitchbook funding data as of 20 July 2022.
Prior to 2011 there has only been a handful of what would be classed as AA companies entering the market. One of the earliest players is Replicel Life Sciences formed in 1967. It is worth mentioning that some of these earliest companies including Replical Life Sciences (1967), Allergan (1983) and Sierra Sciences (1998), focus on several therapeutic areas and applications apart from skin aging. However, since 2013/2014 period, there has been a substantial growth in the number of AA companies coming into the antiaging and longevity market and the overall trend is showing a steep rise. The year 2013 also marks the year when the “The Hallmarks of Aging” paper was published (López-Otín et al, 2013), and this could very well explain the rising of the number of AA companies and possibly resulting in the earliest companies moving into the AA field. The cosmetics industry has always been a promising market to enter with a great deal of consumer demand. However, it is often saturated, and few companies have made groundbreaking developments to revolutionaries the skincare industry. The new approach of targeting hallmarks of aging with skin and hair products and targeting the very mechanism causing the age-related changes would certainly be “groundbreaking” and have a clear competitive edge.
From a consumer side, the rise in disposable income among the urban population of developing economies and an increase in the healthy and premium lifestyle have led to the increasing demand for luxury skincare and hair products (Million Insights, 2022). The AA market falls well into this category. Furthermore, increasing consumer focus towards personal appearance and grooming will be a major factor behind the market growth at the global level. The increasing brand recognition of many companies with the help of social media would certainly further fuel the AA product demand (Million Insights, 2022).
From 2020 there has been a halt in new AA companies entering the market, likely due to the COVID-19 pandemic. During the pandemic, manufacturing facilities of beauty devices and antiaging products were affected owing to the lockdowns and other strict government regulations across the world. This led to the decreased production of antiaging product (Prescient Strategic Development, 2021). Product based business, especially those that would need to operate at large scale such as AA likely would, were probably more cautious about entering the market during this time for exactly those reasons. It is promising that demand for such products has remained high, therefore, as the world recovers from the effects of the pandemic, new companies will likely start entering the market.
On the other hand, established companies in the market, often remain resilient during times of recessions and economic downturns like the Covid-19 crisis. This is due to the “lipstick effect” in other words consumers see beauty as an affordable, small luxury during uncertain economic times (CB Insights, 2021). Another positive insight comes from a February 2021 PowerReviews survey which found that consumers are now 40% more willing to try new beauty products than before the pandemic, and 59% report spending the same or more on beauty as they did prior to Covid-19 (Team PowerReviews, 2022).
Capital invested and deal count
Total capital invested
Advanced Aesthetic companies venture capital investment ($B) analysis by Longevity.Technology, according to Pitchbook funding data as of 19 July 2022.
Please note that for the purpose of this analysis the company Allergan has been removed from the analysis. The large biopharmaceutical company focuses on many therapeutic areas, and it was not possible for us to determine the extent of the AA division itself. The data would have been skewed and not representative of the AA trend itself.
The overall trend for both deal count, and total investment has been on the rise. Although there was a dip in investment activity in the 2019-2020 period likely to be in part caused by the COVID 19 pandemic, in 2021 the investment activity and deal count returned to high levels showing promise for future investments and deals. The year 2021 was particularly successful in terms of venture capital raised, largely due to three large deals that have occurred that year. Nuritas raised $45.5 million in Series B funding, Erion raised $43 million in Series A funding and Moder Age $27 million in Series A funding, highlighting their success and future potential of this market.
Percentage of companies: skin vs hair
% of all companies
The skincare is certainly the leading category within the cosmetic, antiaging and beauty market and this is reflected by the large proportion of AA companies focusing on skin. While nearly a quarter of the companies are focusing on both skin and hair and only a small fraction looking at hair alone.
Furthermore, the global skincare market is currently nearly two times more profitable estimated to be worth US$ 130.50 billion in 2021, compared with $77.15 billion in 2021 for hair care (Fortune Business Insights, 2021)(Grand Review Research 2021).
Apart from the fact that skin is the largest organ and one that most visibly shows age associated changes, it also has many functions that are vital to our health. This could also play a role in the amount of focus placed on skin compared with hair. Skin aging is associated with a higher prevalence of skin infection, increased radiation sensitivity, increasing incidence of skin cancer. This is one key reason why AA could dominate the skincare industry because it targets the aesthetic and functional role of the skin in one.
Percentage of Skin and Hair Companies by Modality
SKIN COMPANIES % BY MODALITY
HAIR COMPANIES % by Modality
Both Skin and Hair AA companies are largely dominated by molecules which includes oral, topical and injectable compounds. These products may require far less and stringent regulation compared with some of the other AA options. Consumers are far more familiar with these modalities as they have been widely used within the skincare and cosmetic industry for decades. Furthermore, they are likely to be available to a far greater demographic due to ease of access and lower price point.
Oral, Tropical, injectable compounds
Laser/VL stimulation, Chemical Peel, Micro-needling
Stem cell and platelet rich plasma (PRP)
For AA companies focused on hair, a large proportion are exploring cellular modalities which include stem cell and PRR treatments. At the moment, these are some of the most promising avenues for restoring hair following hair loss in both men and women and could prove to be the most effective (Knoepfler, 2022).
With regards to AA companies looking as skin, a large proportion termed ‘other’ are companies developing platforms for skin testing and analysis as well as discovery of new skincare and skin-aging solutions. Both playing an essential role for the future expansion and development of the AA field
The rise in average life expectancy has resulted in the emergence of the geriatric population. The rise of beauty consciousness among the general public has aided the expansion of this massive industry, which caters to a variety of issues that people may have with their looks. The safer and more efficient services have been provided as a result of technological advancements, and they have become quite popular.
The antiaging cosmetics industry categories likely to see the biggest growth
Within antiaging cosmetics industry, the hair restoration category is expected to witness the fastest growth in the coming years. The increase in the number of hair treatments due to the rise in prevalence of hair loss and baldness among adults will be the primary cause. At present the skin focused companies are dominating the AA market however, the rising interest in hair treatments with a lower market competition could be a promising space for both new companies as well as investors.
In 2020, the anti-wrinkle segment dominated the market and the AA companies which improve this skin concern could outperform companies focusing on other aspects of aging skin (Precedence Research, 2021).
When it comes to devices laser aesthetic devices segment was fastest growing segment of the antiaging cosmetics market in 2020 (Precedence Research, 2021). There is a growing popularity in skin and hair treatments that are non-invasive, give quick results, cause less discomfort and have little recovery time (Business Wire, 2022). Laser based treatments tick those boxes.
Personalisation of products
A Forrester study found that 77% of consumers have chosen, recommended, or paid more for a brand that provides a personalised service or experience, while Accenture found that 75% of consumers are more likely to make a purchase when recommendations are personalised to them, propelling the push for brands and companies to personalise their products (CB Insights, 2021).
An appropriate AAs therapeutic framework requires considering the age, health history, current health status, skin type, ethnicity, microbiome, gender, ageotype, lifestyle and many other factors. Each combination of factors requires a different therapeutic paradigm.
Deep molecular profiling to elucidate cell type specific and individually personalised ageotype characterisations are the fuel of next gen AAs. AI and high throughput screens can help design libraries of AA molecules, cellular formulas, technological protocols and precision biome products. The goal of AAs is to formulate combinatorial strategies, suitable for each consumer’s skin type, while respecting their anatomical and physiological assets (hormonal and genetic factors, skin thickness, age, skin complexion) and taking into account behaviours (diet) and environmental exposures (extrinsic factors) (Rizzi, 2021).
Due to the heterogeneity and complexity of the skin/hair and the integrated network of interactions between aging drivers, it is clear that there is no single modality that will prove to be effective in prevention and rejuvenation of aging. Therefore, combinatorial treatments that act in synergy (including molecules that target multiple hallmarks of aging, lasers, micro needling, PRP, stem cell therapy, &c) provide opportunity of increased efficacy by stacking therapeutics based on the hallmarks they target and their individual strengths and weaknesses. Further, due to the unique aging hallmark vulnerabilities between layers of the skin and the hair follicle, combinatorial therapeutics offer a means to a holistic rejuvenative strategy.
