Will 2020 be the year that sees a step change in Longevity? We review technology readiness levels for key Longevity domains.

Yep, we have a lot to thank NASA for: freeze-dried food, cochlear implants and TRL scores.
The Technology Readiness Level system was developed by NASA in 1974 to help categorise the stage of a project so that it either wasn’t ignored or wasn’t taken too seriously, too early.

For a domain that’s so wide, it would be very easy to answer both ‘yes’ and ‘no’ to the above question depending on your focus. Either way, the sector is coalescing nicely and activity is set to grow significantly over the coming 12 months.

Here’s how we’ve applied TRLs to the Longevity technologies we address:

While we are now getting to grips with the factors that drive aging and the biomarkers that measure age (and if age is being halted or reversed), there is still a long way to go until there is a widely-available therapy that’s proven to increase lifespan: 20 years away according to SENS’ Dr Aubrey de Grey.

AgeX Therapeutics’ Dr Michael West told us last year: ”We now know enough about aging that we can design new products that we believe will have an unprecedented impact on aging … it is now a routine procedure to reverse the aging of human cells in the laboratory dish.”

So while we detect a maturing of the argument and a toning-down of the 1000 year lifespan rhetoric, there is growing confidence from both the research and the investment communities into the sciences of lifespan and healthspan.

There are now over 100 companies dedicated to research and product development in the fields of senolytics, telomeres, stem cells, mitochondria and gene editing: These are the domains from where genuine therapies that increase lifespan will emerge. 

However, at Longevity.Technology we consider Longevity in a wider context – this is why we’re just as interested in technologies such as neural, biocybernetics and nano – these are the technologies that will sustain healthspan and lifespan while anti-aging therapies pass through the clinical pipeline into commercial availability. An app that nudges you to eat more wisely and exercise more often is just as relevant to Longevity as a replacement heart grown in a pig.

So as we enter a new decade, here’s our take on the TRLs for each of our key Longevity domains:

Tissue/Organ

Biocybernetics is still emerging as a sector, with pancreatic technologies being the most progressed in terms of closed-loop systems to deliver insulin for type 1 diabetics – artificial hearts and lungs are expensive, risky and a long way from scalability. Dr Peter Scott-Morgan, who has motor neurone disease is transitioning his body toward a fully cyber version of himself as he loses movement in his body except for his eyes. So with the exception of the pancreas, we score Biocybernetics’ Longevity TRL as a 4.

Organ growth as a concept, growing a new heart from personalised stem cells is a long way off, but smaller organs, organoids are gaining traction. Organoids are three-dimensional bundles of cells grown in culture in a lab.

Derived from stem cells, the organoid cells possess an incredible ability to organise themselves into tissue structures, meaning researchers have been able grow a whole range of tissues and mini-organs, including kidney, pancreas, liver, prostate and even brain tissue. LyGenesis’ lead program in liver regeneration will begin with a Phase 2a clinical trial for patients with end stage liver disease in 2020.

The company recently raised $4 million in private financing of convertible notes and we’re expecting a significant Series B this year. We’re excited about organoids’ contribution to Longevity but the diverse range of R&D activity scores this TRL as a 3. 

Xenotransplantation is the use of animal tissue and organs in humans – the technique requires the marrying gene editing techniques with superior transplant protocols. A burns unit at Massachusetts General Hospital recently became the first ever to use pathogen-free swine tissue to close the wound of a burns patient; the “skin” used in the successful transplantation was Xeno-Skin, the first product from XenoTherapeutics, a Boston-based regenerative medicine company.

So after a series of failures in the early 2000s Xenotransplanation is fighting back with some big clinical and financial swings: Scientists in Beijing have created pig-monkey chimeras that looked like regular piglets but inside they contained monkey cells and are particularly significant as it is the first time that monkey-pig chimeras have been brought to full term. The gene editing technology company eGenesis, announced it has raised $100 million towards advancing its xenotransplantation into clinical testing and support its other programs in organs such as livers, hearts and lungs. We score Xenotransplantation’s TRL at 3.

3D Bio-printing splits across 2 domains: the 3D printing of organ/tissue repairs and organs-on-a-chip which are synthetic emulation of an actual organ for use in lab research. In the former, organ and tissue creation, the big challenge now is vascularisation (connecting to the printed organ/part to an active blood supply), which will be followed by innervation (connecting to the printed organ/part to the nervous system).

