By David Polinsky, founder and chairman, and Rivka Szafranski, CEO, ClinicalTrials.Co
In 1993, Cynthia Kenyon, Ph.D., a molecular biologist at the University of California, San Francisco, triggered an explosion in aging research when she doubled the lifespan of C. elegans, a tiny, soil-dwelling roundworm, by partially disabling a single gene, the daf-2 gene. Not only did the treated worms live longer, but they were also more resistant to stress and disease and were smoother and more youthful looking than the untreated worms, which were feeble and wrinkled.
Years later, Kenyon would describe her feelings when she learned that the treated worms had remained young: “You think, ‘Oh my God, they should be dead.’ It was like finding something that shouldn't be. It makes your hair stand up." Then she described her follow-up realization: "'Wow. Maybe I could be that long-lived worm.'" Until Kenyon’s experiment, aging biology was considered a scientific backwater. The assumption was that there was nothing to study — you just wear out. But Kenyon changed all that. Suddenly science was faced with the eye-opening idea that aging is subject to modification.
Recruiting Older Adults For Clinical Trials Of Anti-Aging Drugs
The result of the explosion of aging research triggered by Kenyon’s discovery is the development of hundreds of new investigational anti-aging drugs, sometimes called gerotherapeutics, to increase health span, or the period of life spent in good health, and maybe even life expectancy. Though the field of gerotherapeutics is still in its infancy — no drug has yet been approved to prolong health span or lifespan — the need for elderly subjects to participate in clinical trials is expected to increase as these drugs move through the development pipeline.
“As with all drugs, the pivotal step for any gerotherapeutic will be undertaking high quality clinical trials that prove clinical efficacy and acceptable safety, and comply with international regulatory guidelines,” wrote Nir Barzelai, MD, the leader of a major anti-aging trial (see below) and David G. Le Couteur, Ph.D., in a recent paper.
While recruiting subjects for clinical trials of gerotherapeutics would seem to be easy — after all, who doesn’t want a longer, healthier life? — it isn’t that simple. The public is largely unaware of recent advances in anti-aging research and, even if they were, they wouldn’t know where to turn for information. A 2021 study conducted by the Center for Information and Study on Clinical Research Participation (CISCRP), a nonprofit dedicated to educating the public and patients about clinical research, found that more than 40 percent of interviewees didn’t recall ever having read or heard about a trial looking for volunteers. The only broad-based information source on clinical trials is the government website clinicaltrials.gov, whose hundreds of thousands of trials are typically described in scientific language. Furthermore, the anti-aging field is rife with scammers offering untested and unproven remedies.
Nor is it easy for clinical trial professionals to find subjects. Not only are older adults significantly underrepresented in clinical trials to begin with, trials involving anti-aging drugs pose special challenges because they typically seek exceptionally healthy subjects. The exclusion criteria often include long lists of morbidities and prescribed medications — a problem when most older Americans suffer from multiple diseases. As for medications, one in three older Americans takes five or more prescription drugs, which can cause side effects that could cloud trial results by interacting with one another or with the study medication. Indeed, recruiting older subjects is such a challenge that the National Institute on Aging and the Centers for Disease Control have joined with others in an initiative called Recruiting Older Adults into Research to improve older adults’ knowledge about clinical research and to promote participation.
Anti-Aging Isn’t Superficial — It’s Foundational To Understanding Age-Related Biological Processes
Modern medicine, in part, has been remarkably successful at prolonging lifespan — the average life expectancy of Americans has increased by nearly 30 years since 1900 — from about 47 to 76 years or more. But it has been less successful at increasing health span. Two-thirds of older Americans suffer from multiple age-related degenerative diseases, a situation that carries enormous costs in healthcare burden, human suffering, and quality of life. (The question of whether maximum lifespan can be increased is still hotly debated; the human with the oldest documented age is Jeanne Calment of France, who died in 1997 at the age of 122.)
As a result of recent research, however, science is now recognizing that age-related degenerative diseases such as Alzheimer’s, some cancers, ischemic heart disease, ischemic stroke, and obstructive pulmonary disease are regulated to some degree by the same genetic pathways that govern aging. This has opened the door to the development of gerotherapeutics that, by addressing the biological processes underlying aging, also prevent the onset of age-related degenerative diseases. The idea that a.) the biological processes of aging are the greatest risk factors for the chronic diseases and disabilities of old age and b.) by intervening in these processes, the onset of age-related diseases and conditions can be delayed or their severity can be mitigated is called the geroscience hypothesis.