Biological age diagnostics for skin and hair
One of the most critical (and still elusive) aspects for the discovery and development of efficacious AA interventions is the use of robust diagnostic and prognostic biomarkers of skin/hair aging. The key features of ideal biomarkers include: easy access in humans, capture age-related change, amenable to early measurement, facilitates ageotype classification and is sensitive to tiny fluctuations in aging rate (Galkin, 2020). Further, biomarker(s) that facilitate assessment of cell type specific effects (such as within dermal fibroblasts, DPCs) will provide invaluable information for therapeutic optimisation and personalisation. One of the most promising classes of aging biomarkers to date are skin epigenetic age clocks. Combinatorial bioage diagnostics, including imaging, molecular clocks, biome tests, etc offer the opportunity to assess several aspects of skin/hair health and improve therapeutic efficacy by giving a more complete picture of the aging process.
Role of AI
There is an increasing realisation of the immense value of artificial intelligence (AI) and advanced bioinformatics for the processing of big data within the rapidly evolving field of AAs. Those companies that don’t integrate such technologies as part of their platform are quickly falling behind the rest. AI and ML can be used to elucidate key aging pathways/geroscience models, design personalised therapeutics based on an individual’s ageotype and aid in characterising the health of skin zones and even individual hair follicles (Zhavoronkov, 2018).
Development of tools that can assess multi-factorial combinations of exposome factors and their influence on cellular hallmarks of skin aging, within different demographics with defined intrinsic aging trajectories (Mohiuddin, 2019). Classifying skin ageotypes based on these factors will lead to “next level” precision therapeutics that facilitate prevention and rejuvenation of skin aging.
The field of AAs has the unique promise to benefit from a symbiotic relationship with AI due to the ease of biodata collection from skin/hair, the prospects of large inventories of post-market data and interest from investors within the cosmetics space. Together, this creates a system that can rapidly iterate, evolve,and be optimised based on novel information.
Safety and regulation
When it come to the antiaging market, consumers are often cautious about the products and services being provided, especially when they are still considered to be in the early stages. Which is why, strict restrictions and regulations surrounding their development and even clinical evidence of their effectiveness can restore the consumer confidence and trust. The antiaging market is increasingly investing in technological developments as well as research and development to facilitate the creation of extremely safe and effective skin care treatments, leading to a rising awareness and acceptance of antiaging products. On the other hand, the strict regulatory standards and societal stigma in certain populations will be adding time to the progress of moving the products and services to market. Nonetheless, the added time will certainly be worthwhile for companies’ long-term success.
Price and Counterfeit
The AA products will see a higher price tag in comparison with cosmetic products available on the market due to their far greater efficacy. This could give rise to a higher prevalence of counterfeit products which contain ineffective or even harmful ingredients and could add a significant barrier to the AA market expansion (Precedence Research, 2021). Controlling this could be difficult due to the rising availability and accessibility of skincare and hair products with more purchasing options. Whereas in the past, people could only access the more premium antiaging products in well-respected stores, they are now widely available through various online retailers, salons and spas. Rising consumer awareness to safely purchase these products will be imperative to prevent negative consequences and maintain consumer trust.
Sustainability is a hot topic across virtually every sector. AA companies will have to be considerate of the increasing focus on sustainability and environmental impact if they want to appeal to an increasingly eco-conscious population. To succeed in the current ecosystem, companies will benefit in being mindful of this shift by investing in things like reusable or refillable packaging. In fact, big players in the beauty and cosmetic market including L’Oréal and Estée Lauder, have announced goals to reach carbon neutrality (CB Insights, 2021).
Adapting to societal change
Along those lines, companies should be mindful of other societal shifts including the rising trends in inclusive beauty, gender neutral products and beauty across generational cohorts. AAs are likely to provide major opportunities in meeting the needs of older consumers including Gen Z and Baby Bloomers, going beyond the young adult cohort whom current marketing strategies target. With one popular niche being that of perimenopausal women, who experience unique skin concerns. This consumer niche has already seen increasing attention in the skincare industry (CB Insights, 2021).
Lastly, AA companies should focus on addressing the discrepancies and lack of representation of people of colour which is already seen in the antiaging, skincare, hair and beauty industry. It is estimated that Black dermatologists make up only 3% of the total in the field in the US which is a major underrepresentation. Furthermore, darker skin reacts differently to skin conditions, is more susceptible to hyperpigmentation due to higher amounts of melanin and may show differences in the aging process. At present many products are tested on lighter skin tones, ignoring efficacy for people with different skin tones entirely. Ultimately, brands that can cater to these demographics will be more likely to succeed in the long-term (CB Insights, 2021).
AAs offer the opportunity for individuals to not only look younger but be biologically younger. The ability to look and feel better from the inside out has a significant role to play in social inequity. AAs will play a significant role in addressing social stigmas and ageism that compromise the continuing healthcare, education and career-spans of elderly individuals. This in turn promises a return worth hundreds of billions of dollars based on an elderly population that is healthier, more educated and continues their immense economic contributions to society. The goal is that eventually, this will land on the radar of healthcare providers and insurance companies.
AAs play a critical role within the longevity ecosystem, perhaps the most important role. Longevity drugs, senotherapeutics, cellular reprogramming — these are all longevity therapeutics that hold great promise, but they are still sometimes away from being available to the general public due to the rigors of the regulatory process. AAs walk the tenuous line between cosmetic and drug as they are not overtly marketed towards treating disease – rather aging – which the longevity field is pushing to be considered as a disease. AAs can take advantage of the current “underdog” status that aging has in the eyes of the FDA by developing therapeutics that target aging hallmarks with the intent of “beautifying” rather than to treat disease. By taking the less stringent cosmetics/supplements regulatory route, AAs offer an opportunity to demonstrate how the longevity field can target the process of aging and achieve rejuvenation, at just a fraction of the time and cost that the longevity biotech realm is investing.
From a regulatory standpoint, the US FDA recognises molecular and microbiome oral supplements as foods and topicals as cosmetics. The use of hormesis technologies (i.e lasers, chemical peels, microneedling) are regulated under the general guidelines of medical devices although they are under much less stringent regulatory standards by the FDA. Further, regulation varies state by state. For example, while some states may have a robust collection of laws for the operation of laser therapies, others are minimally regulated. Technology devices typically take 6 months – 2 years for approval (as opposed to a decade for drugs ), but this depends on whether there is a predicate device (Katta, 2020).
PRP is regulated by regulating the device used to manufacture it and the wide range of PRP systems that are currently available have been brought to market using the 510(k) pathway. The 510(k) pathway “clears” products that are “substantially equivalent” to an already cleared predicate device. Autologous stem cell treatments (and their media/exosome derivatives) also have markedly less stringent regulatory barriers in place within the aesthetics market. Autologous application is a one-stage medical procedure and considered a minimal manipulation product. In many cases, development of such products and protocols in aseptic conditions do not require good manufacturing practice (GMP) rules for preparation, good clinical practices (GCP) for the clinical application, or ethical committee underwriting.
This distinction between beauty and medical products has multiple ramifications, including the fact that manufacturers generally do not have stringent requirements to prove efficacy, safety, or quality prior to sale. Therefore, physicians and consumers must evaluate each supplement ingredient, formulation, technological device and cellular product individually. While this provides excellent advantages in regard to cost and time to market for companies developing AAs products, it does come with its own issues (Katta, 2020).
According to an analysis in 2010 by Consumer Reports, the independent organisation Natural Medicines Comprehensive Database listed over 54,000 supplements. Of these, 12% were associated with safety or quality concerns. In the same analysis, about two-thirds of the listed substances lacked any information on safety and efficacy as supported by scientific evidence (Katta, 2020). Consumer Lab, an independent testing organisation, has reported multiple quality issues with supplements. Their results indicate that overall, about 1 in 5 supplements are considered poor quality, with herbal products even higher at 39%. Documented issues range from poor quality ingredients to little or no ingredient, to inadequate disintegration of pills. Hormesis technologies and cellular therapies face many of the same issues, resulting in ill controlled protocols, compromised scientific rigour and sub-optimal results. Therefore, AAs companies that go the extra mile to validate their longevity products and equipment with government regulated certificates and copious amounts of preclinical data and/or human (clinical trial) data, truly stand out in this market.
Haut.AI is an industry-leading global artificial intelligence company that specialises in skincare and longevity. By combining advanced deep learning techniques for machine vision, deep generative models for synthetic data generation and reinforcement learning with expert human dermatologists, nutritionists and biogerontologists, the company develops advanced, hyper-personalised recommendation engines for the beauty, skincare and longevity markets.
