Taming the Diseases of Aging
In pursuit of a global wisdom dividend
By Ivan Amato
A HEALTHSPAN MOONSHOT Delaying the onset of cancer, cardiovascular disease, dementia, frailty, and other diseases and conditions of aging extends the healthspan — the period of life during which people are disease-free, pain-free, and independent. The young field of geroscience, which focuses on the biology of aging, appears to be on the cusp of uncovering interventions that can extend the population’s average healthspan. This could lead to economic benefits estimated to be as much as $7 trillion-dollars over the course of 50 years, as well as more seniors living longer lives for the most part without suffering from diseases of aging.
THE PHILANTHROPY OPPORTUNITY As a new field, geroscience is in need of funding for students and young researchers aiming to join its ranks. In addition, translating scientific discoveries in labs into FDA-approved, healthspan-promoting medicines entails clinical trials that can cost tens of millions of dollars with no guarantee of success. As the portfolio of potential geromedicine agents worthy of clinical trials grows, it will take more resources to make those trials happen.
Earlier this year, Nir Barzilai, head of the Institute for Aging Research at the Albert Einstein College of Medicine in the Bronx, New York, was preparing for an invited trip to Singapore to advise the government about trends in aging and health. He asked the country’s prime minister, Lee Hsien Loong, to send any questions that were of interest to him. One of these stood out. Barzilai says Loong asked if spiking his country’s water supply with metformin, a common diabetes drug with an anecdotal reputation for staving off diseases of aging, was worth considering. “The answer was no,” Barzilai was quick to say. But he also tells The Moonshot Catalog that the question was not entirely crazy. Rather, Barzilai explains, “think how forward looking the government is to ask such a question.”
Often wearing his enthusiasm in plain sight, 63-year-old Nir Barzilai is a prime mover in an accelerating biomedical research and development campaign to extend the healthy years of billions of people and to keep many of them alive and healthy well beyond their hundredth birthday. Imagine a planet within the next few decades rife with many more healthy, independent, and active centenarians who are disease-free, pain-free, and physically and mentally active. Barzilai, who runs his institute’s 40 aging-research laboratories, routinely catches glimpses of this future in the human centenarians and senior rodents that star in his own investigations.
Realizing this vision of a general population that lives healthy longer has become the mission of Barzilai and colleagues in the emerging field of geroscience, a term coined about a dozen years ago by geneticist Gordon Lithgow of the Buck Institute, which is a research center in Novato, California, devoted to the science of aging. “It will be a catastrophe if we do not succeed,” says S. Jay Olshansky, a social scientist and epidemiologist at the University of Illinois at Chicago, who a decade ago coined the term “longevity dividend” to refer to the health and economic benefits of delaying the aging process.
Water sanitation, vaccines, antibiotics, ever-better medical practice, and other public-health advances over the past century have reduced infant and childhood mortality and prolonged the lives of sick and injured adults who otherwise would have died. This accounts for why people today, in developed countries at least, are living 30 years longer on average than their progenitors who were born and living a century ago. But today’s longer-living men and women are also suffering longer with cardiovascular disease, cancer, dementia, frailty, and other diseases and conditions associated with aging. “The time has come for us to take control of our own biology,” Olshansky says. “Instead of dealing with the consequences of aging, let’s modify aging itself. Let’s try to slow the process of aging because to do so would have a cascading effect on every fatal and disabling disease that appears in old age today.”
This is not just another expedition in search of the mythical fountain of youth driven by wishful thinking. This time, the geroscience community contends, the science is in. Researchers over the past few decades have uncovered molecular and cellular bases of the aging process, many of which apply across the animal kingdom, from worms and flies to mice and people. By using drugs to intervene in these fundamental aging processes — among them protein biochemistry gone awry and the accumulations of senescent cells that have stopped dividing but remain alive in tissues where they can act like disease-causing bad apples — it may be possible to stave off the onset of many of the diseases of aging.
