Targeting aging with therapeutic interventions to slow the inexorable march of biological decline is moving from the fringe of biomedical research to legitimacy, but numerous challenges remain before pharmacies start dispensing prescription medicines for a longer life.
For starters, governments do not recognize aging as a disease or a treatable condition; most experts believe convincing them otherwise will be a critical step in defining regulatory pathways for approval and subsequent reimbursement of this new class of future medicines.
In the U.S., the FDA has taken a first step by approving the study design for a clinical trial, called TAME, which stands for Targeting Aging with Metformin. The five- to six- year clinical trial will evaluate whether metformin, a diabetes drug, can slow the rate of aging by delaying the onset of a composite of age-related diseases, such as cardiovascular disease, cancer, cognitive decline, and death.
In the meantime, the number of companies targeting aging is growing. Most are focusing their new drugs –which aim to disrupt the aging process – on specific age-related diseases, such as cancer or Alzheimer’s disease. Their goal is to reach the market in the near term and then expand into improving health span and lengthening life span.
One example is Nir Barzilai, M.D., founding director of the Institute of Aging Research at the Albert Einstein College of Medicine, who has launched a series of start-ups with David Sinclair, Ph.D., co-director of the Paul F. Glenn Center for the Biology of Aging at Harvard Medical School.
Barzilai says the companies have had no shortage of venture capital investment, and while established biotech and pharmaceutical companies have expressed interest, he believes they will become more excited with the success of the TAME study, which he is leading.
In addition to starting companies, Sinclair is waging a global effort to get governments to recognize aging as a disease. Whether they respond or not, he says, drug development to slow aging and radically lengthen human life span is a legitimate medical goal and will accelerate.
“We’re at the point in human history where we understand what to do; it’s just a matter of doing it, and executing on the drug development programs, to target the anti-aging (molecular) pathways that we know exist.”
Barzilai agrees. “What happened to us in the last decade is we went from hope to promise. While we knew there was a biology of aging, we didn’t know if it can be targeted. But we have been targeting it all over in many labs with many methods and we have shown in preclinical studies that aging can be targeted.”
Speculation varies on when medicines for aging will be available. Gary Hudson, co-founder and acting CEO of Oisin Technologies, observes, “We expect that there will be a suite of complementary therapies that will be brought to bear on the root causes of aging. All we can be sure of is that progress is rapidly accelerating and there will be many surprises and new technology to emerge in the next decade.”
Among those surprises may be prickly challenges involving economic, social, and ethical considerations of radical life span extension. While there is a debate among scientific experts on how long humans can live, many agree drugs could extend life expectancy to about 120 years.
However, whether people want to live that long may be another variable in the pharmaceutical quest for longevity. For example, a 2013 Pew Research Center report, “Living to 120 and Beyond,” found that 69% of Americans are happy living between 79 and 100 years, with 90 being the median ideal age. When asked if they want to live to 120 or older, 56% answered no.
WuXi AppTec – a leading global pharmaceutical and biopharmaceutical open access capability and technology platform – assists biotech and pharmaceutical companies from discovery to manufacturing and beyond. An important element of this support involves offering a communications platform to facilitate the exchange of ideas among the most innovative companies and the creative people behind them.
In this installment of WuXi’s new communications platform on the future of drug discovery and development, leading experts in aging research and drug development discuss the prospects for this exciting new field of medicine. They include Nir Barzilai, David Sinclair, Gary Hudson, Methuselah Health CEO David Grainger, Alkahest Vice President of Business Development Joseph McCracken, and AgeX Therapeutics CEO Michael West. Their complete interviews also are available on this website.
Slowing human aging and radically extending average life expectancy at least 35 years beyond current limits (79 for men; 81 for women in the U.S.) has become a legitimate scientific research target and clinical pursuit, but still suffers from an identity crisis, as in: What is aging? Is it a disease or natural condition?
“This is an interesting question, isn’t it,” says Michael West, Ph.D., CEO of AgeX Therapeutics, which is applying the properties of cell immortality and pluripotency to treatment of aging and age-related diseases.