Gerotherapeutics Needs The Backing Of The FDA
While biotech and pharmaceutical companies are moving full speed ahead on the development of gerotherapeutics, regulatory agencies have yet to catch up. Drugs are approved by the FDA for specific indications. Since aging hasn’t been designated by the FDA as an indication, no clear regulatory path exists for approval of drugs that target aging. To address this obstacle, the American Federation for Aging Research (AFAR), with FDA approval, has launched the TAME (Targeting Aging with Metformin) Trial under the direction of Barzelai (see above), director of the Institute for Aging Research at the Albert Einstein College of Medicine and AFAR’s scientific director. The trial, which is the first to address aging as an indication, will study the anti-aging effects of metformin, a drug that has been used to treat type-2 diabetes for more than 60 years and was used as an herbal remedy for centuries before that. Interest in the gerotherapeutic potential of metformin was triggered by a 2014 study of diabetes patients that found that — much to researchers’ surprise — diabetics taking metformin not only lived longer than those who weren’t taking it, they lived longer than healthy matched controls. Metformin has subsequently been found to have beneficial effects on many of the hallmarks of biological aging.
While metformin isn’t the brightest star in the gerotherapeutic firmament — its anti-aging effects are believed to be fairly modest — its track record, safety, and low cost make it well suited for use as a tool to achieve the primary goal of the TAME trial, which is to serve as a proof of concept for the FDA’s designation of aging as an indication that can be modified by drug treatment. Since longitudinal studies of human lifespan aren’t practical because of the time it takes for a human to age, the TAME trial will use the onset in non-diabetic subjects of major age-related diseases and conditions such as cancer, cardiovascular disease, and cognitive decline, as well as mortality, as surrogates for aging. Plans call for the double-blind, placebo-controlled trial to recruit more than 3,000 subjects between the ages of 65 and 79 in a series of six-year trials at 14 leading research institutions across the country. An adjunct of the larger trial, TAME BIO, has been proposed to develop biomarkers to evaluate the efficacy of anti-aging interventions from samples such as blood, serum, urine, or DNA.
Targeting The Diseases Of Aging
If the paradigm-shifting TAME trial establishes aging as an indication, it will open the floodgates of pharmaceutical industry interest and investment. Meanwhile, those on the leading edge aren’t waiting around. Dozens of biotech companies are working on new gerotherapeutics, including Google, whose Calico R&D venture (where Kenyon is now vice president of aging research) aims to “better understand the biology that controls aging and lifespan,” according to its website. To get around the indication hurdle, they are positioning gerotherapeutics as treatments for specific age-related diseases and conditions such as Alzheimer’s or cardiovascular disease. Once aging has been designated as an indication by the FDA, they will move to deploy gerotherapeutics as a preventive solution. Cambrian BioPharma, for example, states on its website that its approach “is to develop interventions that treat specific diseases first, then deploy them as preventative medicines to improve overall quality of life during aging.”
The result of this whirlwind of research activity is, at present, a maturing pipeline of investigational drugs targeting specific age-related diseases — and, for the future, the aging process itself. All of this will create demand for participation in clinical trials by older adults, especially healthy older adults. Resources for subjects interested in gerotherapeutic drug trials, and for the companies seeking to bring these drugs to market, are limited, but options include online databases like Clinical Trial Guide. As a review on the business of anti-aging science in Trends in Biotechnology concluded: “Anti-aging biotech [is] … risky” — but added, “if one company is successful the outcomes [will be] monumental.”
About The Authors:
David Polinsky is the founder of Clinical Trial Guide and is committed to helping those suffering with major unmet clinical needs. Having spent over 20 years in the pharmaceutical industry, Polinsky founded Clinical Trial Guide to help those seeking information not otherwise readily available.
Rivka Szafranski is the CEO of Clinical Trial Guide. She is a lifelong project manager and a biotech enthusiast and strives to create a better world by building resources for patients and their families. Szafranski has a master’s degree in biotechnology management and entrepreneurship from the Katz School at Yeshiva University and previously worked in business development for both profit and nonprofit companies.