The Path Forward — 1

Mr. R. P., on the other hand, had heart bypass surgery and later some stents along with extensive cardiovascular care. He had a shoulder replacement accompanied by a heart attack, and, with prompt medical care, he survived COVID.

While I did provide Mrs. L. R. some modest professional attention, and it is fair to say Mr. R. P. received critical state-of-the-art health care in his tenth decade, neither of them had any kind of whole-body aging halt or reverse. Overriding the aging process poses profound challenges. It’s hard to prove in people. The gold standard of a large-scale randomized trial, with one group of participants receiving the intervention and the other a placebo control, on a blinded basis (double, for both the researchers and participants), would require many years of follow-up, likely a decade or more. None of the many companies that are developing interventions to slow aging are going to invest in such a clinical trial. So we are left with having to use surrogate endpoints like epigenetic or proteomic clocks, which do not represent clinical outcomes.

As I have noted, many of the potential ways we must alter the pace of aging carry a serious risk of cancer. That’s because the biologic hallmarks of aging are remarkably convergent with the hallmarks of cancer. Aging is characterized by genome and epigenome instability, shortened telomeres, loss of protein regulation (proteostasis), dysfunctional mitochondria, old senescent cells and exhausted stem cells, impaired cellular waste disposal, chronic inflammation, diminished immune system responsiveness, and an imbalance of the gut microbiome. Most, if not all, of these features of aging promote cancer. As we’ve seen, epigenetic reprogramming, lengthening of telomeres, and engineered T cells all have a potential liability for inducing cancer or its progression. Take senescent cells in our body as an example. They can no longer divide, so this is a way to protect against cancer. But the trade-off is that these cells are dysfunctional and secrete pro-inflammatory proteins. The burden of proof is that “eradicating” old cells through senolytics is advantageous compared to our natural way of shutting down these cells. Senolytics don’t simply vaporize the senescent cells; they may leak and become deleterious in the process. It’s hard to precisely target them, so healthy cells may be roped in. Or revving up our waste disposal system (autophagy) could provide a distinct benefit for any cancer cells that exist in the body. Improving mitochondrial function could also lead to a gain of metabolic fitness for cancer cells. Moreover, the various strategies for antiaging assume a homogeneous effect on all cells. If we do partial epigenetic programming, there’s no assurance that will occur evenly; some cells might be fully reprogrammed and potentiate the risk of cancer. Likewise, what if we rejuvenate our immune system, reversing immunosenescence, but set off self-directed autoimmunity?