Founded in 2018 and headquartered in Estonia – the digital hub of the European Union – Haut.AI prides itself on supporting diversity and inclusion by developing AI that is effective across a range of different skin types and skin tones, in addition to developing novel techniques for identifying bias. With 65 global partnerships, the company’s SaaS solution currently serves international skincare brands, retailers and contract research organisations in 28 different markets.
“Haut.AI is an end-to-end digital innovation platform for next-generation, AI-driven, hyper-personalised, science-backed skincare and beauty solutions. We are focused on bringing the highest quality experience to our customers and building an ongoing interaction with consumers. We want to be there for them when they need our expertise and unbiased skin evaluation.”
– Anastasia Georgievskaya (CEO)
The Haut.AI team was among the first to enter the AI-powered skincare market. By building a tech platform that analyses skin in real time (or within two seconds) with high accuracy at a dermatologist-level, Haut.AI’s goal is to give consumers much more – namely, digital skincare products, the tools to visibly transform their skin and feel better about its appearance, as well as access to a community and trusted environment where they can learn about products and skin tech innovations, share feedback, build routines and discover new brands and trends.
Flagship Product Deep Dive: Skin SaaS®
Haut.AI’s Skin SaaS® software prompted a complete paradigm shift in skincare personalisation. Skin SaaS® is software for skincare hyper-personalisation using non-invasive skin aging biomarkers. Instead of relying on very basic analytics – such as age, gender and location – or endless surveys, Haut.AI offers skincare businesses a reliable and simple software tool for instant, quantifiable analysis of the skin’s actual condition, and all from a single selfie. But not just any selfie. A “perfect” selfie captured with a mobile phone using Haut.AI’s Live Image Quality Assurance®. Haut.AI replaced biased consumer self-assessment with an approach that says:
“Don’t trust – measure!”
The platform’s technological capabilities are not limited to facial skin analysis. It allows data on hair, hands, fingernails, toenails, teeth and skin elsewhere on the body to be easily collected and analysed. Early detection of aging biomarkers gives the customer a holistic understanding of the concern and helps identify early signs of impacts on their skin and hair. The earlier issues are detected, the easier it is to decelerate aging.
Aging is a disease that affects every single person. Haut.AI’s technology will help to slow this down – and, ideally, revert it. Currently, the main goal is to learn how to maintain the skin’s condition. Because the origin of all skin conditions, like spots or irritation, is complicated, the Haut.AI team understands that neither a single product nor targeting one skin concern at a time could reasonably address the underlying reasons for skin aging. With this knowledge, Haut.AI crafted a different approach to the recommendation engine: the SkinArt routine. This novel approach allows consumers to select products that will improve their skin’s condition in the short and long term.
Tested on three million images, the Haut.AI algorithm, which can be seamlessly integrated into e-commerce platforms and social media – provides highly effective, AI-based, data-driven, science-backed recommendations that have increased conversion, consumer engagement and retention to a degree that brands never expected. Haut.AI also offers API and SDK solutions for clients who want to build a fully customised experience. For SMEs, Haut.AI offers a simple web-app constructor that allows accurate skin analysis and recommendation apps to be built in under two hours. Furthermore, Haut.AI has proprietary technology for face image anonymisation, the algorithms can efficiently process anonymised data, and the platform is secured with end-to-end encryption.
Haut.AI recently announced a strategic partnership with Ulta Beauty. Following its collaboration with Johnson & Johnson’s Innovation JLabs in Shanghai, it has also declared its goals for expansion into the Asian market. Looking ahead, the company plans to invest more resources into promoting its product in new international markets, expanding its partnership network and tripling its number of clients globally.
Haut.AI is currently working on a product that will disrupt the digital skincare and beauty tech market by making it possible to scan not only the face but also the whole body (hair, hands, arms, teeth, neck and décolleté), positioning Haut.AI as the number one platform for omnichannel sales and the leading provider of skin and longevity assessment technology.
Every population group can benefit from different aspects of Haut.AI’s Skin SaaS®.
Haut.AI’s algorithms perform equally well on any skin type and condition, and there is no dependency on gender or age group either.
Typically, the skin is viewed either from an aesthetic or a functional perspective. Attractive and healthy skin is the most common desire, but Haut.AI cares about all aspects of the skin, including its visual attractiveness and its ability to perform its key physiological functions.
With Haut.AI, it takes just a couple of seconds for a customer to get a comprehensive analysis of their skin. For groups with pronounced skin concerns, the system will support the trajectory for short- and long-term improvements. For consumers who don’t have alarming skin concerns, the system suggests a strategy to preserve its condition and slow down any deterioration.
Channels to Market
Haut.AI recently declared its strategic goals for 2022. In particular, the company aims to expand its presence in Asia, Latin America and the US.
Four of the five top countries in the sale of skincare products are based in Asia (Japan, China, South Korea and India). While the US is the global skincare market leader right now, Japan is not far behind and is expected to outperform it in 2024. To successfully compete on the global market, Asian cosmetics companies must gain an advantage by staying ahead of emerging trends, such as by offering hyper-personalised and highly effective products. Thus, the demand for Haut.AI’s technology in Asia will certainly continue to grow.
Team and Reputation
Haut.AI’s team includes 25 dedicated deep learning engineers, software engineers and biologists on a mission to bring AI-assisted skincare to every household.
Haut.AI’s two founders, Anastasia Georgievskaya (CEO and co-founder), Konstantin Kiselev (CTO and co-founder) and Alex Zhavoronkov (Founder and CEO at Insilico Medicine) first met at hackathons in 2015. In 2016, a Kickstarter campaign was launched for their latest project – a solution for tracking aging biomarkers from photographs with the help of AI algorithms, which caught the attention of R&D representatives from some of the largest global beauty and personal care companies on the market. Anastasia and Konstantin have backgrounds in biophysics and science and are dedicated to frontend innovation. Alexis also the founder and CEO of Insilico Medicine, holding several degrees in business and a PhD in physics. Haut.AI as we know it today was officially founded in 2018.
Haut.AI’s scientists appreciate an evidence-based approach, as well as tech innovation, digitalisation and the benefits of skincare hyper-personalisation. With a team of developers with a track record of successfully launched partnerships, Haut.AI has always felt uniquely positioned to take a radically different approach to skincare and break the established opinion that skincare traditionally uses for marketing.
Haut.AI’s main competitive advantage is the scientific accuracy of its technology. The product leverages super-accurate skin analysis and allows simple integration into any web platform via API and SDK with a high level of customisation or a no-code builder for companies that want to instantly enable AI skin analysis. Haut.AI advocates the idea of processing primarily anonymised data.
Haut.AI’s digital innovation platform allows beauty and wellness brands to remotely conduct various types of consumer studies without any significant loss of efficiency or accuracy. It also integrates the gathered insights into their marketing and consumer communication strategies, bringing data to a new level of medical-level accuracy in the skincare industry.
At present, funding information remains undisclosed. However, Haut.AI declares that it is revenue-generating and profitable.
“From the frontier of brain aging comes the vanguard of skin antiaging”
IDEO Skincare is a revolutionary antiaging brand that was born out of the pioneering work of Dr John Paul Blass at JPB Labs in 2020. From Harvard undergrad to doctoral studies in biochemistry as a Marshall Scholar in London on his way to both a PhD and MD, Dr Blass is an award-winning neurologist who has spent more than three decades studying Alzheimer’s disease. During this time he developed a (once) radical theory on the primary cause of brain aging, which during his career brought buzz of a potential Nobel nomination. The pioneering science conducted in JPB Labs, and now in other labs across the globe, supports the theory that Alzheimer’s disease (AD) is the consequence of impaired (and consequently slower) metabolism within the “power-house” of cells, the mitochondria.
Working within this framework, Dr Blass formulated a compound (called Resveratrol-Glucose-Malate or RGM) that improved mitochondrial health and slowed down the progression of Alzheimer’s disease in preclinical studies. It was also found to be safe in humans within clinical trials. Despite this promise, pursuing clinical trials targeting Alzheimer’s disease with such a contrarian approach was expensive and it was difficult to acquire funding. From these challenges, a renewed opportunity emerged. One that has the potential to breathe new life into the skin antiaging industry.
