December 13, 2015
To most of the scientific community, “anti-aging” is a dirty word.
A medical field historically associated with charlatans and quacks, scientists have strictly restricted the quest for a “longevity pill” to basic research. The paradigm is simple and one-toned: working on model organisms by manipulating different genes and proteins, scientists slowly tease out the molecular mechanisms that lead to — and reverse — signs of aging, with no guarantee that they’ll work in humans.
But it’s been a fruitful search: multiple drug candidates, many already on the market for immune or psychiatric disorders, have consistently delayed age-associated diseases and stretched the lifespan of fruit flies, roundworms and mice. Yet human trials have been far beyond reach — without the FDA acknowledging “aging” as a legitimate target for drug development, researchers have had no way of pitching clinical trials to the regulatory agency.
This year, the FDA green lighted an audacious proposal that seeks to test in 3,000 volunteers a drug that — based on animal studies — could extend human lifespan by up to 40 percent and decrease chances of getting age-related diseases. The double-blind, multi-centered trial, Targeting Aging with Metformin (TAME), is the first that pushes aging as a bona fide disease — one that may eventually be tamed with drugs.
“We think this is a groundbreaking, perhaps paradigm-shifting trial,” said Dr. Steven Austad, scientific director of the American Federation for Aging Research (AFAR).
A Sea Change
Without a doubt, TAME is an odd one in the realm of clinical trials. Spearheaded by Dr. Nil Barzilai, an ebullient scientist based at the Albert Einstein College of Medicine, TAME receives no support from the pharmaceutical industry. The brainchild of a team made up solely of academics, TAME is sponsored by the nonprofit organization AFAR.
Even more of a head scratcher is this: if the drug were to work in humans — making it the first scientifically proven longevity pill, an elixir worth billions — none of the team members stand to make any money. This is because metformin, the star of the trial, is a generic diabetes drug that costs only a few cents a dose.
It’s not about the money; it’s something far bigger.
What we’re talking about here is an idea that fundamentally changes how we look at aging and disease, said Dr. S. Jay Olshansky, a biodemographer at the University of Illinois and TAME team member.
The idea is this: rather than tackling the top medical killers — cancer, cardiovascular disease, dementia — individually, we should instead focus on slowing or reversing the single most prominent risk factor associated with all those diseases — age.
It may be as close to a silver bullet as we’ll get.
The Drivers of Aging
TAME is built on decades of basic research on aging, mostly conducted in short-lived model organisms such as fruit flies, nematode worms and mice. By individually tweaking genes and measuring the resulting effects on healthspan and lifespan, scientists gradually teased out individual molecular pathways that drive aging forward.
Within the last few years, the field has built a solid theoretical framework of the aging process. Endearingly known as the “major pillars of aging,” the framework includes pathways related to metabolism, stress response, inflammation, stem cell quality and proteomic homeostasis — that is, the body’s ability to keep groups of proteins functioning in harmony.
Yet scientists have not yet teased out the so-called “master regulators,” or central cross points that bridge the different pathways and drive aging forward.
Some of us think that the brain is the central regulator, that inflammatory processes in the hypothalamus are sufficient to drive aging of the body, said Dr. Dongsheng Cai, a neuroscientist at the Albert Einstein College of Medicine.
Our current anti-aging apothecary contains antidepressants, said Dr. Michael Petrascheck, a researcher at the Scripps Institute, to Singularity Hub. And we think those drugs act on the brain, which in turn regulates gene expression in the body to increase stress resistance and increase lifespan.
Others, in contrast, think pro-aging factors in the blood drive brain aging. Last year, a series of groundbreaking studies laid bare the rejuvenating effects of young blood. When researchers diluted the blood of an old mouse by infusing it with blood from a young mouse, the old mouse’s brain, blood vessels and muscles all reverted back to a younger state.
Although master regulators remain elusive, research has uncovered an impressive list of drug candidates. Metformin, TAME’s test drug, sits solidly at the top of that list.
It’s a truly ancient drug. Widely used in humans since the Middle Ages, metformin reduces blood sugar and works on multiple pathways involved in cell growth, inflammation and metabolism — all of which constitute the major pillars of aging.
Epidemiological studies suggest that metformin reduces the risk of cancer and dementia. What’s more, a large 2014 study of 78,000 people showed that on average, people with Type 2 diabetes who take the drug live longer than those of the same age who don’t.
Metformin seems to fit the bill of a longevity drug. But it was the chemical’s two other perks that made it a winner to the TAME team.
First, it’s very safe. When taken as prescribed, the drug has few side effects, and those that do occur are well documented.
Second, and perhaps the kicker, is that in addition to extending lifespan, it also extends healthspan — the number of years that an organism remains healthy, even in old age.
Our goal is not to extend life per se, explained Olshansky. In fact, that was the basis of our proposal to the FDA, he laughed.
Healthspan, Not Lifespan
TAME is based on a promising — if surprising — result repeatedly found in multiple organisms: increases in lifespan have often been associated with increased healthspan. That is, with some manipulations such as caloric restriction, not only have the animals lived longer, they also stayed mentally sharp and able-bodied in those extended years.
If this holds in humans, it could fundamentally change our health care system, said Olshansky.
In many people’s minds aging is not a disease, it’s simply humanity, said Barzilai. So instead of pitching a drug trial that targets aging to the FDA, we proposed to look at comorbidities — that is, chronic diseases that sharply rise in incidence as people age.
The goal is to see whether metformin delays the onset of age-related comorbidities. This strategy, part of a concept called the “longevity dividend,” was first proposed by Olshanky and colleagues back in 2006. The concept argues that slowing the process of aging has significant benefits in terms of health and wealth for individuals and the health care economy as a whole.
In a 2013 paper published in Health Affairs, Olshansky broke down the numbers. Based on animal models, even a small delay in aging could raise life expectancy by an additional 2.2 years, most of which is spent in good health. Over fifty years, the economic value of delaying aging is estimated to be $7.1 trillion. In contrast, targeting comorbidities separately — for example, heart disease and cancer —would end in diminishing improvements in health by 2060, mainly due to competing risks, argues Olshansky. It’s basically changing one disease for another.
“We’re not arguing — and we’ve never argued — that we’re trying to achieve life extension,” said Olshansky in an interview with Science News. “We’ll probably live a little longer if we succeed, but that’s not the goal. The goal is the extension of the period of healthy life.”
If TAME goes well, it’s only the first step towards battling aging in humans.
In addition to testing the effects of metformin, the TAME team also plans to take muscle and fat biopsies of volunteers before and after taking the drug. By using a big-data technique called RNA deep sequencing, which looks at what genes are expressed at what levels, the team hopes to identify biological “fingerprints” for aging.
Gene expression is like an orchestra — some groups of genes always turn on together, others always shut off. With age, however, gene expression patterns slowly drift out of whack, a phenomenon that researchers call “transcriptional drift.”
Reversing transcriptional drift is a great readout when trying to test the effects of new longevity drug candidates, said Petrascheck. In a study published this week, Petrascheck identified miaserin, an antidepressant already on the market, as a new type of “longevity pill” that extends young adulthood in worms without affecting later years.
Without a doubt, data from TAME will be incredibly valuable for judging other anti-aging drug candidates.
Regardless of how the trial turns out, the TAME team is optimistic.
The main reason we set out on this is to convince the FDA to approve aging as an indication, so that it can be a target for future trials with even better medications said Barzilai.
We got it, he said.