Longevity: the definitive definition

Defining longevity isn’t straightforward; to get there we must negotiate its determinants, drivers and diseases.

If you ask someone what the definition of longevity is, I can guarantee you will get a range of different answers everything from healthspan through to longevity escape velocity.

If you review much of mainstream media, you may be convinced that longevity is just for the super-rich. If you ask an actuary, they will define it as an individual’s life expectancy based on calculations and statistical modelling.

And if you ask Alex Zhavoronkov, CEO of Insilico Medicine (which we have) he will reply: “It’s easy! Everything that increases the healthy productive lifespan is a longevity business.”

Longevity.Technology: There are many theories as to the processes and drivers of aging, but not one has been identified as the main cause. What is agreed, however, is that aging is plastic (flexible) and is a balance between ‘quality control systems’ that maintain the integrity of our cells and the effects of ‘wear and tear’.

As such aging, as a process, is not fixed to the pace of chronological time; it can speed up or slow down. At some point, internal programming and wear and tear may result in disease, easily illustrated by the sheer number of pathologies and diseases that have a strong association with age.

As interest in longevity grows in the research, investment, clinical, policy making, and consumer communities – it is increasingly important that longevity is defined and its definition locked-down.

The Longevity.Technology team has been developing its thesis during 2022 and it’s time to share!

The path to longevity is complicated and intertwined. To be able to understand longevity, we must modulate the longevity trajectory, which we have defined using three targets: longevity determinants, aging drivers and aging disease.

The longevity trajectory – three targets

  • Longevity determinants – longevity is determined by three main factors: genetics, environment and lifestyle. These three factors influence aging drivers by either programming or inducing damage.
  • Aging drivers – molecular drivers that are impacted by longevity determinants include IGF-1,  Sirtuins, mTOR, FOXO, AMPK, and the hallmarks of aging. As each driver is linked to another, they begin to drive biological age higher.
  • Aging disease – any disease phenotypes that have a strong link to aging like cardiovascular disease, atherosclerosis, sarcopnenia, or Alzheimer’s disease. This means the manifestation of the disease has been driven by an accumulation of damage and programming driven by longevity determinants and aging drivers.

Internal damage and programming and external damage might finally manifest as an aging disease that can impact any of our organ systems:

Through our analysis, it is clear that every company in the longevity industry is based around these three targets and aims to modulate the trajectory by prevention, diagnostic, renewal or treatment. These are the four pillars of longevity intervention.

Longevity intervention – the four pillars

1. Prevention – prevent damage that accelerates aging and modify longevity determinants and aging drivers.

2. Diagnostics – early identification of health status and accumulation of aging damage. Diagnostics span across longevity determinants, aging drivers and at the point of aging disease.

3. Treatment – treatment of damage that has occurred. This means direct treatment of an aging disease.

4. Renewal – reversal of damage that has occurred. This includes either accumulated damage before disease has arisen, damage arising from aging drivers, or that which occurs at the point of disease.

Next stop: longevity domains

Out of these four pillars there begin to form market clusters. We have termed these market clusters longevity domains, and our market intelligence unit is continually analysing (and adding to) over 500 longevity-specific companies that are categorised across these domains. The resulting datasets we are building identify the technology readiness and investment traction these companies are making – this gives us a unique advantage to identify serious longevity companies and help them build relationships with investors.

Longevity domains are popular market clusters that are frequently used to view the different domains in the longevity industry.

Longevity genetics the study of longevity genes is a developing science. It is estimated that about 25% of the variation in human lifespan is determined by genetics, but which genes, and how they contribute to longevity, is not well understood. Longevity genetic companies are on a mission to identify these genes and develop gene therapies that facilitate a longer life.

Longevity diagnostics – by tracking what is happening intrinsically within our bodies as we age, or monitoring our exposure to longevity determinants, longevity diagnostics have the potential to promote a healthier aging process through early detection and tracking of improvements – metabolic age is a key indicator for both healthspan and lifespan.

Longevity functional foods – the concept of “functional food” was introduced in Japan during the Eighties and refers to natural or processed foods that can exert beneficial properties on health, being able to improve a specific physiological function or reduce the risk of contracting a disease – these are growing in popularity as food conglomerates realise the benefits of marketing longevity-boosting food ingredients.