“When you see what this formula does for your aging skin, just imagine what it can do for your aging brain”
Dr Blass’s studies strongly suggest that mitochondrial dysfunction and inefficient metabolism are ”primary triggers” in the process of neuronal (brain cell) aging. In other words, they are the first domino to fall that initiates the “aging cascade”. Further, Dr Blass realised the inherent commonalities between how all cells and tissues age, through damages posed by the fundamental hallmarks of aging. Accordingly, if RGM could target and remedy the root driver of brain aging, it could be effective at rejuvenating aging skin as well. To optimise for targeting skin aging, Dr Blass reformulated his compound to create topical RMA (Resveratrol-Malate-Antioxidants). Around this time, Dr Blass’s wife (Gitte) had a surgical procedure that left a deep and long scar on her body that was not healing well. With the spirit and mindset of true scientific trailblazers, the couple decided to test RMA on Gitte’s scar and found that treatment with topical RMA helped it heal within a few weeks.
Inspired by these promising results, the couple teamed up with polymath Andrew Shemin (Founder and CEO) and IDEO Skincare emerged. The fuel for starting IDEO Skincare arose from the team’s intense desire to help other individuals seeking to rejuvenate their aging skin and maximise their healthspan. In doing so, they would use their results on the skin as a demonstration, and an advertisement, for what RMA could do for aging tissues throughout the body. Restoring youthful function to the aging and damaged brain is the ultimate hope for Dr Blass’s life’s work.
“The Science of Skin memory”
Dr Blass’s research suggests that with age, brain cells (i.e. neurons) “forget” how to engage basic maintenance and repair processes that help efficiently use fuels and manage oxidative stress (toxic byproducts produced by “everyday metabolism”). This “cellular amnesia” leads to slower metabolism, increased production of toxic metabolites (i.e. reactive oxygen species) and damage to critical cellular machinery including DNA and mitochondria. Over time, the inability of mitochondria to provide enough energy for aging neurons results in cellular dysfunction and neurodegenerative pathologies.
Promising early results suggests that RMA facilitates skin rejuvenation through targeting a similar mechanism in aging skin. In other words, RMA works by “helping skin cells remember” how to efficiently generate energy and effectively remedy oxidative stress, as they did in their youth. This pivotal concept led to IDEO Skincare’s flagship product – the Skin Memory Serum. This serum holds potential to rejuvenate the skin by boosting mitochondrial health, metabolism and antioxidant capacity to address the major drivers of skin aging. “With the development of IDEO’s Skin Memory Serum, we seek to transform the cosmetic industry. Taking it from a strategy that focused on disguising and concealing wrinkles, to one that addresses the root cause of skin aging and achieves true rejuvenation.”
IDEO Skincare’s potential is quickly being realised as it was named by Forbes Magazines as among the best beauty and wellness products for self-care in 2021.
Flagship Product Deep Dive: IDEO Skincare’s Skin Memory Serum (RMA)
“Unlearn what you know about age”
The geroscience hypothesis suggests that aging unfolds at the cellular and molecular level first, ultimately leading to aging of whole tissues, organs and the organism itself. Therefore, ameliorating aging on a cellular level (by targeting hallmarks of aging) can restore the youthful function and appearance of organs and tissues. But there are several different types of damages and dysfunctions that contribute to cellular aging, with various longevity companies focusing on distinct types to address age-related diseases. Dr Blass and the IDEO Skincare team’s unique approach involves targeting what they believe to be the primary trigger and root cause of cellular aging, namely, metabolic insufficiency (MI).
MI occurs when cellular metabolism and energy production cannot keep up with the energy demands required to maintain the structure and function of the aging cell. Dr Blass has published a large body of peer-reviewed scientific papers supporting the observation that mitochondrial metabolism slows down with aging, and this leads to oxidative stress, damage accumulation and age-related disease. IDEO Skincare’s Skin Memory Serum increases cellular metabolism within skin cells, thereby enhancing energy production, facilitating damage clearance and improving mitochondrial health. On a visual level, this translates to improved skin tone, decreased sagging and wrinkles, brighter, more radiant and overall healthier looking skin.
Skin Memory Serum
The key component within IDEO Skincare’s topical skin memory serum is the Resveratrol-Malate-Antioxidant complex. Each factor within the complex was carefully selected and included in precise ratios to address and resolve different aspects of metabolic insufficiency.
- Resveratrol is an antioxidant that has been shown to help cells repair DNA damage caused by ultraviolet radiation (UVR), reduce inflammation that leads to skin redness, activate key regulators of healthy gene expression (Sirtuins) and mitigate the consequences of oxidative stress in the skin.
- Malate is the “rate-limiting factor” of mitochondrial metabolism. Meaning, when there isn’t enough malate, metabolism slows down. As metabolism slows down, oxidative stress increases. Increasing malate speeds up mitochondrial metabolism and makes it more efficient at extracting energy from the food we eat and reducing the amount of toxic by-products produced in the process.
- Antioxidants help detoxify destructive byproducts (i.e. called free radicals) that are over-produced as cellular metabolism slows down with age. They also help “clean up” free radicals that are produced upon exposure to environmental stressors such as UVR, pollutants and ozone.
Other ingredients in the Skin Memory Serum include vitamin C derivatives (antioxidant), niacinamide (immune support) and various forms of hyaluronic acid that penetrate different layers of the skin to support structure, moisturisation and healthy signalling between skin cells. The Skin Memory Serum is uniquely formulated for optimised delivery of RMA through the robust barrier of the skin (epidermis) using a proprietary bio-topical matrix.
IDEO Skincare chose to demonstrate RMA’s ability to achieve cellular rejuvenation by targeting the skin as it has a quick “time to market”, is less expensive to develop and resonates with individual’s on a personal and psychological level. “After all, who doesn’t want to look and feel better in their own skin as they age?” Ultimately, IDEO Skincare plans to use the data and insights gleaned from its flagship product as a platform to expand its pipeline to target (and rejuvenate) several other aging tissues – especially the brain.
Evidence of safety and efficacy
IDEO Skincare operates with the strong belief that “rigorous science produces robust results”. Accordingly, the team prides itself for conducting meticulously designed studies and being completely transparent with its results. A truly rejuvenative skin antiaging compound doesn’t need any bells and whistles.
IDEO Skincare has currently completed one (third party conducted) clinical trial with its Skin Memory Serum. This landmark trial involved 30 female subjects that applied skin memory serum to their face and neck every day for 4 weeks. During the trial, 10 clinical parameters were used to evaluate the effectiveness of IDEO’s Skin Memory Serum in rejuvenating aged skin. Statistically significant improvements were observed in 8/10 parameters by the end of the trial. Improvements in skin redness (erythema) and “even skin tone” were observed within 1 week of the regimen and improvements in “radiance” and “global fine lines” were observed within 2 weeks. Further, the skin memory serum significantly improved pore appearance, mottled hyperpigmentation, global wrinkles and pinch recoil (elasticity/resiliency) after 4 weeks of treatment. In regards to safety, no significant side effects were observed within the 4 week clinical trial time frame.
- 63% of individuals experience improvements in skin redness
- 50% of individuals experienced improvement in hyperpigmentation
- 67% of individuals experienced improvement in skin tone
- Greater than 70% of individuals noticed at least one “antiaging” benefits after using the serum
Dr Blass has also amassed a wealth of data supporting the promise of targeting brain aging with orally delivered Resveratrol-Glucose-Malate (RGM). This includes positive clinical trial data on the safety of RGM in individuals with mild to moderate Alzheimer’s disease. This is relevant data for the safety of RGA as it is similar in formulation to RGM, albeit topically delivered. Overall, RGA (and its derivatives) have a promising, systemic safety profile with no significant side effects. This bodes well for its potential application in rejuvenating other areas of the skin, hair and beyond.
“The positive results many people are seeing in the rejuvenating effects of IDEO’s Skin Memory Serum™ is only a taste of the youth and beauty we hope to restore to the minds of those who currently suffer from age-related brain diseases.”
IDEO Skincare is currently focused on increasing revenue through ecommerce and retail sale of its skin memory serum. In this vein, the company is working on expanding its sales to Europe and other locations throughout the US. IDEO Skincare is also working on developing different vehicles and formulation of RMA to target and rejuvenate different regions of the skin. The company plans to release its RMA Skin Memory moisturiser in the first quarter of 2023.