HERE’S TO YOUR HEALTH
“We are not talking about having 500-year-old people, but we are talking about people who stay healthy another decade or two relative to what we do now,” explains biologist Steven Austad of the University of Alabama at Birmingham, who also serves as scientific director of the American Federation for Aging Research (AFAR), a grant-giving and advocacy organization in New York City. Rather than pursuing a goal of extending how long people live, Austad stresses, the goal of geroscience is to apply the growing insight into the biology of aging into interventions and practices that extend people’s healthspan. Fellow geroscientist and gerontology physician James Kirkland of the Mayo Clinic in Rochester, Minnesota, defines healthspan as “the period of a life when individuals are able to live independently, free of disease, free of pain, and basically can do what they want to do.”
Extending healthspan so that it coincides as long as possible with overall life span, says Austad, “is one of the signature problems of the 21st century.” People will be living longer, he says, but the driving question is whether “we are going to be living longer in a healthy fashion or are we just going to extend our period of debility?” Every additional year of senior life without one or more of the diseases of aging is a year with less physical, emotional, psychological, medical, and economic costs. Anyone who has taken care of aging and infirmed loved ones has a first-person understanding of this reality.
“We are not talking about having 500-year-old people, but we are talking about people who stay healthy another decade or two relative to what we do now.” — Steven Austad, University of Alabama at Birmingham
One of the most-cited analyses of the health and economic returns to society that delayed aging would bring, published in 2013 in Health Affairs, estimated the economic value derived from longer health on a population scale in the United States would amount to $7.1 trillion over the half-century spanning from 2010 to 2060. That’s more than $140 billion per year. Although taxpayer costs for Social Security and other entitlements for a healthier, longer-living senior population would also grow, the analysis indicates these could be more than offset by other factors. For one, the effect of compressing the diseases of aging into a shorter stretch of time before death would dramatically reduce medical expenses on a national scale.
Beyond health-cost savings in dollars, delayed aging would yield unquantifiable gains in categories like quality of life, the joys of living, and prolonged access to the wisdom that comes with age.
The Health Affairs analysis also states that, “with people staying healthy until a much later age, it might be more feasible to justify raising the eligibility age for public programs for seniors.” That too would reduce the public costs of a generally increased healthspan. “It would allow people to remain in the workplace longer, if they want to,” explains Olshansky, one of the authors of the analysis. “It would allow them to avoid high health costs during their last decade of life. The economic benefits are huge, even for a minor slowdown in aging.”
There are two foundational concepts underlying the healthspan movement and the geroscience that accompanies it. One is that chronological age, the number of years a person has lived, is the single most influential risk factor when it comes to contracting any of the diseases of aging. “About 80% of risk of getting Alzheimer’s disease is chronological age,” Kirkland says. A family history of high blood pressure, high blood sugar, and high cholesterol boosts your risk of having a heart attack by factor of two to four, he says, “but if you are 85 instead of 30, your risk is increased 1000-fold.” What’s more, he adds, “if you get one of these age-related disorders, your time to get the next one is shorter, and then shorter for the next one after that. So older individuals become completely dependent, or you find people with multiple conditions on 10 or 20 drugs.”
Felipe Sierra, director of the Division of Aging Biology at the National Institute of Aging, headquartered in Baltimore, Maryland, argues that only by way of a radical new framework, such as geroscience, will society be able to “avert the incoming health and economic disaster represented by the silver tsunami of population aging.”
A midterm goal for the next few years, he says, is to develop a platform of basic biology, drug development, and clinical studies “to delay the onset of a panel of major diseases as well as conditions [that], while not lethal, rob us of our quality of life.” Among these conditions are urinary incontinence, fatigue, and frailty. “A longer-term goal is to achieve a 5-year delay in the onset of most chronic diseases,” Sierra says.