Longevity supplements longevity supplements haven’t been designed to just top-up nutrients missing from your diet. Companies in this space are deriving potent natural substances to target aging pathways or longevity determinants to improve healthspan at any age. Therapeutic supplements are a future cross-over with pharmaceuticals – they have emerging evidence of efficacy in tackling diseases including cancer.

Longevity clinics with so much work going into the research and science behind longevity, it’s easy to forget what is happening on the front line. Longevity clinics are a first step in implementing longevity science at the point of care and, in many respects, are the missing link in the longevity supply chain. A number of initiatives are underway to scale-up accredited training in longevity for certified physicians.

Senotherapeutics senotherapeutics encompasses a range of different methods when addressing senescence including senolytics, senomodulators, senoblockers and senescence-associated immunomodulators. Each method comes with its own opportunities and challenges and ultimately could be used in combination to tackle cellular senescence (a phenomenon characterised by the cessation of cell division).

Reproductive longevity companies that are tackling infertility and menopause by modulating aging drivers of reproductive organ aging. The potential to delay menopause to better align with the increasing healthspan of women is a growing part of the longevity economy.

Advanced aesthetics advanced aesthetics (AA) are therapeutics and technologies that preserve and/or rejuvenate the parts of our body that we associate with vitality and beauty. This essentially means skin and hair, but what makes AAs differ from cosmetics is that they go beyond merely concealing the by-products of the aging process (wrinkles, hair loss, skin discoloration, etc.) to address the root longevity driver that gives rise to the skin/hair aging phenotypes.

Companion longevity there are many reasons why working on aging interventions in dogs makes sense. Not only is it heartening to believe that our four-legged best friends could live longer, healthier, and happier lives, but they are also a much more relevant model when it comes to translating these effects in humans – we share the same homes and are exposed to the same environment.

Longevity discovery platforms – drug discovery is a long, expensive and often unsuccessful process. Platform technologies are considered a valuable tool to improve efficiency and quality in drug product development. There are many companies in the longevity space that are developing proprietary discovery platforms to enable the discovery of therapeutic targets for longevity.

Longevity drugs the longevity pharmacology field promises to revolutionise the healthcare of a growing aging population. A longevity drug is any novel molecule that was designed or discovered to specifically act on a longevity gene/pathway (rapalogs, pgc1-activators, sirtuin modulators, etc.).

Inflammaging efficient immune defence mechanisms play an important role in the extension of an organism’s lifespan and the absence of diseases. Immunological studies have shown that centenarians exhibit important differences in their immune systems when compared with other elderly persons between the ages of 65 and above. Longevity immunity companies target the immune system directly to modulate and improve longevity.

Metabolic rejuvenation inhibition of high-nutrient-sensing pathways (for example, the insulin-like growth factor [IGF] and mechanistic target of rapamycin [mTOR] pathways) and activation of low-nutrient-sensing proteins (for example, 5′ AMP-activated protein kinase [AMPK] and sirtuins) extend lifespan in various model organisms. Companies that are interested in metabolic rejuvenation study diet-based interventions, such as dietary restriction, and pharmacological interventions, including the mTOR inhibitor rapamycin, to improve aspects of aging, even when administered later in life.

Longevity microbiome increasing evidence suggests that the gut microbiome could contribute to many age-associated changes, including immune system dysregulation and susceptibility to diseases. The gut microbiota undergoes extensive changes across the lifespan, and age-related processes may influence the gut microbiota and its related metabolic alterations.

Longevity neurotech neurotech offers a unique solution in the face of an aging population, and the associated rise in neurological conditions, because it can improve detection and diagnosis of conditions, facilitate their treatment and maybe even provide a solution for their prevention. Neurotech can help us monitor the impact of our lifestyles and environments on our brain health and can also play a key role in aiding our understanding of pathology – not only early detection of pathology through better screening, but modifying neuronal activity diseases’ early stages to halt their progression and prevent manifestation of symptoms.

Rejuvenation rejuvenation has many definitions in the longevity industry. Arguably, anything that reduces the biological age of a cell, organ or person is “rejuvenating”. Longevity.Technology has made rejuvenation a distinct category from reprogramming and regeneration, although both will technically rejuvenate cells and systems. Rejuvenation in this context is anything that takes the contents of a cell to a younger state due to intracellular clearance or rejuvenation of organelles within the cell.

