Reeling Through the Years

Pharmaceutical and Medical Device Policy Aging

I think I get a pretty good measure of how old I am by the number of prescription bottles in my medicine cabinet. Each decade has added some chronic condition that I manage through pharmaceuticals. There are the steroids I am taking to calm the sciatica in my leg that results from the wearing away of a vertebra in my spine. There are the statins I started in my forties as my cholesterol seemed to rise and rise no matter what I did to alter my diet and lifestyle. There are my eyedrops to keep me from going blind from glaucoma. And that’s not to mention my reading glasses and the hearing aids that I need to don to even have a fighting chance of understanding what’s going on in my own college classroom. Each of these treatments is a testimony to the power of modern medicine. Statins alone are estimated to decrease mortality from cardiovascular causes by a significant proportion. Glaucoma, once a leading cause of blindness in older adults, is now a manageable condition. And the cataracts I am slowly developing according to my ophthalmologist (forgot to mention those!) once caused blindness to descend upon the elderly. Now they are rectified in an outpatient procedure.

But while these fixes have turned me into a functioning Rube Goldberg machine for the time being, they do nothing to address the underlying conditions. By underlying conditions, I don’t mean hypercholesterolemia or osteoarthritis of the spine or any of the particular diseases I have described above. I mean aging. I may be suffering from hearing loss at a younger age than most, for example, and ditto for the degeneration of my spine. But they are no doubt related because they are both conditions of old age.

Since before Ponce de Leon’s quest for the fountain of youth that led him to discover what is now Florida and Cervantes’ Don Quixote’s likeminded search, humans have sought a way to slow or even reverse the aging process. Now, however, we have preliminary evidence that there are indeed methods of slowing down senescence. There’s a calorie restricted diet. Intermittent fasting. Blood transfusions from the young. Not to mention pharmaceuticals such as metformin or rapamycin. The evidence is only preliminary, however, that any of these extend the lifespan because the only way we can assess such lifestyle or pharmacological interventions is indirectly. We know that fasting, rapamycin, and metformin all extend the lifespan of mice. And, there’s little reason to suspect that humans are any different; after all, we are practically cousins with mus musculus in the tree of life. We also have additional evidence for metformin, for example, from diabetic humans. Metformin is a drug that is prescribed to manage blood sugar levels in diabetics. However, prospective analyses show that, as in mice, it lowers mortality from other causes—such as cancer—that seem to be unrelated to the target effects on glucose homeostasis. Extrapolating from diabetics to the rest of us suggests that metformin may have a multifactorial effect on human aging and mortality risk for the general population as well.

Still, we cannot know for sure: There have been no randomized controlled trials (RCTs) in humans for aging interventions. (Granted, there has never been a clinical trial testing whether smoking tobacco causes lung cancer, but that doesn’t mean we aren’t pretty darn sure about the causal link.) This lack of RCTs stems from two reasons.

The first obstacle to controlled trials is technical, and it’s the same reason that Alzheimer’s drugs have a tough time in drug discovery. Namely, it’s hard to wait decades to see if a drug works to extend life a few years. Even if it were not for the fact that privately owned pharmaceutical companies have a much shorter profit-loss time horizon, the longer a study goes on, the harder it is to run. Researchers lose subjects who drop out or fail to comply with the protocol or die from other unrelated causes (like accidents, for instance). There’s also the ethical problem of subjecting healthy humans to an intervention that may have negative side effects when there’s nothing wrong with them. The Alzheimer’s research world has tried to do an end-run around both these issues. First, drug companies have clear measures of disease progression in the form of cognitive tests. And, second, they run trials with subjects who appear to already be suffering from early signs of the disease. This latter issue is not an ideal solution since most theories of dementia suggest that the process begins—and starts its own forward feeding cycle—long before symptoms manifest and that ideal treatment regimens would begin much earlier in the life course.

With clinical trials on age-retarding interventions we face more severe versions of both those issues. First, until recently, there has been no test equivalent to the cognitive assessment, that can tell us who is “suffering” from accelerated aging processes. Recently, however, the biomarker revolution has made progress on this front. There are now a number of molecular measures that can be gleaned from analysis of bloodwork that seem to indicate one’s biological age as distinct from one’s chronological age. One of the most promising of these biomarkers is “methylation age.” Methylation is the addition of a methyl group (CH3) to an area of DNA. Methylation of DNA represses the expression of that particular sequence of DNA from being transcribed into RNA in order to be turned into protein—the building blocks of cells. In other words, certain genes are turned on at younger ages and others are turned on at older ages. By predicting age based on thousands upon thousands of genome samples, scientists such as Altos Labs’ Steve Horvath and Morgan Levine have developed algorithms that can then be used to measure the ages of new subjects (“out of sample” individuals). I am 53 years old as of this writing. Analysis of my mDNA (DNA methylation pattern) might show that I have a molecular age (at least this aspect of molecular age) of 56 or of 48. In turn, these methylation ages have been validated by prospectively predicting life expectancy.

But methylation age is like a snapshot. If I am 58 in terms of my methylome profile, that quicker aging may have been due to the fact that I suffered from spinal meningitis as an infant or it could be due to a medication I am taking now. It would take a long time to see an impact of any slowdown in my rate of aging due to a treatment I am undergoing. Granted, not as long as waiting to see how long I end up living, but still not as quickly as we would like for drug discovery. Luckily, there is now a measure developed by Daniel Belsky and colleagues that measures not just a snapshot of my molecular age but takes a short video clip, if you will. That’s called the Dunedin Pace of Aging measure. It purports to tell scientists not how old you are at the moment they drew your blood but how fast you are aging in that moment. The benefits of this measure of velocity over the earlier measures of position is that, putatively, it should be more elastic to what is going on right now in one’s life—and thus to an anti-aging treatment. Aging markers are being improved yearly, but now they offer us a way to quantify whether Don Quixote’s elixir of youth is having its effect. In other words, they serve the same function as the cognitive test with respect to Alzheimer’s research: they give us a metric against which to gauge efficacy. That paves the way for clinical trials of drugs and other non-pharmaceutical interventions meant to solve the underlying problem that links my hearing loss, eye issues, and bone loss.

However, the second obstacle remains: We want to test such approaches in otherwise healthy individuals. But is that ethical and would the FDA allow such a trial? The answers, are, I believe, yes, and no, respectively. The bureaucratic obstacles to aging research will be explored in my next opinion piece in the Milbank Quarterly, so stay tuned!

Conley, D. "Reeling Through the Years." Milbank Quarterly Opinion. April 12, 2023.

About the Author

Dalton Conley is the Henry Putnam University Professor in Sociology at Princeton University and a faculty affiliate at the Office of Population Research and the Center for Health and Wellbeing. He is also a research associate at the National Bureau of Economic Research (NBER), and in a pro bono capacity he serves as dean of health sciences for the University of the People, a tuition-free, accredited, online college committed to expanding access to higher education. He earned an MPA in public policy (1992) and a PhD in sociology (1996) from Columbia University, and a PhD in Biology from New York University in 2014. He has been the recipient of Guggenheim, Robert Wood Johnson Foundation and Russell Sage Foundation fellowships as well as a CAREER Award and the Alan T. Waterman Award from the National Science Foundation. He is an elected fellow of the American Academy of Arts and Sciences and an elected member of the National Academy of Sciences.

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