My previous post was all about my “stack” – my nutrient-based line-up of supplements which I believe can improve my healthspan and quite possibly my lifespan. But because Big Pharma isn’t rushing in to do randomized controlled trials of relatively inexpensive, non-patentable supplements, I can’t prove that assertion, despite the encouraging animal research and the positive results on biomarker testing that I do for all my patients. But prescription pharmaceuticals are a somewhat different “gero-science” proposition: higher risk of significant side-effects but potentially higher reward.
For the past twenty years or so, two pharma drugs have cornered the lion’s share of attention in the longevity world, metformin and rapamycin. They’re both prescribed for specific disease indications (metformin for type 2 diabetes and rapamycin to combat organ transplant rejection) but there’s evidence that both may protect against a range of chronic diseases of aging, maybe even pushing back against the aging process itself. So, it’s notable when Dr. Nir Barzilai, one of the world’s leading investigators of geroscience compounds, and a tireless booster of metformin, co-authors an article, An Updated Prioritization of Geroscience-Guided FDA-Approved Drugs Repurposed to Target Aging, that ranks a newer and less well-known class of drugs, the SGLT2 inhibitors, as the most promising such drugs on the market.
The SGLT2is have actually been prescribed for about a decade to lower blood sugar in type 2 diabetics. But more recently, data from a number of clinical trials has shown surprisingly large reductions in the mortality rate of patients both with heart failure and with chronic kidney disease, in some cases, without accompanying type 2 diabetes. (One study looking at heart failure patients recorded a 32% drop in deaths from any cause.) Observational studies suggest that these drugs, which are able to cross the blood brain barrier, may protect against neurodegenerative diseases, as well as other diseases, cancer included. The longevity community is starting to take notice, as well it should.
The SGLT2i story goes back over a hundred years ago when somebody figured out that the bark from the apple tree lowered blood sugar. In the intervening century, pharma industry chemists synthesized and tweaked the relevant molecule and came up with a pretty good type 2 diabetes drug. But the FDA, having been burned by an earlier class of type 2 drugs, the sulfonylureas, which turned out to lower blood sugar while raising the death rate, required an unusually large number of trials to pin down safety. That’s when the startling drop in those mortality figures revealed the true and hitherto unsuspected efficacy of these drugs.
So why are the SGLT2is (think, empagliflozin, dapagliflozin and sotagliflozin) so good at so many things? For starters, they lower blood sugar by a straight-forward mechanism. By inhibiting the action of the sodium-glucose transporter, they block the reuptake of glucose into the system after the kidneys have filtered some of it out. And when you lower blood sugar in a type 2 diabetic, you get all sorts of improvements in cardiometabolic health. But what’s so distinctive about the SGLT2s is that they seem to directly act on the mTOR system that regulates cell growth, turning it down to promote cell maintenance -- autophagy in a word -- recycling old cell parts into new cells. (Rapamycin does much the same thing but its long-term safety is still not well worked out and its potential side-effects are more serious.)
That is precisely what we want as we age. Two downstream effects of having enhanced autophagy are fewer senescent cells to clog up the works and less fibrosis – scarring in the tissues caused by a build-up of dysfunctional connective tissue. Both go a long way to explain how the drugs protect blood vessels, large and small, in the cardiovascular system and the kidneys, accounting for those eye-opening mortality statistics. Indeed, it’s looking like the SGLT2s may be pushing back against most of the so-called Hallmarks of Aging which, collectively, are responsible for robbing us of our vitality.
So, am I recommending we add SGLT2s to the water supply? No. We don’t yet know whether these drugs will provide any meaningful benefit to the healthy person. However, if I have a patient whose hemoglobin A1C or cardiovascular or kidney function is not where I, or they, would like it to be, I now seriously consider an off-label prescription. One caveat is an increased risk of genital yeast infections in both women and men, which comes with the territory when you excrete sugar in your urine. Fair to say, this intriguing story of the SGLT2s as an all-purpose gero-protector is still playing out.
Leone M and Barzilai N. An Updated Prioritization of Geroscience-Guided FDA-Approved Drugs Repurposed to Target Aging. Medical Research Archives 12(2) (2024). doi.org/10.18103/mra.v12i2.5138
James H O’Keefe and Robert Weidling et al. SGLT inhibitors for improving Healthspan and lifespan. Prog Cardiovasc Dis. 2023. Oct 17;81:2-9. doi: 10.1016/j.pcad.2023.10.003
Eugene Braunwald. SGLT2 inhibitors: the statins of the 21st century. European Heart Journal, Volume 43, Issue 11.14 March 2022, Pages 1029-1030. doi.org/10.1093/eurheartj/ehab765
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