“Historically, medical researchers would have answered in the negative, that is, that aging is not a disease,” West says. “However, it is very clear that modern research is beginning to see aging in a new light.” Even if they don’t call it a disease, he observes, scientists are treating it like one by trying “to understand the process and devise novel technologies to intervene.”
Gary Hudson, CEO of Oisin Biotechnologies, which focuses on the role of senescent cells in aging, is more direct. “I view aging as a progressive loss of function, especially in the ability to respond to stressors. There’s much debate whether it should be called a disease, but for me there is no debate that it should be treated as if it were a disease.”
Albert Einstein College of Medicine’s Nir Barzilai agrees aging is a treatable condition, but he stops short of declaring it a disease “because not everybody who ages is sick and because we do not want to have ageism.”
David Grainger, Ph.D., CEO of Methuselah Health, which is researching proteome instability as an underlying cause of aging, says, “Fortunately, there is a much simpler scientific definition to fall back on: aging is the time-dependent change in the rate of mortality within a population, enshrined in the classical Gompertz equation,” which calculates that the risk of death increases exponentially with age.
The same equation, Grainger observes, “describes your likelihood of developing many age-related diseases. The simple question behind all of aging biology is, why should this be so?”
Joseph McCracken, DVM, Alkahest’s vice president of business development, says, “Aging is not generally considered an illness, although aging is a risk factor of a number of age-related illnesses.” Among the risk factors are plasma proteins, which Alkahest is studying as a target to counterbalance aging.
Harvard University’s David Sinclair says there’s no question aging is a disease. “If you look up a definition of what is a disease and what is aging in the Merck Manual of Geriatrics, the gold standard, you will see that if a deterioration of the body occurs to less than half the population, we call it a disease,” he explains. “If it happens to more than half the population, we call it aging. That’s as simple as it is. It’s a 50% cut off.”
Whether it’s considered an illness or not, the various biological processes of aging have been opened to discovery with advances in genomics, and the race is on to understand the science, intervene, and slow down the impact of time on human biology.
Where are we now?
Most companies that target aging as a treatable condition have developed a strategy of first getting to market by focusing on specific-age related diseases because they already have established regulatory pathways.
Barzilai explains a major challenge researchers and entrepreneurs must overcome is convincing governments to recognize aging as an indication. “I’m at the FDA, I’m at the Congress,” he says. “I think we have a path forward. But we have to do the TAME study first.”
Until then, he adds, “We need to find some disease indication to target sooner and then it will become aging later. We’re looking now at a company that actually has another kind of metformin. This drug is a super metformin and our indication is actually a therapy for cancer. With cancer we can get to the market much faster.”
Metformin is a pill that has been on the U.S. market for 25 years. It is only one of many strategies for treatment of aging. Other companies are targeting a range of genetic pathways implicated in the biological decline associated with growing older.
For example, Sinclair is researching the role of sirtuin genes. “Back in the early 1990s I was part of a team that worked to discover the role of the sirtuin gene in our bodies’ defenses against aging.” Sirtuin genes and their proteins, he suggests, may be key targets in all areas of illness.
Hudson says Oisin Biotechnologies is targeting senescent cells, which are cells that become irreversibly damaged and instead of being cleared from the body they turn into “zombie” cells, which may play a role in many age-related diseases. Oisin is developing a genetic therapy aimed at killing senescent cells.
West, of AgeX Therapeutics, describes his company’s strategy as “applying the biology of the immortal regenerative potential of the germ-line (cells) to human aging and age-related degenerative diseases. By this, we mean that there are some cells in human biology that don’t age.”
Another approach is that taken by Methuselah Health. Grainger says his company’s technology is based on its discoveries that “protein stability, and not DNA stability, is the fundamental clock of aging.”
As a result, Grainger says, the company has developed a “platform capable of looking for damaged proteins with quantitative accuracy. If we can identify these damaged variants that accumulate, we have the opportunity to design treatments to prevent or remove them.”