The founders of IDEO Skincare plan to iterate on the current RMA formulation to extend its reach beyond antiaging skincare. This includes applications for healing scars, burns and for hair regrowth. The company’s ultimate mission is to raise enough awareness, interest and funding to optimise the RMA formulation to target and reverse Alzheimer’s disease. IDEO Skincare is actively seeking funding and partners to make this new line of research and development a reality.
IDEO Skincare’s skin memory serum is a high-end cosmetic product that is targeted towards a wide range of individuals across the whole gamut of skin aging. This includes everyone from individuals invested in maintaining their youthful skin to those seeking skin rejuvenation.
Channels to market
IDEO Skincare currently sells its Skin Memory Serum through its e-commerce store as well as its luxury and clean beauty retail partner Shen Beauty. IDEO Skincare also has a contract with a top-rated television shopping platform, the name of which cannot be disclosed at this point in time, but which should premiere in Q4. The team plans to raise further awareness and sales through the publication of a book chronicling Dr Blass’s extensive experience as a neurologist, including his revolutionary insights for reversing brain aging and achieving skin rejuvenation.
Team and Reputation
Key Team Members:
Dr John Blass MD, PhD – Co-founder. Award winning neurologist, clinical psychiatrist and Alzheimer’s disease research specialist. Dr Blass has been a maverick within the field of Alzheimer’s research. His research is helping to initiate a paradigm shift that transforms the scientific field’s understanding of the etiology and treatment of Alzheimer’s disease. Dr Blass has published hundreds of scientific papers in his extensive career and held leadership positions of national prominence in aging and brain research journals and scientific committees.
Gitte Blass – Co-founder. Wife of Dr John Blass, Gitte’s support of Dr Blass over 61 years of marriage helped make the great strides of his hard-working career possible, all the way up until the launch of the skincare line, which she leaned on him for years to develop and produce while he was deeply engrossed in brain research. Her drive kept the promise of the cosmetic line running until IDEO was founded and finally flourished under the leadership of Andrew Shemin, whom she brought on as CEO. Born in Copenhagen, Gitte’s honesty and transparency and determination to make her husband’s work a gift to all people, is the beating heart of IDEO’s brand.
Andrew Shemin – CEO and co-founder. Andrew translates his entrepreneurial experience as a producer and director from the world of film and fashion to launch the IDEO brand with a focus on storytelling about beauty and science with the prestige of luxury branding. His vision and tenacity, developed in previous creative projects, here brings IDEO from brain science to beauty and back again to an unfinished investigation of treating the aging brain, that will build upon Dr Blass’s vision, reaching far into the future.
“We believe in honest Science”
The IDEO Skincare team is intent on practicing honest science. The cosmetics field is filled with charlatans, snake oil, as well as individuals and companies that place revenue above all else. IDEO Skincare’s core values revolve around “Real science and real results that are not inflated”. By conducting science in this way, IDEO Skincare seeks to form a deeper connection and cultivate trust with its customers and partners. They have experienced both the anecdotal and scientifically validated results from its RMA complex (and its derivatives) and fully believe in its immense potential for achieving rejuvenation of the skin – and beyond.
Aging biology is complex and full of nuances. By practising rigorous science and being transparent about results, the IDEO Skincare team believes that they will be better informed to continuously optimise the formulation, delivery and efficacy of their product. In this way, it will continue making a tangible difference on a wide range of individuals within varying skin aging demographics.
IDEO Skincare’s funding resources are undisclosed
LADIÈRE is a Franco-Swiss brand that is revolutionising the world of cosmetics thanks to its solutions to improve health and longevity of the skin. Founded in 2019, LADIÈRE specialises in biotechnology and cellular research solutions linked to age-related skin problems. In collaboration with the Buck Institute for Research on Aging and Seneque Laboratories, LADIÈRE has developed its first skincare treatment “RENAISSANCE”, with a focus on the aging skin process. LADIÈRE believes cellular research and nature, are, together, the best and most efficient solution for skin-related problematics. Thanks to a seven-year research partnership with the Buck Institute for Research on Aging and the Sénèque laboratory, LADIÈRE can integrate cutting-edge technologies in cell science and longevity research into its formulations.
Stress, pollution and UV exposure are just a few examples of the aggressions suffered by the skin and the cause of its premature aging. As it is often difficult to find truly effective antiaging products, LADIÈRE has developed a unique ritual of 3 premium age defying treatments to improve skin firmness and maintain its health. The 3 products are the most advanced longevity skincare solutions the ritual name “RENAISSANCE” and include:
The products contain a signature active ingredient, NMN which is an essential molecule for cell longevity. With this unique ingredient combined to glacier water from the Titlis known for their rich minerality and purity, LADIÈRE has patented a unique patented proprietary formulation called the NADO +COMPLEX®. This revolutionary NADO+ COMPLEX® not only enhances complexion, but deeply revitalises and regenerates the skin cells, ensuring visible results within 32 days of application and are reinforced in the long term.
LADIÈRE is the world first and only cosmetic skincare brand to include this novel longevity molecule in a skin formulation. It also meets the most stringent European standards for approval and quality testing for a NAD+ booster in skincare. The product is over 92% natural, and all formulas are guaranteed to be free of endocrine disruptors, nanoparticles, parabens, mineral oils, silicones, sulfates, aluminum salts and dyes. On products scan apps, products obtained an excellent score.
Flagship Product Deep Dive: LADIÈRE RENAISSANCE
The LADIÈRE Renaissance ritual is a set of 3 complementary skincare products designed to treat the visible signs of aging on the face and décolleté. The 3 products consist of:
Premium and highly effective, the LADIÈRE Renaissance ritual combines the most advanced research on cell longevity with the best of Swiss nature.
The combination of these 3 treatments reduces the appearance of all types of wrinkles (age, expression, dehydration) as well as dark circles and puffiness.
The NADO+COMPLEX®, is a world-exclusive technological innovation and the star ingredient of the LADIÈRE Renaissance range
It combines the natural molecule – NMN – a derivative of vitamin B3 and trace elements from Swiss Titlis glacier water.
Together, they fight the visible signs of aging by:
Thanks to these formulas, LADIÈRE products can prevent skin aging and revitalise aged skin. With regular use, the results of NADO+ Complex® are increasingly visible:
- The degenerating senescent cells disappear.
- The stem cells, responsible for the daily regeneration of the layers of the epidermis are boosted.
- Aging is delayed and the skin regains its original health.
The application of these treatments is also recommended to prevent the first signs of aging.
NMN is short for nicotinamide mononucleotide, a form of vitamin B3 found naturally in all living organisms. Every day, the body uses NMN to produce the NAD+ that every organism needs to survive.
The epidermis is completely renewed every 28 to 31 days, which is why it is important to fuel its metabolism. NAD+, a molecule naturally present in all living cells, allows this stimulation.
Unfortunately, past 25 years of age, the availability of NAD + start to decrease and the skin gradually loses its ability to regenerate in depth. Its elasticity, texture and firmness weaken over time. By introducing a NAD+ precursor – NMN – into products, this accelerated aging phenomenon can be interrupted. NADO+COMPLEX® is the most effective innovation to date to stimulate natural skin rejuvenation.
Seneque has developed the purest form of NMN, called NMN-C that has been elaborated thanks to a proprietary process of production that is the only GMP (pharmaceutical grade) form available on the market (worldwide).
Water from the Titlis glaciers
Water from the Titlis glaciers is a concentrate of trace elements, antioxidants and anti-inflammatories. Combined with NMN, this combination becomes an exceptional antiaging active ingredient, concentrated in hydration and protection.
A Sensory Experience
Beyond its benefits on skin health, the LADIÈRE Renaissance ritual has been designed and formulated as a sensory experience, both soothing and invigorating, where efficiency and pleasure are one.
The choice of natural olfactory components provides a fragrance with a relaxing virtue. The fresh, soft and light textures provide an invigorating sensation.
Taking care of your skin with the LADIÈRE Renaissance ritual, with daily application, morning and evening, becomes a pure moment of well-being, like that experienced in a high-end institute or spa.