Wyss Institute and Harvard researchers have overcome this significant obstacle by 3D-printing vascular channels into living matrices made from stem-cell-derived organ building blocks. For organ-on-a-chip pharma giant AstraZeneca is partnering with Canadian company Novoheart to create the first of a kind ‘heart in a jar’ model.

This is a very interesting development of organ-on-a-chip (OOC) technology which is a multi-channel 3D microfluidic cell culture chip that simulates the activities, mechanics and physiological response of entire organs and organ systems, effectively a type of artificial organ. The market is projected to reach $220m by 2025. Currently both areas are in vitro which scores this TRL as a 3.

Nano

Diagnostic tools delivered at nano-scale are emerging. Our vocabulary: replicated on a chip; could help; and step-nearer – demonstrates that we consider Longevity applications for nano diagnosis early-stage. A team of researchers at the Centre of Research on Adaptive Nanostructures and Nanodevices (CRANN) at Trinity College Dublin has found a way to use a single drop of blood to tell if a patient is at a risk of bleeding or thrombotic risk. Early detection saves lives, this process will form part of regular routine screening, meaning it would have a real impact on lifespan and healthspan – picking up cancers, bleed susceptibility as well as thrombosis risk. Exciting stuff, but still very early stage so a TRL of 2.

Micro-surgery at the one millionth of a millimetre scale with robots that can manipulate individual cells is, surprisingly, not new. Some designed and built over the last 20 years by Professor Yu Sun’s lab at the University of Toronto have been used in a number of helpful procedures like in-vitro fertilisation and personalised diagnosis. However, we haven’t seen anywhere near industrial level nano yet, but there are promising developments:

Researchers at Northwestern University in Illinois and the University of California in San Diego have developed peptide-based gels that flow freely through blood and hone in on unhealthy cardiac tissue that upon arrival at their target site are bio-activated to form a structure to catalyse healing. Current R&D activity scores this TRL as a 3. 

Targeted delivery nanobots will ultimately be programmed to repair aged or diseased cells on an individual basis, mimicking and enhancing our immune system and natural healing processes. Not yet though, however, we recently covered NaNotics’ breakthrough in nanotech – clever NaNots that use geometry, rather than biochemistry, to distinguish between soluble and membrane forms of T Cell inhibitors – an approach that will work on nearly every pathogenic target.

In Israel, a team has found a way to deliver the neural growth factor directly in the brain (having crossed the tricky blood-brain-barrier) using nanoscale silicon chips. In animal studies the chip was able to slow-release the required protein over a month-long period directly to the target area in the brain; once it had delivered its payload, the chip broke down harmlessly in the brain and dissolved. Early days but a TRL of 4 from us.

Senescence

Senolytic drugs are coming, but the road ahead will be bumpy. Senescent cells accumulate with age and contribute to degenerative disease, despite their many beneficial roles earlier in life. “Senolytics to selectively destroy lingering senescent cells continue to show great promise in animal models, and as a class of therapy appear about as close to a panacea as it is possible to be,” according to Reason of FightAging.

“A great deal of research is ongoing into the biochemistry of cellular senescence, not least because any particular mechanism might turn out to be the basis for therapies that meaningfully turn back aging – there is a little of the element of a gold rush to the work.” In a 2019 landmark trial, researchers from the Mayo clinic demonstrated (for the first time in humans) that senolytic drugs can remove senescent cells from the body. But don’t go popping any pills just yet – Senolytics scientists aren’t sure of their long term effects on the body. TRL 4. 

Telomeres help protect the genetic material inside the DNA. As we age telomeres shorten with each cell division until they cannot divide anymore. The longer the telomere length, the longer the lifespan. Believing that telomeres hold the key to a treatment for aging, US company Libella has developed a therapy to express the enzyme telomerase in humans – the company is running (in Colombia) the world’s most expensive pay-to-play trial with a $1 million price tag to enrol. The aim is to lengthen telomeres and, therefore, treat aging. However, there is still debate surrounding whether the shortening of telomeres is a direct cause of aging, or simply a measure of the aging process in the same way as a loss of hair pigment, for example. The early R&D stage scores this TRL as a 2. 