Geroscientists often talk in terms of “pillars of aging,” each of which represents a fundamental aging process that has become more or less accessible to biomedical interventions that can slow them down, stop them, and sometimes even reverse them. Most of the evidence for these slowdown effects derives from molecular biology and animal studies. However, it’s the accumulating epidemiological and drug-trial data that has geroscientists shifting into a drug-development phase. With fervor they have entered the pharmaceutical startup game, forming venture capital and development firms such as the multi-company hub Life Biosciences (Barzilai is the chief medical advisor) and Unity Biotechnology, which has raised hundreds of millions of dollars and is conducting human clinical trials for an arthritis drug. Other geroscientists have pivoted into opening up nonprofit and advocacy organizations such as AFAR and the new Academy for Health and Lifespan Research. And still others are working to design potentially transformational drug trials, which they hope will convince the U.S. Food and Drug Administration (FDA) to designate aging itself as a medical indicator just as high blood sugar is a druggable indicator for diabetes and declining bone density is a druggable indicator for osteoporosis.
“A longer-term goal is to achieve a 5-year delay in the onset of most chronic diseases ...” — Felipe Sierra, National Institute of Aging
Kirkland organizes his own geroscience thinking around four pillars of aging. One is low-grade inflammation, which in elderly people can smolder in many tissue types and locations associated with chronic diseases. Inflammation in blood vessels associates with atherosclerosis, for example; in the brain, it appears to be linked to Alzheimer’s disease. A second pillar of aging for Kirkland amounts to things going awry inside cells. Misfolded proteins, DNA and chromosomal flaws, and mitochondrial and metabolic problems reside in this pillar of aging. Kirkland’s third pillar encompasses stem and progenitor cells going awry by, for example, failing to replicate or differentiate into specific cell and tissue types. Senescent cells and the tissue damage they can wreak demarcate a fourth pillar of aging for Kirkland, who observes also that the pillars of aging are interlinked. Targeting one pillar genetically or with drugs tends to affect the rest, he says. “It is beginning to look like there are a number of interventions that can delay, prevent, or alleviate multiple age-related diseases and conditions as a group, as opposed to picking them off one at a time,” Kirkland explains.
That view accounts for the name of the healthspan-driven company Unity Biotechnology. It “comes from the idea that [cellular] senescence is perhaps an underlying theme across multiple diseases of aging,” explains Keith Leonard, CEO of the 8-year-old firm based in Brisbane, California. Its osteoarthritis drug candidate, UBX0101, has shown initial promise in a Phase I trial to test its safety. And now Unity is queuing up a second compound, designated UBX1967, for clinical trials against a bevy of eye conditions, including age-related macular degeneration. In earlier phases of development are drug candidates for lung, liver, kidney, and brain-related conditions of aging. “We are a moonshot company in that we are charting a future where one by one these accepted aspects of aging are defeated and we just won’t have to deal with them anymore,” Leonard says.
Geroscience Comes of Age
Austad identifies two facts of life as persuasive signs that an era of increased healthspan is in the offing. First, he says, “we already have a subgroup of people who [naturally] stay healthy to the age of 100 and all we are trying to do is expand that group of people by using some kinds of intervention.” Secondly, he says, almost everyone in his field feels that increasing the healthspan is plausible because of what they have collectively shown is possible in lab animals, especially mice. “We now have dozens and dozens of ways to keep laboratory animals healthy longer,” Austad points out.
Results in animal studies over the last decade with rapamycin (a well-known soil-bacterium-derived drug for preventing rejection of transplanted organs in recipients and for coating stents to keep cells from clogging them up) has had a rallying effect on the geroscience community. Among its benefits are keeping senescent cells in check and helping to recycle molecular debris from cellular activity. It’s at the heart of the University of Washington-based Dog Aging Project to study and promote longer healthspans in dogs. Adding to the excitement about rapamycin for the healthspan movement, Austad says, is that rapamycin treatment also preserves cognitive function and immune function and lowers cancer rates in test animals. This is just the sort of multi-condition effect that is consistent with the geroscience hypothesis that positive interventions in one or more of the pillars of aging can prevent — or at least delay — the onset of multiple diseases of aging.