These benefits are confirmed by our users (1):
- 95% appreciated the smell of the range
- 90% attested to the rapid absorption of the care products
- 90% approved the texture of the range
(1) User test panel, self-assessment, % satisfaction
Evidence of safety and efficacy
LADIÈRE has done 11 clinical trials to date double blind versus placebo in Europe, China and the United States. These clinical trials were carried out on more than 50 volunteers of all skin types and all skin tones. The studies highlighted the benefits of the exclusive LADIÈRE Renaissance formulations on the health of the skin from 7 to 56 days of use.
LADIÈRE products respect the most stringent European standards for approval and quality testing for a NAD+ booster in skincare (EC No. 1223/2009 and ISO 22716:2007).
LADIÈRE is targeted for 35-65 years old women and men. Age related skin problems impact everyone after 25 years old, this equated to >50 million people.
Channels to market
LADIÈRE mainly focuses on a direct to consumer (D to C) approach through their E-shop www.ladiere.com, as well as through:
- High-end retailers in France, Switzerland and US
- High-end specialised e-shops
- Retail trials in high-end cosmetic drugstores in France
- Retail trials in boutique hotels and 5-star hotels in France
- Support of relevant influencers
Team and Reputation
Key Team Members:
ERIC VERDIN, MD Chair, Seneque Scientific Advisory Board President, Buck Institute for Research on Aging
DR ALESSIA GROZIO Chief Scientist, Seneque Scientific Advisory Board Biochemist, Buck Institute for Research on
DR ALEJANDRO OCAMPO Advisor, Seneque Scientific Advisory Board and Assistant Professor at the University of Lausanne.
LADIÈRE also have a marketing and sales team of 7 specialists.
LADIÈRE has a Dedicated educational content strategy to promote understanding and knowledge of the product.
There are four main pillar that make LADIÈRE unique:
- Scientific partner with the Buck Institute for Research on Aging
- 11 Clinical trials performed by a state-of-the-art CRO in France with outstanding results
- Over 90% of natural ingredients
- World first and only cosmetic skincare brand to include a novel longevity molecule to skincare products – NMN
Currently, LADIÈRE (supported by Seneque Laboratories) has received a commitment of US$ 50 million.
Mitra Bio, founded in 2020, is developing a platform that provides actionable insights into the skin’s genetics and epigenetics with the goal of powering skin longevity.
Mitra Bio has non-invasive skin sampling technique together with unique epigenetic biomarkers to track skin aging directly on human volunteers (not on skin models or animals as it is today)
The biomarkers identify the impact of rejuvenation therapies on skin’s own cellular aging. This powers the development of skin rejuvenation compounds that target the root cause of aging not just the symptoms (wrinkles)
We are transforming skincare by approaching aging as a disease to be fought – Mitra Bio
Mitra Bio was created by Dr Shakiba Kaveh and Dr Cristiana Banila. Dr Shakiba Kaveh worked at a large skincare company where she first saw the efforts being made to create personalised skincare by extracting insights from individual skin. She has a PhD in Materials Science from Cambridge University. Dr Cristiana Banila studied Biochemistry at Oxford and Princeton. As part of her PhD, she developed a non-invasive molecular tool to replace pap-smears based on epigenetics biomarkers, a tool currently in trial by the NHS. Combining Dr Shakiba Kaveh’s experience in the skincare industry and Dr Cristina Banila’s knowledge of developing diagnostic tools, Mitra Bio was founded. Bringing together domain insight from skincare and the epigenetics know-how to disrupt the market, Mitra Bio’s aim was to build a tool that skincare companies can use to develop efficient and effective antiaging skincare products.
The global antiaging market is estimated to be worth $49.93 billion in 2022 (“Anti-Aging Global Market Report 2022”, 2022) while the global skincare products market was worth $148 billion in 2020 with a projected growth reaching $189 billion by 2026 (“Global Skin Care Products Market Report and Forecast 2022-2027”, 2022) . These trends demonstrate a clear interest and growth trajectory for both markets. Nonetheless, at present skincare and antiaging products simply target the signs of aging without targeting the root cause at a cellular level. This is largely due to the lack of comprehensive understanding of what causes cellular aging of the skin, a lack of ways of qualifying skin aging and lack of non-invasive skin sampling techniques which have limited research in this area. There is also lack of data from multiple skin ethnicities and how different skin tones react to the environment. Most clinical trials are performed on white skin. Mitra Bio hopes to overcome some of these obstacles by developing non-invasive skin sampling tools that provide insight into skin aging inclusive of all skin types and can facilitate the development of real effective skincare products that target skin aging at cellular level.
Skin has been disregarded in many longevity studies. The goal of Mitra Bio is to fight skin aging like a disease and power personalised rejuvenation solutions for the individual skin types. By using multi-omics with a focus on epigenetics biomarkers, Mitra Bio can gain the necessary insights to understand skin aging and understand its interaction with lifestyle choices, the environment and topical/edible supplements. The combination of non-invasive sampling technology and proprietary biomarkers gives Mitra Bio a quick way to gauge the effectiveness of antiaging compounds. This reduces the time to market of compounds as it could take years with currently available tools.
On top of that, Mitra Bio’s biomarker database will drive a revolution in the discovery of new effective antiaging compounds. By using the platform researchers will turn genetic and epigenetic biomarker data derived from skin-patches, into actionable insights for progress. By deeply understanding aging, Mitra Bio’s partners will be able to develop the next generation of skincare products that target the root causes of aging, not just the wrinkles.
Furthermore, Mitra Bio is adamant in that the use of in vitro skin models or animal models are not enough in the discovery of antiaging compounds. Instead, Mitra Bio approach is to use of non-invasive skin sampling methods to extract epigenetics biomarkers from volunteer’s skin at scale. Through on-going clinical trials with different skincare companies, Mitra Bio can build a proprietary database of biomarkers encompassing all skin types. This enables Mitra to guide the design of new compounds using in vivo insights from the human skin and its interaction with the environment without having to rely on the more unreliable insights provided by in vitro studies and animal models.
Flagship Product Deep Dive: Mitra Bio
Blood or saliva samples will never give accurate indications of skin health, and this is one of the reasons why Mitra Bio wanted to use a different approach. Mitra Bio is the only company that uses non-invasive skin sampling to read skin’s biological age, UV damage and other skin health metrics based on epigenetic signatures.
As an Illumina’s portfolio start-up, Mitra Bio had access to state-of-the-art laboratory facilities that enabled Mitra Bio to optimise sample collection and to preform deep sequencing on over 300 skin samples. Mitra Bio performed whole genome sequencing, reading all 28 million CpG sites compared with only 850,000 CpG sites which is the industry’s norm, and this led to the identification of unique biomarkers specific to skin types, skin age, effects of menopause and UV exposure.
Now, Mitra Bio has proprietary biomarkers which can quantify healthy skin and predict accelerated aging of skin based on the interactions with the environment. This enables the company to identify efficacious compounds that can make molecular improvements in the skin during in vivo trials. All without the need of taking a skin biopsy as Mitra Bio can take samples from human skin painlessly, quickly and cheaply.
Mitra Bio is involved in strategic clinical trials to understand the effects of the environment on the skin.
Evidence of safety and efficacy
Mitra Bio is conducting clinical trials in collaboration with skincare companies that are at the forefront of developing longevity skincare. The outcome will be published in the near future.
Skincare consumers are leaning towards science-backed and ingredient-led skincare products. In a recent report published by Deloitte, skincare efficacy was ranked the top factor driving skincare purchases above even sales promotions.
The future of skincare is gearing towards a medicinal approach where a skin diagnosis can inform a more efficacious solution for the individual skin. It is forecasted that this approach will double the size of skincare market to $400 billion. This is only enabled by getting real data from the skin.
Channels to market
Mitra Bio is working with the top skincare brands and manufacturers via B2B research collaboration.
Mitra Bio will also be launching their B2C membership in 2023.
Team and Reputation
Mitra Bio is a great example of founder-led biotech movement. The founders come from complementary backgrounds.
Shakiba Kaveh (CEO) worked at a skincare company, having witnessed first-hand the importance of data-driven approach for skincare development. Shakiba worked 5 years as a management consultant advising companies on their operations and route to profitability.
Cristiana Banila (CSO) is an epigenetics scientist who developed non-invasive diagnostics test for early cancer detection. Cristiana understands exactly how to power clinical trial claims with data. The founders are applying the latest development in the epigenetics field to power development of longevity skincare products to disrupt the skincare market. This is enabled by their data-driven approach to inform performance of actives in the skin rejuvenation.
