Reeling Through the Years – Part 2

In my last Opinion piece, I discussed the theory that many diseases typical of our advanced years are actually different manifestations of a single underlying “condition”—aging. I also discussed one of the main obstacles to developing anti-aging drugs in a rigorous, scientific manner: that prospective studies of long-term mortality take too long to be feasible. However, today multiple molecular measures of aging have been developed—most notably DNA-methylation clocks. These clocks—some of which tell us the cumulative toll of aging on our cells and others that provide us with a snapshot of the rate of aging at the time the test was taken—offer a novel way to experimentally test interventions meant to treat not just one aspect of aging—say cognitive decline or atherosclerosis—but the underlying rate of our body’s senescence, that is, our deterioration unto death.

That’s just what Columbia University professor Daniel Belsky did. He used his own pace-of-aging measure as an outcome and tested, for the first time in humans of normal weight, what long-term calorie restriction did to that rate of senescence. Funded by the National Institute on Aging, the study was trademarked as “CALERIE.” (If you guessed it was a cute acronym, you were correct; it stands for Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy.) The CALERIE study randomized 220 healthy men and women at three sites in the United States to a 25% calorie-restricted diet or a normal diet for two years. Compliance wasn’t perfect, obviously, since these were free-range humans and not lab mice, but even with a limited degree of control over the subjects, the researchers still found a 2-3% retardation of the pace of aging in the treatment group as compared to the control group. That might not sound like much, but it translates to a 10-15% reduction in mortality risk.

The fact that the National Institutes of Health funded this study in the first place leads me to the topic of this post: The institutional obstacles to anti-aging interventions. Given its name, it should come as no surprise that the National Institute on Aging has been among the leading government agencies shifting toward a paradigm of seeing aging as a disease in itself. While most NIA funding still goes to specific diseases associated with older age—such as Alzheimer’s—there have been important studies of the aging process writ large that have been supported by NIA. Besides CALERIE, one of the most notable has been the Interventions Testing Program (ITP).

This humbly named program is exactly what its title says: Interventions that are suspected of having an ameliorative effect on lifespan are subjected to rigorous randomized controlled trials—on mice. The ITP program has been up and running for over 20 years and has identified a number of compounds that extend the median lifespan of our furry cousins, including acarbose, aspirin, and rapamycin.

Meanwhile, some strong contenders that have been fads in the human dietary world—such as fish oil or resveratrol (a compound found in red wine)—have failed to show life-extending results in the lab mice under controlled conditions. The big caveat, of course, is that these experiments are conducted on mice, so anything we learn has to be translatable to humans. In general, this is not too troubling. As much as we think we are different from mice, on the grand tree of life, we are pretty close cousins. (That said, there are specific examples of disease interventions that worked in mice but failed spectacularly in humans.)

NIH has not been the primary institutional obstacle to gerotherapeutics, however. That role has been played by the FDA, which currently  does not recognize aging as a “disease” for which a treatment can be approved. Luckily, that may soon change thanks to TAME.

The Taming Aging with Metformin (TAME) randomized trial aims to capitalize on animal studies that show metformin, a Type 2 diabetes treatment, to extend lifespan even in healthy subjects. Metformin has been used for over six decades in humans and reduces all-cause mortality among diabetics, and not just for causes of death clearly related to blood sugar level maintenance. Metformin costs pennies a day, so there is no gain for Big Pharma in these trials, which are being funded by scraping together various sources (including individual donations). Besides funding, the big obstacle to getting underway is finding enough volunteer subjects ages 65-79. It’s already hard to find older subjects for clinical trials aimed at specific conditions (such as arthritis or cardiovascular disease) because most older Americans suffer from multiple comorbidities (i.e., not just arthritis or cardiovascular disease but both—hence the aging hypothesis) that could muddy any results for the target intervention. And a majority of people in this age group take multiple prescription drugs, which may interact with the target drug being tested. Moreover, for a study on aging like TAME, researchers seek more or less completely healthy individuals, which is a big ask among older adults.

Once enough subjects are enrolled, TAME will measure the onset of age-related health outcomes such as cancer, cardiovascular disease, and cognitive decline—in addition to actual mortality—as the indicators of general aging. While it might have been more efficient to use some of the biomarker clocks, what’s critical is that the FDA has approved this protocol. If TAME comes off successfully, it will have paved the way for more FDA-recognized trials with aging per se as an indication. In other words, TAME will have broken the regulatory glass ceiling for gerotherapeutics. That may unleash a raft of investment by pharmaceutical companies seeking regulatory approval for anti-aging drugs. Such new anti-aging drugs may hold great promise for extending life expectancy as well as for improving quality of life in older adults.

This shattering cannot come a moment too soon. In fact, waiting for TAME is too long. Currently, of course, drugs like metformin, acarbose, or rapamycin, have all been approved by the FDA for specific conditions (the first two for diabetes and the last for organ transplantation). Thus, medical professionals can theoretically prescribe them for off-label uses such as a for a patient who requests them in a preventative effort to stave off age-related bodily and mental decline. However, it’s time to bring these drugs out of the shadows. More importantly, big pharma won’t invest in new therapeutics, targeted specifically to the aging process, until there is a secure path forward with the FDA. With a rapidly aging population in the United States and worldwide, that path is more important than ever. It’s time for the FDA to formally recognize aging as an indication so that the creative power of gerontologists can be unleashed. Fighting our ultimate decline shouldn’t just be the province of billionaires who pay for blood transfusions, cryopreservation, and other treatments. Anti-aging treatments should be as accessible to all as aspirin—since we are all target patients.

About the Author