Alkahest is also targeting proteins, but McCracken says the company is focused on the plasma proteome. “Circulating plasma, which connects the brain and other organs, contains thousands of proteins that signal or mediate biological processes in healthy aging and in age-related diseases,” he explains.
Proteins that increase in age-related diseases, McCracken says, could be targets for inhibition while those that decrease could be replaced.
Despite the efforts of these companies and others, the prospect of moving this new class of medicines from the laboratory to the bedside depends not only on better understanding the science of aging, but also achieving public acceptance of the goal, or endpoint. For example, treating patients with cancer is relatively straightforward. Treating old age, however, seemingly would apply to everyone.
Where are we headed?
In traditional drug development the goals are clear –cure the illness, slow its progression or relieve the symptoms. Such defined outcomes of drugs to treat aging are far from settled.
For example, is there a limit to human life span? Will regulators determine approval by the number of healthy years added to life expectancy? What will define success?
Barzilai bristles at the notion that aging research is all about living longer. “Life span,” he says, “is a side effect. I’m really looking at health span.”
By improving health span, Barzilai believes people should be able to live to 115. “We argue, is it 113 or 122?” he says. “But it’s around 115, and we die at age 80 from diseases, so we have the capacity as a species of 35 more years.”
Sinclair contends there is no limit to humans’ life span. “If you look back in history there is an apparent life span limit of about 120 or 122,” he explains. “But that would be like saying in 1870, there will always be pain during surgery or in 1900 that humans will never have powered flight.”
Grainger acknowledges the Methuselah Health is trying to extend life span. “We believe we understand, for the first time, why the risk of disease and death increases exponentially, that we can intervene to slow the fundamental clock of aging,” he says. “Doing so will improve quality of life as well as average life span.”
West says AgeX Therapeutics is focused on increasing the number of healthy years as people age. “Extending human life span without a corresponding extension of health span provides no useful purpose,” he contends.
Hudson observes that current drug development efforts have “just about reached the limits of extending life in humans who are suffering the ravages of aging-associated disease. No one really wants to perpetuate suffering. Our goal has to be extending health span. If we accomplish this, it is my personal belief that life span extension will be an added bonus.”
Other challenges loom
Assuming humans can live 20, 30 or 40 years longer, what are the societal implications?
“There will be big changes to society,” Sinclair says, “similar to what we went through in the 20th century.”
But he suggests extending health span and subsequently life span are the best hope of overcoming the escalating financial crisis associated with health care spending. “The economic impact of increasing health span cannot be understated,” Sinclair explains. “It will raise global economic wealth by up to 10 % in the short term. Long term it will allow countries to afford health care and education for all.”
Successfully slowing the rate of aging will yield what Barzilai calls a longevity dividend. “It’s estimated that by 2050, if we extend health span by two or three years, we will save $7 trillion in medical bills,” he explains.
Hudson foresees no greater challenges than what society has experienced with dramatic increases in average life expectancy during the last century. “It’s useful to remind ourselves that at the time of the U.S. Civil War, the average life span was only half what it is today. We survived that doubling of average life span and created a prosperous society as a result of increased productivity.”
Sinclair acknowledges that among concerns raised by ethicists is the question of access to drugs that radically extend life span.
“There could be a billion people who would be prescribed these medicines,” Sinclair observes, “potentially everybody over the age of 40. But what’s not appreciated is that the cost savings far outweigh the cost of the drugs.”
So how will governments pay for these wonder drugs and insure equal access? For his part, Sinclair has a plan.
“Some people worry that these drugs will be available only for the wealthy,” he observes. “I’ve already pledged to make the drugs that we are developing available to the entire world; not just developed countries, because I think this is just too important to provide the drugs to people who can afford them and leave out large sections of the globe.”
Aside from the uncertainties involved in pursuing radical life extension and regardless of the ultimate outcome, Barzilai wants to correct any misconceptions of what he and his colleagues are pursuing.
“We’re trying in our labs to target aging,” he explains. “We’re not anti-aging. Anti-aging and organizations that are anti-aging are people usually selling snake oil to the public. The word anti-aging is the enemy of the biologists of aging. It gives us a bad name.”