Key scientific advisors:
Advisors include professionals who had top position at leading skincare companies, established academics experienced in machine learning as well as dermatologists who are keen to innovate the industry.
Mitra Bio is the first and only company to have a skin-based epigenetics testing to infer biological aging and other age-related biomarkers. The aging clocks built using saliva or blood cannot inform of molecular changes that specifically happen in skin. Epigenetics is tissue specific and cannot be inferred using other tissues. Mitra Bio is analysing epigenetics by bypassing the use of invasive biopsies.
The company has raised a total of £1.1M from private and non-dilutive funding. Notable investors include Illumina, Entrepreneur First, First-in Ventures, Innovate UK Biomedical Catalyst as well as private angels. Mitra was also part of the Oxford University accelerator (Oxford Foundry)
Aging reinvented: “Aging is inevitable, how you age is not”
OneSkin is a San Francisco based company that is catalyzing a paradigm shift within the cosmetic’s industry by targeting a root cause of aging within the skin, thereby rejuvenating it from the inside out. In this way, skin doesn’t just look healthier, it functions like younger skin on a cellular and molecular level. This is enabled by a cutting edge and proprietary R&D platform that is used to develop, validate and optimise novel longevity molecules that prevent and rejuvenate damages that drive the process of biological aging.
Founded in 2016, OneSkin’s origins began with four female scientists within a doctoral lab in Brazil that were united by a common passion: to liberate biotechnology insights from the confines of the academic setting and instantiate them in the real world. In doing so, OneSkin’s central mission is to alleviate age-related suffering by developing technologies that can reverse the aging process. With this mission in place, they decided to start with the largest organ in the body and most accessible target in the longevity market, the skin. This marked the beginning of a journey to transform the way humans experience aging, so that they could age in a healthy and vibrant way and live their best lives, every day.
“We are not a skincare company, we are a skin longevity company”
In an effort to truly characterise the state of the cosmetics market, the founders started their journey by developing biological age assays to validate existing antiaging products. From this process, they learned that most products targeted and/or concealed symptoms of skin aging and not its underlying, cellular and molecular drivers – the hallmarks of aging. This was OneSkin’s “call to action”, to transform the status quo “skincare approach” into a strategy that encapsulated true skin longevity.
There are several hallmarks of aging that are viable targets to improve skin health. For the founders of Oneskin, one hallmark of aging stuck out above the rest as a candidate for achieving rejuvenation – cellular senescence. This is due to its profound influence on skin aging and potential to spread inflammation and damage throughout the body like “wildfire”. As such, senescent skin cells have been alleged to accelerate biological aging and are implicated in driving chronic diseases such as cardiovascular disease, diabetes and Alzheimer’s.
This spurred OneSkin to develop its proprietary screening platform to identify novel peptides that effectively target and neutralise senescent skin cells, a class of molecules called senotherapeutics. This led to the discovery of the senotherapeutic peptide OS-01, which OneSkin subsequently incorporated into a “first of its kind” line of topical supplements designed to extend skin health (i.e. skin-span) on the molecular level by targeting cellular senescence. The company’s current pipeline includes:
- OS-01 Face Topical Supplement
- OS-01 Body Topical Supplement
The field of senotherapeutics is still young and most data is confined within the lab or lengthy clinical trials. OneSkin is the first and only company using senotherapeutics within the aesthetic field. This puts them in the unique position to collect data en masse and translate their insights to not only other skin zones, but other organ systems of the body and chronic diseases of aging.
“Science First Approach”
One of the core tenets of OneSkin is its “science first” approach. The company operates end-to-end R&D in-house with a team of experts in stem cell biology, skin regeneration, tissue engineering, biochemistry, bioinformatics, molecular biology, immunology and aging. Their proprietary technology and lab process includes growing 3D human skin (from cells derived from skin biopsies) weekly and measuring how various compounds influence skin aging and longevity at the molecular and cellular level. This results in data driven products that evolve with the fast pace of biotechnology and are rooted in the scientific process. Further, its customers are connected to every step of the process and new piece of data that arises. Ultimately, OneSkin seeks to use its scientific rigour and senotherapeutic approach to help power its pipeline and empower its customers to take control of their aging trajectory.
“We believe the best antiaging treatment is one that is rooted in science, with data-backed claims. That’s why our topical products go beyond placing a metaphorical band-aid on aging skin – it addresses the molecular changes associated with aging to not only boost skin health, but overall health as well’
Flagship Product Deep Dive: OneSkin’s OS-01 Face and Body
“Enhancing Skinspan with Senotherapeutics”
OneSkin coined the term “skinspan”, which refers to the length of time that an individual’s skin is healthy and functional. But those are just surface level attributes that can be temporarily maintained while the deeper, molecular damages of biological aging accrue and ultimately result in disease. Therefore, truly healthy skinspan is driven by youthful cellular and molecular functioning of the skin. Cellular senescence is one of the most insidious drivers of biological aging due to its self-perpetuating, systemic effects. Targeting senescence with senotherapeutics is one of the few longevity interventions that have been shown to achieve systemic rejuvenation in multiple animal studies.
Cellular Senescence – a programmatic shift that is initiated when cells accumulate damage past a certain “threshold” that is characterised by an inability to divide, death resistance and the secretion of factors (called SASP) that drive inflammation, degrade extracellular matrix proteins and induce further senescence in neighbouring tissues.
Unlike other skincare products that offer short-term solutions (and might even cause long-term damage), OneSkin’s mission is to extend skinspan by addressing skin aging at a grass-roots level. This is accomplished with its topical senotherapeutic peptide OS-01, which targets those cells that are most vulnerable to cellular senescence and have the greatest impact on skin aging.
“The power of OneSkin’s proprietary platform technology and process”
OneSkin’s patented senotherapeutic peptide OS-01 wasn’t just stumbled upon, it was identified and optimised via an extremely rigorous screening process that involved:
First, OneSkin’s R&D team used computational algorithms to build a library of over 800 novel peptides predicted to have substantial senotherapeutic properties. Each peptide was then evaluated for its effectiveness at reducing the amount of senescent cells within 3D human skin models. From this process, OS-01 shined above the rest at reducing cellular senescence in the skin without inducing toxic effects. Not only that, OS-01 demonstrates unique capabilities as a senotherapeutic by targeting key genes involved in longevity signaling and the suppression of SASP factors. In doing so, OS-01 not only neutralises the inflammatory and aging effects of senescent cells and suppresses their “self-propagating” effects, but it also enhances damage repair to prevent senescence in the first place. A two-in-one prevention / rejuvenation strategy.
Working in harmony with its “Science first” tenet, OneSkin went on to evaluate OS-01 for its ability to reduce the biological age of the skin in a sample set of 40-70 year old donors. This was done through a comprehensive array of skin health diagnostics, including the construction of the very first biological age clock for the skin called MolClock. The clock was constructed using machine learning to analyze over 500 human skin samples and 2000 DNA methylation (DNAm) markers to detect important epigenetic alterations that occur as skin ages. The result was a highly accurate skin biological age diagnostic that could predict the molecular age of someone’s skin more robustly than any other diagnostic tool in existence. OS-01 reduced the skin’s biological age by 2.5 years after only 5 days of treatment and significantly improved other skin health markers including epidermal thickness, cellular repair and collagen production. Improvements in skin health were observed even relative to retinol and rapamycin treatment, the gold standards for “antiaging” treatments within the cosmetic and pharmaceutical realms, respectively.
OS-01 Face and OS-01 Body
The different skin zones of the human body feel, behave, react and age differently. Therefore, they have very different characteristics and needs. OneSkin has appreciated the depth of these nuances by developing two, personalised topical supplements: OS-01 Face and OS-01 Body. Each of its products are specifically formulated for different areas of the skin but are both powered by their proprietary senotherapeutic peptide.
OS-01 Face was formulated for areas of the skin that are thinner, more delicate and most vulnerable to damage from environmental stressors (UV radiation, air pollution, &c) – including the face, hands and neck. Accordingly, this formulation includes a higher concentration of OS-01 to boost cellular repair, while also keeping the formula light and non-irritating. Supporting ingredients were chosen for their additional damage repair, barrier enhancement and hydration properties. This includes hyaluronic acid and andiroba oil which support cellular repair and regenerative capabilities of the skin.