Metformin is another poster-child compound for the geroscience club, as well as for the Prime Minister of Singapore and for those Barzilai describes as an “underground” of healthspan-minded people who are not waiting for FDA-approval or doctors’ advice. Metformin is the most commonly prescribed drug in the world for treating type 2 diabetes (the kind that usually starts later in life and often can be managed by diet and exercise). It has a solid safety record dating back more than 60 years. “From an observational epidemiology point of view, it looks like metformin is protective against a whole range of things, including cancer, dementia, and cardiovascular disease,” Austad says. “If untreated, diabetes looks a lot like accelerated aging, so it makes sense that something effective for treating diabetes will slow down a lot of aging processes.”
“It has been shown that metformin delays the onset of many diseases of aging,” notes Stephanie Lederman, executive director of AFAR, which was founded in 1981, around the same time that the National Institute of Aging was established as one of the National Institutes of Health (NIH). The most head-turning study revealed that diabetes patients taking metformin come down with “less cancer, less heart disease, and less Alzheimer’s than the general population that has not taken metformin,” Lederman says. It’s complicated, of course. One recent study with a small group of people in their 60s hinted that a metformin regimen also could confer some negatives, including reducing the aging-battling benefits of aerobic exercise. What has been lacking is a rigorous, large-scale, gold-standard clinical trial (double blind, placebo-controlled) to test if a regimen of metformin given to a diverse group of non-diabetic individuals will delay the onset of major age-related diseases.
This is where the Targeting Aging with Metformin (TAME) trial comes in. Beginning this year, TAME researchers at 14 medical centers will begin recruiting 3500 men and woman, ages 65 to 80 years, who have just begun to show age-related diseases and/or deficits, among them slow gait, cardiovascular disease, cancer, and mild cognitive impairment. The primary question of the 6-year trial is this: Does the incidence rate of new age-related chronic diseases in the metformin-receiving test group differ from the incidence rate of these diseases in the placebo-receiving control group? The TAME researchers, which includes Barzilai and Olshansky among others, will also be looking for differences in the incidence of age-related declines in physical and cognitive abilities between the metformin and control groups. A third aim is to test whether measured improvements in health parameters are mirrored in cellular and molecular biomarkers that previous research in cells and animals has associated with slowing aging. “The research protocol we came up with for the TAME trial was designed to find an answer quickly, because we were not interested in waiting 20 years for an answer,” Olshansky says.
Lederman says AFAR has raised some $20 million, mainly from philanthropists, in support of the TAME trial, though that is only about half the amount originally envisioned for a broader agenda of tests and measurements.
“We already have a subgroup of people who [naturally] stay healthy to the age of 100 and all we are trying to do is expand that group of people by using some kinds of intervention.” — Steven Austad, University of Alabama at Birmingham
A lot is riding on the TAME trial. A prospectus of the trial, which Barzilai, a principal investigator, says was developed in consultation with Robert Temple in 2015 when the latter was the deputy director of FDA, states that the greatest possible payoff of the trial is “a proof-of-concept that by targeting aging itself, healthy lifespan can be increased, paving the way for a new indication for drugs to prevent age-related diseases.” In a pivotal meeting of the TAME planning team and Temple that filmmaker Ron Howard captured in “The Age of Aging” episode of his documentary series, Breakthrough, Temple projected that “it would be revolutionary if they could pull it off.”
“The main issue in regard to treating aging as an indication is when such a broad, and so far unprecedented, claim would be considered supported,” explained FDA press officer Amanda Turney in an email exchange in March. “We would consider whether an overall anti-aging claim was supported based on the scientific evidence presented to us,” Turney wrote. “We are aware of interest in studying aging and the FDA is looking forward to seeing this area of science evolve.”