Cellular

Stem cell therapy is the use of stem cells to treat or prevent a disease or condition. Bone marrow transplant is the most widely used stem-cell therapy, but some therapies derived from umbilical cord blood are also in use. In terms of Longevity, with current knowledge of stem cells, it is feasible to design and test interventions that delay aging and improve both health and lifespan.

Forever Labs freezes and stores people’s stem cells as a kind of back-up drive for their future selves. Pluripotent stem cells are capable of becoming any cell in the body: Induced Pluripotent Stem Cells (iPS) are “reprogrammed” or “induced” to retrace their developmental age and regain the potential to form all of the young cell and tissue types of the body. In 2019 AgeX Therapeutics and Lineage Cell Therapeutics were awarded a US patent for ‘Method of Generating Induced Pluripotent Stem Cells’. A way to go in terms of a scalable Longevity therapy but very promising TRL of 2.

Mitochondria are clearly important in the progression of aging but how they relate to the underlying molecular damage of aging remains a question – if and how they can be controlled to support anti-aging therapy remains unanswered, but many are searching.

Animal studies and human trials continue, as does the more fundamental research into the biochemistry of NAD+ in mitochondria. Dr Nir Barzilai is close to funding his TAME trial which will track the off-patent drug Metformin’s support for life extension, which includes mitochondrial analysis.The SENS Research Foundation team continues to work on allotopic expression of mitochondrial genes as a way to prevent certain forms of mitochondrial DNA damage from causing cells to become pathological. The early R&D stage scores this TRL as a 2.

Gene editing has received plenty of media coverage thanks to CRISPR babies and Chinese prison sentences. CRISPR gene therapy has enormous potential in the field of delaying senescence and providing a cure for genetic and age-related illnesses. This is an exciting field of emerging technology for investors.

Researchers have developed a novel and more powerful form of CRISPR (Prime) that offers the possibility to correct most disease-causing genetic variations in DNA – new hope for the treatment of age-related disorders? Given the early stage of trials, much more work is needed to establish effectiveness and potential side effects before any claims can be made in the field of Longevity. TRL 2.

Drugs

Development of a drug therapy that extends life is summarised by much of the work in senolytics, telomeres, stem cells, mitochondria and gene editing. It would be possible to simply TRL score the domain with a ‘1’: Preliminary idea with well characterised theoretical case; however, there is much work in the space with over 100 well-funded companies working towards using these techniques to both cure disease as well as slow-down or halt aging. An aggregate TRL score delivers a theoretical 2.4, so with a weighting of journalistic optimism, we currently score the development of a life extension drug with a TRL of 3.

Clinical trials of a drug therapies that extend life are (technically) most drug trials – if a drug is being tested that reduces hair loss, it’s not Longevity; if a drug is being trialled to cure breast cancer, then of course it affects the recipients’ lifespan and could classify as Longevity. But, this is effectively the line of demarcation between Longevity and Healthcare. So, the progress of drugs in clinical trials that treat aging as a disease is the focus. Of the 120+ companies designated as developing Longevity therapies, 68 are pre-clinical, while only 3 are at Phase 3 clinical trials.  Tempered with journalistic pragmatism: TRL 3.

Indication expansion is the use of approved (therefore TRL 10), and often off-patent, drugs in Longevity applications. Metformin and Rapamycin are the best known in this category – the former is a medicine to treat type 2 diabetes and is being used in the 2020+ TAME trial to see if it does actually treat the diseases of aging; the latter is drug that prevents organ transplant rejection – it also slows Alzheimer’s in rats.

Not all drugs are off-patent; a new drug known as ISRIB, which reverses Down’s Syndrome memory deficits in mice, has been licensed to Google’s Calico for aging research. Rituximab is a drug for the treatment of lymphomas, leukaemia and some autoimmune disorders; doctors figured out through observation that if a stroke victim is on rituximab, their chance of having dementia is lower.

Indication expansion is both fascinating, but risky in terms of prescribing a drug for a condition the patient doesn’t have. Many are also still at animal study stage, however, the safety data and approvals are in place, so we’re scoring the domain of indication expansion at TRL 5.

AI

Diagnosis using AI is an exciting field and the diagnostic performance of deep learning models to be equivalent to that of health-care professionals is definitely in the ‘it’s gonna’ get there’ category. In the UK, the first systematic review and meta-analysis programme found that artificial intelligence (AI) is just as good at diagnosing a disease based on a medical image as healthcare professionals.