OS-01 Body was formulated for all other areas of the skin that are typically more robust, less exposed to environmental stressors and follow a different aging trajectory. The concentration of OS-01 was optimised for skin penetration and to support the relative levels of cellular repair required for the rest of the body. Supporting ingredients, such as sulforaphane, have powerful anti-inflammatory and antioxidant effects that help combat the damages caused by intrinsic skin aging. Further, prebiotics (Saccharid Isomerate) are included to support the health of the skin microbiome on those areas of the skin. This level of personalisation between OneSkin’s products is a testament to the quality of its scientific rigour and expertise.
Evidence of safety and efficacy
Scientific evidence in support of efficacy and safety
“Beauty” does not have to be painful or complicated; neither does aging. We believe what we put on our skin should be safe, effective and contribute to maximising our human potential.
The longevity scientist’s at OneSkin have applied vigorous scientific rigour and exacting standards into formulating the safest, most effective topical formulations possible that are vegan and cruelty free and include safe and clean ingredients. OneSkin’s formulations even take into account avoiding disturbing the skin microbiome, a factor that is a blindspot for many companies within the skin health space. The safety of OneSkin’s products is demonstrated by the stellar performance of OS-01 Face on the Environmental Working Group’s safety scale and cosmetic database. Further OS-01 Face was tested for human sensitisation and toxicology in clinical studies and was found to have no adverse effects.
In addition to the safety studies performed by the company, OneSkin has currently completed 1 clinical trial for its OS-01 Topical face product and another clinical trial is underway and should wrap up this year. The completed trial was a 12 week clinical study (conducted by a 3rd party CRO) on 22 females aged between 47 and 65 years with dry, normal and combination skin types.
This trial showed that twice daily application of OS-01 Face provided remarkable visual and functional benefits based on blinded clinical evaluations as well as self-report assessments. This includes improved skin barrier function, hydration, evenness, pores, radiance, firmness, increased skin elasticity, fewer wrinkles and improved overall smoothness and appearance.
A second clinical trial with OS-01 Face is still ongoing and will assess biological age (using MolClock) in individuals using the product over the course of a year. The trial is set to complete by Q3 2022. OneSkin is also executing a third clinical trial which will test the efficacy of OS-01 Body topical cream on addressing whole body skin aging in 60-80 year old individuals. Aside from classic phenotypes of skin aging (wrinkles, elasticity, smoothness), outcome measures from this trial will also include measuring plasma levels of various inflammatory markers including IL-6, IL-8 and IL-1 alpha – all of which are indicative of chronic inflammation, are markers of senescent cell burden and drive diseases such as osteoarthritis, IBS and Alzheimer’s disease. This trial is set to run for 3 months, involve approximately 70 participants and will be critical for demonstrating how OneSkin’s OS-01 topical creams mitigate overall, systemic biological aging.
One key takeaway from OneSkin’s clinical trials is that daily application of OS-01 topical creams are required to promote skin longevity and healthy skinspan. Rather than providing a quick fix or temporary relief, OneSkin promotes long-term skin care and health. As such, most users start seeing healthier, stronger and better-looking skin in 4-8 weeks with daily use.
“Some people want to buy us, but OneSkin is not for sale”
OneSkin is currently closing a successful round of Series A funding and is steadfast in its mission to transform the cosmetics and longevity industry with its powerful senotherapeutic powered pipeline. Accordingly, the OneSkin founders have no plans for big exits. Rather, they are focusing on growing the team to help with operational responsibilities and expanding partnerships to include dermatologists, health professionals,and other companies making “big waves” in the longevity field with their powerful aging diagnostics including Mitra Biosciences. This and other partnerships which are still under negotiation will provide great value in strengthening OneSkin’s product pipeline as well as their sustainability as leaders in the forefront of both the cosmetic and longevity fields.
OneSkin’s cutting edge R&D platform and process is one of their strongest assets. It keeps them ahead of the competition by providing them with the ability and agility to continuously test, iterate and optimise previous senotherapeutic products as well as discover novel skin longevity compounds and create new formulations. OneSkin completely owns and meticulously oversees its whole supply chain from research and development, to formulation and validation. There are only two steps the company outsources. One is clinical trial testing, which lends further credence to the quality of their results and elimination of scientific bias. The second is production, but the company keeps a close eye on product quality.
OneSkin also plans to expand its R&D to optimise its OS-01 senotherapeutic to target hair loss as senescent cells are a primary driver of hair aging. OneSkin’s expansion into other areas of aesthetic health is a harbinger for future applications to address diseases that affect other tissues such as the brain, kidneys, gut and muscles.
Currently, OneSkin is focused on optimising commercialisation (packaging, sustainability, eco-friendliness) and adding international shipping options for their products.
OneSkin is targeted for a range of individuals starting from people in their early 30s (and beyond) as this is when individuals start seeing changes in skin age biological markers and their products hold promise to be a critical factor in a skin aging preventative strategy. As OneSkin’s preclinical and clinical results are mostly demonstrated in older demographics, it is also primed to help elderly individuals seeking skin rejuvenation.
Channels to market
OneSkin mainly focuses on a direct to consumer (DTC) approach through their E-shop https://www.oneskin.co/collections/all. The company also operates an extensive partner program with certified skincare and health professionals at the forefront of advanced skincare technology and science in areas such as longevity, aesthetics and holistic health. OneSkin plans to further expand its reach to dermatologists before entering the retail market.
Team and Reputation
Key Team Members:
OneSkin is a product of the IndieBio startup accelerator and backed by Peter Diamandis. The company currently has 10 employees.
Peter Diamandis MD – Advisory Board member. Founder and executive chairman of the XPRIZE foundation and Singularity University. Recently named by Fortune as one of the “World’s 50 Greatest Leaders”.
Lear Brace PhD – Director of Research and Development. Harvard University graduate studies and Postdoctoral Research Fellow in Brian Kennedy lab, Buck Institute for Research on Aging
Carolina Reis Oliveira PhD – co-founder and CEO. Biotechnology entrepreneur and Alumnus of IndieBio, the world’s leading biotechnology accelerator
Alessandra Zonari PhD – co-founder and CSO. Training in stem cell biology, skin regeneration and tissue engineering. Co-inventor of 7 patents and has published in 20 peer-reviewed papers in scientific journals.
Mariana Boroni PhD – co-founder and Head of Bioinformatics. Head of Bioinformatics and Computational Biology Lab at the Brazilian National Cancer Institute. Co-inventor of 7 patents and has published in more than 35 peer-reviewed papers in scientific journals. Juliana Carvalho PhD – co-founder. Trained in molecular biology, biochemistry and immunology. Professor of Pathology and Faculty of Medicine at the University of Brasilia. Co-inventor of 10 patents and has published in 50 peer-reviewed papers in scientific journals.
“We want to be transparent about our developmental process, and we want to empower people to take action about their health. We want to demonstrate a warmth and approachability for our customers, but never forget it’s all about the science!”
OneSkin boasts a strong team of female leaders and scientists that supplement each other with their diverse backgrounds. There are several components of OneSkin’s strategy that makes it unique as an Advanced Aesthetic’s company:
- They are the first company to target aesthetic health with topical senotherapeutics
- They have created the very first biological aging clock that is specifically for the skin and can be used to screen and validate longevity enhancing compounds
- They use state-of-the-art laboratory models to generate preclinical data, including 3D culturing of skin cells from fresh, human biopsies. This offers an unprecedented level of personalisation and data collection
- The OneSkin founders pride themselves in creating educational content that addresses skin health, aging and overall longevity. OneSkin’s connection and dedication to their customer’s go even deeper than this, as their “customer family” is consistently updated on preclinical results fresh from the lab as well as results from completed clinical trials. This data is presented in a way that helps their customers make key health decisions as well as engage and motivate them to optimise their longevity regimens.
- OneSkin’s dedication to democratising longevity goes beyond the individual human, as they are also concerned with the longevity of the planet. This is reflected by their partnerships with Zero Carbon and efforts to use environmentally friendly, green and sustainable packaging and distribution. “We are committed to environmental sustainability and protecting the planet. We constantly aim to reduce our environmental impact while creating cutting-edge, scientifically formulated topical supplements that improve the health, appearance and vitality of the skin”
As of July 2022, OneSkin has raised a total of US$ 13.3 million from two investment rounds.
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