An FDA acknowledgement of this new application for drugs could greatly boost an already building R&D momentum among startups and large pharmaceutical companies to develop novel and more effective compounds to extend the healthspan. The potential market for such drugs could be huge. An NIH-funded Census Bureau report in 2015 assessed the above-65-year-old global population at 617 million. But a healthspan drug regimen designed to preempt the onset of diseases of aging would likely begin earlier in life, thereby upping the potential market into billions of people.
LET THE HUMAN TRIALS BEGIN
Even as recruiting for the TAME trial begins, Kirkland is among a cadre of scientists and entrepreneurs homing in on senescent cells and a class of candidate drugs called senolytics. These agents can kill senescent cells, which are also referred to as “zombie” cells. Many factors can drive cells into senescence, among them high levels of glucose in the blood and signals from pathogens. Senescent cells can accumulate in many tissues where they emit inflammatory, protein-destroying, stem-cell-poisoning, and other disease-promoting factors, including ones that induce other cells into senescence.
By asking how senescent cells manage to survive even as they are causing the destruction of cells around them, Kirkland and colleagues discovered that the zombie cells manage to shut off a variety of pathways associated with the normal, health-promoting, cell-death process known as apoptosis. He and colleagues searched for agents that would turn the apoptosis process back on in senescent cells without harming normal cells. The researchers found at least eight. “They work by transiently disabling these pro-survival pathways in senescent cells that normal cells don’t need to survive,” Kirkland says. In an interview with The Moonshot Catalog in March, he noted that the count of senolytic agents reported in the scientific literature then stood at 16 or 17. “There are many more that people have in their laboratories and in companies,” he said.
So far, the strongest data indicating that senolytics work as envisioned derive from mouse studies. “We found with collaborators here at Mayo that we could alleviate age-related osteoporosis and partially reverse it. We found reduced cirrhosis in mouse models of that condition. Others found that in mouse models of Alzheimer’s these drugs would partially reverse brain atrophy and improve neurogenesis and nerve-cell thickness.” The list goes on. “We found that all age-related diseases were delayed as a group in mice,” Kirkland said.
The accumulating data that senolytics can target fundamental evolutionarily-conserved processes of aging has inspired researchers, entrepreneurs, and financial backers to take the leap into human clinical trials. Kirkland, for one, is involved with various collaborators on six human clinical trials with two different senolytic compounds. One is quercetin, a plant pigment found in fruits and vegetables and foods made of them, among them apples, onions, red wine, and green tea. The other is dasatinib, an FDA-approved drug for treating certain leukemia conditions. “We are planning another six trials at Mayo very shortly,” Kirkland said.
“We found that all age-related diseases were delayed as a group in mice.” — James Kirkland, Mayo Clinic
Always vigilant for signs of serious side effects and other potential showstoppers in clinical trials, Kirkland says development of senolytic medicines should progress cautiously, building from small-scale safety trials like one that he and colleagues reported in January 2019 and ultimately building toward trials that represent the general population. That first tiny trial using a “dasatinib plus quercetin” (DQ) regimen enrolled 14 patients with idiopathic pulmonary fibrosis, a fatal lung disease in which senescent cells accumulate in the lungs and cause inflammation and fibrosis. Five days after the patients received their last DQ dose, the researchers documented what Kirkland described as “clinically meaningful improvements” in a battery of physical performance tests including gait speed, walking distance, and the ability to get out of a chair.
“This told us we should move to bigger studies” with senolytics, he says. What he has in mind now is a “slow march” from 1) trials with patients who are seriously ill with senescent-cell-caused conditions, to 2) trials with senescent-cell-bearing patients who are not as sick, to 3) trials with still-well patients whose tissue-loads of senescent cells suggest they are likely to get sick, and finally to 4) trials that represent the general public.
A MARKET GROWS IN HEALTHSPAN-LAND
Quickening the march toward what could become a new era of healthspan medicine are the proliferating startup companies that are determined to bring new healthspan-extending medicines to what potentially can be one of the largest markets possible.