However, a major finding of the review is that few studies presented externally validated results or compared the performance of deep learning models and healthcare professionals using the same sample. The trajectory makes AI diagnosis a very exciting field with more development necessary, particularly beyond medical imaging. AI applications will require certification so we score the sector overall as being at TRL 7.

Intervention via AI monitoring systems is bridging the devices and software domains. We consider these AI intervention applications to be outside of the clinic and used by individuals being managed by monitoring systems that trigger alerts and interventions within machine-learned parameters that are personalised to the the individual.

The ECG technology on the Apple Watch Series 4 uses electrodes to capture heart rhythm irregularities and has been approved by the FDA and we’ve seen Biofourmis create an AI digital health biomarker that can predict heart failure 14 days prior to an incident – this is now in trials on the Apple platform. The amount of R&D and trials in this space scores a TRL of 6.

Digital health as an AI application delivered via a mobile device to support Longevity is coming. There will be a surge in apps that use recognised aging biomarkers to track individuals’ health and lifestyle to improve healthspan and lifespan.

Competing within a crowded marketplace will be a challenge and app-fatigue means that participants will need to partner-up with health providers and insurers to achieve the volume of users to succeed. Many apps still fall outside of formal regulatory regimes but practices are tightening-up so we score digital health in the context of Longevity at TRL 6. 

Neural

Neural integration took a big leap forward last year with the release of information from Neuralink with its brain-to-machine interface; the potential in this technology lies in the variety of applications of the new brain chip implant, which could be used not just for daily tasks and entertainment but in enhanced bionics control, enhanced tele-presence and space exploration.

Neuroceuticals (replacing drugs with an algorithm) is an emerging term which we will see more of. Reading neural signals is of course possible, but they’re noisy – so AI is required to tune-out the interference. Likewise, controlling organs and muscles requires neural techniques that are only emerging through approvals. A very exciting field that is set to grow fast, but with many regulatory hurdles: TRL 4.

Singularity in terms of Longevity is the integration of mankind with machines, others interpret the Singularity is the surpassing of human intelligence by machines. We’re focused on the former as we like to stay in control. In his book, ‘The Singularity is Near’ Ray Kurzweil, director of engineering at Google, predicts that “by the 2030s, we will connect our neo-cortex, the part of our brain where we do our thinking, to the cloud”. One-day it may be possible to retire to the cloud without any of those pesky bodily functions and a body to ‘house’ somewhere. Early days, still so a TRL 1.

Agetech

Independent living is something we’re all going to have to get used to. The economics of staying outside of the care system for as long as possible is as relevant to individuals as it is governments. Technologies to support independent living in terms of managing medication, supporting people through early Alzheimer’s and even loneliness are already on the market, but the sector hasn’t exploded yet, and is set for significant growth (Apple, Google, Amazon and the Zigbee Alliance have announced they have decided to “play nice” by working together in a bid to make home technology devices compatible with different smartphones and voice assistants.)

Many of the technologies will fall under less rigorous approvals regimes than medicines so the Agetech sector is ripe for growth as global populations age. The amount of R&D and trials in this space scores a TRL of 6.

Diet and its contribution to wellness is obvious. Our focus is dietary compounds that can be added to food and supplements to mitigate diseases and support longer lifespans and healthspans. Peptides are a key areas for a Longevity diet and Dublin-based Nuritas has developed a peptide in the consumer arena that improves glucose regulation over time;

taken as a drink or a cereal bar, it will help prevent people from moving from pre-diabetes into full-blown diabetes. Data from a Chinese study shows that spermidine increased the lifespan and healthspan across different species such as flies, mice, yeast and nematodes. Eating to live longer is a new area of Longevity development with lower market entry challenges than drugs, so, TRL 5.

Wellness is a very wide subject so we define it as being a derivative of technologies like Age-tech, AI and digital health where devices and platforms will intersect to improve the wellness of an individual.

Recently we interviewed the developers of TrueLoo; these are smart toilet seats that optically scan and analyse the contents of a toilet bowl and, leveraging computer vision and machine learning, can detect dehydration, Urinary Tract Infections (UTIs), gastritis, Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD). Systems to track and maintain wellness will range from AI and VR through to apps to track everything from hearing to loneliness. Many are already in early stage market traction so we score a TRL of 7.