It took more than eight decades since the landmark experiments on calorie restrictions in 1930th to get to a point when the first wave of new anti-aging drugs have begun human testing. This first generation of longevity therapeutics, including senolytics, rapamycin, mitochondrial gene therapy, and WNT pathway regulators among others, are not directly targeting ageing (yet), rather they aim to treat specific ailments by slowing or reversing a fundamental process of aging. However, the rate of progress in this area allows for some constructive optimism towards being able to actually expand the healthy lifespan in the foreseeable future.
Over the last decade, and especially after the 2013 landmark paper “The Hallmarks of Aging”, published in Cell, the area of anti-ageing research has been booming in many directions -- from senolytics discovery, to drug repurposing, stem cells, genomics, discovery of biomarkers of aging (“aging clocks’) and more. At the beginning of 2020, MIT Technology Review selected anti-aging drugs for their list of 10 Breakthrough Technologies 2020.
The anti-aging drug discovery startup ecosystem is in its early days now, with only a little above one hundred emerging companies -- largely at the preclinical stage of development. At the moment, there is no one FDA-approved treatment to specifically slow or revert aging, but a few candidates have made it to phase 3 clinical trials. Venture capital investments into longevity-focused companies have been growing over the last few years and will probably keep that trend up -- until the inflection point when the first anti-aging drug is approved for the market. At that moment of going “from zero to one” the longevity industry will explode with investments and acquisition deals. Already today some longevity-focused companies achieved striking funding levels and multi-billion dollar valuations (e.g. Samumed).
The below chart summarizes some notable companies across the so-called “hallmarks of aging” classification framework -- specific mechanisms believed to be the key drivers of body deterioration over years. Those include the four primary hallmarks, precursors of damage: genomic instability, telomere attrition, epigenetic alterations, and loss of proteostasis. They catalyze a series of responses to damage -- antagonistic hallmarks: deregulated nutrient sensing, mitochondrial dysfunction, and cellular senescence. Finally, the integrative hallmarks appear to be the culprits of the phenotype: stem cell exhaustion, and altered intercellular communication.
Stem cells and aging research
Samumed is one of the few companies that currently have anti-aging drugs in Phase III clinical trials. The most advanced program in their pipeline is for cartilage regeneration and osteoarthritis treatment. Osteoarthritis is an age-related disease, as well as many others, caused by deterioration and malfunctioning of molecular pathways and tissue degeneration. Samumed’s treatment approach is designed to force stem cells (through WNT pathway) to perform as they usually do in healthy conditions regardless of the body part where they reside.
Samumed is strikingly well-funded, having raised more than $658M (disclosed rounds A and B), and with a valuation of $12 billion as of 2018.
A notable company in the area of age-related stem cell reprogramming Agex Therapeutics, one of the daughter companies of BioTime. Earlier this year they published a paper, where they were able to reprogram centenarian cells of a 114 years old woman to pluripotency. Additionally, Agex Therapeutics’ preclinical pipeline consists of cell-based therapeutic candidates to cope with cardiac ischemia and age-related metabolic disorders, and drug-based candidates to restore regenerative potential of aged tissues afflicted with degenerative disease. At this moment, the startup attracted $63.8M of total funding.
Tackling mitochondrial dysfunction
The mitochondrial theory of aging is one of the most elaborated hypotheses: by producing energy for cells, mitochondria may become a source of leakage and production of ROS (reactive oxygen species), which damages the cell and mitochondrial DNA.
One of the strategies to combat mitochondrial aging is to protect mitochondrial DNA by expressing it in the nucleus. A therapy exploiting this idea was created by GenSight Biologics to cure Leber hereditary optic neuropathy (lhon), which causes blindness. Despite this genetic disease affecting predominantly young adult males, the approach to treat this disease might be a good model to treat aging-related loss of vision, as the disease causes loss of retinal cells. Success of GenSight‘s therapies was covered in The Economist.
Another example of a drug in phase 3 clinical trials is SkQ1, developed by Mitotech. This drug is created to treat dry eye disease by protecting the eye from oxidative stress.
One of the reasons for the dysfunctions connected with age-related diseases is senescence, a phenomenon that occurs when senescent (“zombie”) cells are accumulating in the body. These cells are not dead and not alive, can cause inflammation and interfere with neighboring healthy cells, disrupting their normal activity.
Recently, a number of biotech startups emerged with a focus on the idea of tackling senescence, including Unity Therapeutics, backed by Jeff Bezos among other investors. Albeit, their senolytic (drug removing senescent cells) candidate previously failed to reduce pain in osteoarthritis, the company has another promising candidate in the pipeline. The drug UBX1325 targets protein in the Bcl-xL pathway on which senescent cells rely to survive.
Another way to get rid of senescent cells is to develop therapeutics antibodies as senolytics. The only company that leverages this approach is Velabs Therapeutics start-up from Heidelberg. Despite the first drug candidate to reach clinical trials could take about 5 years, the advantage of antibody therapies is the possibility to target senescent cells without harming healthy ones. However, an important milestone for such therapies would be discovering precise surface biomarkers.
The rise of longevity biomarkers
Being able to reliably measure the biological age of organs, tissues, and ultimately the whole body is an essential need for any aging research project and the longevity industry in general -- because the dynamics of change in the biological aging process (acceleration or deceleration) is the most comprehensive and illustrative biomarker relevant to measuring effects of anti-aging therapeutics, lifestyles, diets, and environmental factors. Another important role of aging biomarkers is understanding aging as a phenomenon. Multiple data types can be used to predict age and associate the prediction with mortality, disease, general wellbeing, or other biological processes including methylation, biochemical parameters of the blood, gene expression, microbiome, imaging data, and so on.
Currently more than a dozen types of “aging clocks” exist, with some of them exploiting methylation profile data, such as Horvath's clocks and Hannum’s age predictor. Recent advances have been made by Deep Longevity, which developed what they claim to be the most accurate epigenetic clocks for today -- DeepMAge. The company also released a new achievement - psychological aging clocks, both technologies are powered by deep learning-based algorithms developed by the company. Whereas with epigenetic clocks they manage to create algorithms superior to its analogs, psychological clocks will allow uncovering the aspect of aging that previously was largely understudied.
Anti-aging drug discovery is becoming an increasingly crowded space, but there are several fundamental bottlenecks in the way of progress. First of all, aging itself is not yet classified as a disease by FDA and other regulatory agencies -- and until then, there is a lack of context and regulatory support for such research. Second, biomarkers of aging are not yet accepted as clinical trial endpoints, making it hard to assess the effects of specific age-related therapeutics or therapies, and benchmark different products or interventions. Finally, there is work to be done in terms of building better preclinical models for age-related drug discovery, where it could be possible to track and study the effects of the anti-aging drug candidates and therapies.
It is expected that the above issues are going to be addressed in the coming years, driven by the growing popularity and relevance of geroscience, increasing consensus among scientists, and more breakthroughs in areas such as gene editing, stem cells, and senescence with specific practical results to be demonstrated. There is an opinion that the anti-aging market could surpass $271 billion by 2024.