An early and visible commercial venture into this new era of healthspan medicine is Unity Biotechnology, a Bay Area firm established in 2011 that subsequently amassed $385 million in funding. Among its contributors are billionaires Jeff Bezos and Peter Thiel. Drug trials for the company’s candidate osteoporosis drug candidate, UBX0101, began in June 2018. Among other medical targets for its senolytic candidates are kidney disease, glaucoma, idiopathic pulmonary fibrosis, and chronic obstructive pulmonary disease (COPD). Another early-in powerhouse is Calico Life Sciences, which was founded with Google money in 2013 and is now involved in multiple collaborations. Its goal, as stated on its web site, is “to devise interventions that enable people to lead longer and healthier lives.”
The list of healthspan startups is extensive and growing. Life Biosciences, a Boston-based geromedicine incubator, by itself accounts for six entrants, each one pursuing therapeutic platforms based on different pillars of aging. “Life Bioscience is a family of companies that uses shared resources and knowledge,” co-founder David Sinclair told Peter Attia on the latter’s long-form podcast, The Drive, which focuses on “the applied science of longevity, the extension of human life and well-being.” Sinclair is a celebrity among geroscience researchers and entrepreneurs, and his book, Lifespan: The Revolutionary Science of Why We Age — and Why We Don’t Have To, is slated for release in September. Like many in the healthspan R&D trenches, he personally is not waiting for all of the science to come in before trying his own regimen of healthspan interventions. His personal untested cocktail of agents includes daily doses of metformin, the focus of the TAME trial, and resveratrol, the red-grape compound long touted for its alleged heart-protective and longevity-promoting powers.
Among the roster of companies with their technical and commercial sights on senotherapeutics (drugs that target senescent cells) and other healthspan blockbusters include the Oisin Biotechnologies, Juvenescence, Grail, Apollo Ventures, Antoxerene, and Cellularity. The list is growing. “There is lots of room for lots of winners,” says Unity Biotechnology’s Leonard.
As the community of healthspan researchers and entrepreneurs grows and companies move candidate drugs toward and into human clinical trials, pressure to raise the money it will take to get the drugs to the clinical finish line will intensity. Small phase I clinical studies designed primarily to test the safety of new candidate drugs can cost between $250,000 and $1 million, according to Kirkland. Phase II trials involving 150 to 200 subjects in tests of efficacy and side-effects can cost between $1 million and $4 million. In the senolytics category alone, there are around 40 conditions for which drug candidates have shown preclinical benefits, Kirkland says. The larger phase III studies, which involve many more subjects to help gather far more data on efficacy and adverse effects, can be hugely expensive. Small companies on the innovation front typically can only undertake these in partnership with big pharma players and with large-scale venture capital or philanthropic support.
“This is all scalable. The more funding we have coming in, the faster we can move. And especially with the clinical trials.” — James Kirkland, Mayo Clinic
“This is all scalable,” Kirkland says. “The more funding we have coming in, the faster we can move. And especially with the clinical trials.” When it comes to the challenge of keeping the new field growing, geroscience pioneer Felipe Sierra says he would like to see a return of the sort of philanthropic presence that Oracle billionaire Larry Ellison brought to aging research during the first decade of the century, in his case to fund basic and applied academic research in geroscience. When the flow of those funds — some $430 million from the Larry Ellison Foundation since its founding in 1997 — ended a few years ago, Sierra says, that left “a gaping hole in the research pipeline that affects primarily early- and mid-career researchers. Renewal of such an effort would provide much needed support for early innovators entering the field.”
“We are all sick of prescribing better wheel chairs and walkers and incontinence devices,” says Kirkland, speaking for himself and other geriatricians. “We want to have something that targets fundamental aging processes.” What these doctors want is what everybody wants — for all of us to be disease-free, pain-free, and capable of doing what we want to do until the day we die.
Ivan Amato is a writer, editor, podcaster, and science cafe host based in Hyattsville, Maryland. He is the editor of The Moonshot Catalog.