The New York Times recently published a thoughtful piece on rapamycin, a well-established pharmaceutical drug that, in high doses, suppresses the immune system – it’s been used for years to reduce the risk of rejection in organ transplant patients and to coat cardiac stents. But that’s not what the excitement is about. Researchers have been amassing evidence that rapamycin can extend the lifespan of lab organisms, from yeast to worms to mice, with newer work being done in bigger animals like marmosets and dogs.
Rapamycin, touted by influential figures like Dr. Peter Attia and Bryan Johnson has, no surprise, captured the imagination of the longevity community. Its longevity effect is seen in both males and females, and, most strikingly, in middle-aged animals (a 9-13% lifespan increase in older mice), making it, in theory, a much more practicable drug for humans. Prescribed off-label, at lower doses, it does not cause serious side effects and does, say its boosters, exert a powerful, if subtle, anti-inflammatory effect, less aches and pains, for instance. But that by itself hardly makes it a cure for aging. Evolution has already wired human genes for a long lifespan (mice, not so much) and in any event, studies that might show rapamycin increasing human lifespan are virtually impossible to do. Meanwhile, research looking at the drug’s ability to combat specific age-related diseases like Alzheimer’s disease have so far produced only middling results. Maybe, the Times piece suggests, it’s time to pump the brakes on rapamycin outside a research setting.
To which I say, not so fast! Within a matter of months, a North Carolina-based bio-tech start-up, Sapere, co-founded by the former head of the National Cancer Institute, is planning to make available to longevity clinics a diagnostic test (SapereX) which will enable doctors to identify the patients most and least likely to benefit from rapamycin. That should significantly upgrade the drug’s clinical track record. Imagine if doctors routinely prescribed statins to their patients without knowing their cholesterol profile. Whatever health gains enjoyed by the high-cholesterol group would be washed out by the non-response of the low-cholesterol group who never needed the drug in the first place. You get the idea. To my mind, the Sapere test is a notable instance of bringing longevity medicine out of “one size fits all” thinking into the realm of personalized or precision medicine.
SapereX gets the job done by measuring the expression of the P16 protein which suppresses cell replication, a necessary check on cancer. However, higher than average amounts of P16 means that an unnecessarily high number of cells in the body have stopped dividing, in other words, become “senescent.” That, in turn, translates to high levels of chronic inflammation -- these senescent cells spit out a nasty cocktail of inflammatory molecules or cytokines. If the test determines that your senescent cell load is high, then rapamycin, in my view, should be on the table for therapeutic consideration, given that chronic inflammation plays a major role in most or all of the most common diseases of aging. Sapere’s conceptual breakthrough was to get a snapshot of systemic cellular senescence by measuring P16 expression only in the immune system’s T cells, done with a blood draw, without the need to biopsy any organ tissues. As T cell senescence goes, so goes senescence throughout the body. If T cells are unable to divide, they can’t perform one of their primary functions which is to orchestrate the immune system’s clearance of senescent cells from the rest of the body. This causes the individual’s senescent cell burden to rise as a whole, increasing the risk of chronic disease and, in some real, functional sense, accelerating the aging process.
The other half of the diagnostic puzzle here is autophagy, the process whereby the body recycles old parts from older cells, to keep them functioning robustly (or, when necessary, killing them). Whereas “senolytic” therapies like the nutraceuticals quercetin and fisetin directly help clear senescent cells, rapamycin functions as a “senomorphic,” promoting autophagy which tamps down the cells’ production of inflammatory molecules (technically, their SASP or senescence-associated secretory phenotype). Accordingly, the SapereX test returns a measure of autophagy inhibition. For someone with a high measure of inhibition, rapamycin serves to inhibit the inhibitor, or, in simpler terms, promotes autophagy, helping the immune system clear out excess senescent cells.
My longevity practice was the first to have access to the new diagnostic tech in an IRB approved registry. For the past two and a half years, I’ve been able to make finer diagnostic discriminations as I work with patients to improve their immune function. Depending on the numbers the test spits back, a senolytic therapy might be indicated or a senomorphic like rapamycin or often just paying closer attention to diet and exercise to slow down the production of cellular waste. Personally, I’ve cut my senescent cell load in half with the help of rapamycin. Still, the choice of approach isn’t a slam dunk and dosage has to be carefully monitored -- even relatively low-doses of rapamycin can produce small mouth ulcers. But I feel like I, and a handful of my patients taking rapamycin, are on the right track.
Adam R. Konopka and Dudley W. Lamming. Blazing a trail for the clinical use of rapamycin as a geroprotecTOR. GeroScience 2023 Oct; 45(5): 2769-2783. doi: 10.1007/s11357-023-00935-x
Joan B. Mannick and Dudley W. Lamming. Targeting the biology of aging with mTOR inhibitors. Nat Aging 2023 Jun: 3(6): 642-660. doi: 10.1038/s43587-023-00416-y
Lei Zhang et al. Cellular senescence: a key therapeutic target in aging and diseases. J Clin Invest. 2022 Aug 1; 132(15): e158450. doi: 10.1172/JCI158450
Yousefzadeh MJ, Flores RR, Zhu Y, et al. An aged immune system drives senescence and ageing of solid organs. Nature. 2021;594(7861):100-105. doi:10.1038/s41586-021-03547-7
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