Cellular reprogramming any company that is aiming to reverse an older cell into a younger cell state by directly reprogramming its code, its genetic or epigenetic makeup. Cellular reprogramming by Yamanaka factors (OSKM) can reprogram somatic cells into induced pluripotent stem (iPS) cells even from an elderly 82-year-old donor. However, this came with therapeutic hazards as the technique involved complete dedifferentiation. There are companies that are aiming to find new genetic targets to reduce the epigenetic age whilst maintain the cells’ somatic identity (partial cellular reprogramming).

Repurposed Drugs various medications that have already been designed, and approved, to treat particular pathological conditions have gone on to show pro-longevity effects in different experimental models. Among them, there are many commonly used prescription and over-the-counter pharmaceuticals such as metformin, rapamycin, aspirin, statins, melatonin, vitamin antioxidants, etc.. Various longevity companies are investigating these compounds in preclinical and clinical trials to repurpose them for extension of human healthspan.

Young Blood emerging evidence suggests that the body co-opts the circulatory system to coordinate aging via the secretion of factors called chronokines. Chronokines can be “progeronic factors” or “youth factors” that accelerate aging or rejuvenate systems, respectively. Most companies developing therapeutics are looking for chronokines in the plasma of the blood to rejuvenate entire systems.

Regeneration: All living organisms have some ability to regenerate as part of natural processes to maintain tissues and organs. Regeneration is the natural process of replacing or restoring damaged or missing cells, tissues, organs, and even entire body parts to full function in plants and animals. Stem cells play an important role in regeneration because they can develop into many different cell types in the body, even producing entire tissues. Longevity companies are aiming to replace entire organs through methods such as xenotransplantation or tissue engineering.

Longevity neuropharma even in the absence of disease, many of us experience some deterioration of brain function as we age, such as a decline in memory, and age is the most important risk factor for the most common neurodegenerative diseases. Hence at Longevity.Technology, we include treatment of the deterioration of the brain as a significant part of longevity. Longevity neuropharma is the developing drugs on the nervous system, aiming to develop compounds to benefit the most common age-related neurodegenerative diseases.

Aging in place part of longevity is being able to manage an unhealthy aging population so that they can be monitored to prevent progression of diseases. Agetech companies are developing technologies such as wearables, sensors, apps that improves the lives of biologically older adults. Longevity.Technology draw-the-line at aging in place and consider care home technologies etc. as effectively ‘too late’ to be considered within the longevity economy.

Longevity platforms companies that have been founded to propel the longevity industry forward by creating knowledge websites, funds or accelerators (Longevity.Technology is one, there are others emerging as longevity becomes more mainstream) – others wrap-in clinical development and support services such as Juvenescence, Cambrian, and Life Biosciences.

Longevity contract research services these are contact research organisations that are developing model organisms, cell types or assays for companies that are investigating longevity.

Longevity education with aging science and technology evolving ever more quickly, there is a huge amount of knowledge and understanding that also needs to be shared beyond the longevity community. The goal of today’s emerging longevity education providers is to enable healthcare providers to learn more about the status and future of the longevity field.

Three company examples

Here are examples of three companies to show how we are categorising them.

Dorian Therapeutics
Target: Aging driver
Pillar: Renewal
Domain: Senotherapeutics

Dorian Therapeutics is a pre-clinical Silicon Valley biotech focused on developing treatments that counteract aging in degenerative diseases and during cellular therapy. Dorian’s innovative therapeutics, called senoblockers, inhibit the process of cellular senescence while activating the regenerative capacity of tissues.

ChromaDex
Target: Aging driver
Pillar: Prevention
Domain: Longevity supplements

ChromaDex Corp is a bioscience company dedicated to healthy aging. The ChromaDex team is engaged in research on nicotinamide adenine dinucleotide (NAD+), levels of which decline with age. The company is the innovator behind NAD+ precursor nicotinamide riboside (NR), on shelves as the flagship ingredient Niagen. Nicotinamide riboside and other NAD+ precursors are protected by ChromaDex’s patent portfolio. It delivers Niagen as the sole active ingredient in its consumer product namely, Tru Niagen.

Loyal
Target: Aging driver
Pillar: Prevention
Domain: Companion longevity, Rejuvenation

Loyal is formed from a team of veterinarians, scientists, and dog lovers devoted to developing medicines intended to treat the underlying causes of aging in dogs. Loyal is researching and developing several drugs that target various cellular processes hypothesised to be relevant to dog aging.

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