Do longevity drugs work?
Mysteriously, however, most people are loth to trade three square meals a day in the here and now for the promise of a longer retirement, so the search has been on for chemical alternatives to fasting. Two molecules in particular have attracted attention: rapamycin, an immunosuppressant used to stop the rejection of transplanted kidneys, and metformin, an anti-diabetes drug. June 19th saw the publication of a paper summarising the evidence of their effectiveness in animals, compared with fasting.
Both rapamycin and metformin have drawn the attention of the 'live for ever' brigade because they inhibit what is known as the mTOR pathway (indeed, mTOR stands for 'mechanistic target of rapamycin'). Overactivation of this in old age is associated with hallmarks of ageing such as inflammation. Conversely, fasting suppresses mTOR activity. That promotes autophagy, a phenomenon in which cells clear out their accumulated crud, which is reckoned lifespan-enhancing. Moreover, both substances also have the advantages of having undergone safety trials as part of approval for their on-label uses, and of being off-patent, and therefore cheap.
Being off-patent, however, cuts both ways. It means commercial sponsors for human clinical trials are hard to find, since they cannot monopolise sales. As a result the Targeting Ageing with Metformin (TAME) trial, a proposal sponsored by the American Federation for Aging Research, a charity, and approved by the Food and Drug Administration in 2015, remains in abeyance for lack of funds. Rapamycin, by contrast, has been tested in what is known as the PEARL (Participatory Evaluation of Ageing with Rapamycin for Longevity) trial, which began in July 2020. But this found no strong evidence that it worked.
Animal tests have proved more definitive. The new paper, published in Aging Cell by Edward Ivimey-Cook of Glasgow University and his colleagues, gathers all the vertebrate-trial evidence that the authors could find. This amounts to 167 studies on eight species, ranging from fish to monkeys. The answers seem clear-cut. To no one's surprise, calorie restriction works. So, to a pretty-much equal extent, does rapamycin. But metformin does not.
That is a blow to those, their number unknown but probably amounting to thousands, who have twisted their doctors' arms to get an off-label prescription of it for life extension. But it is a boost to those who have opted for rapamycin. These include Vinod Khosla, one of Silicon Valley's best-known venture capitalists, and, until recently, Bryan Johnson, another Californian techie, who has made a second career out of his quest for immortality. Mr Johnson, however, dropped rapamycin in 2024 because of its side-effects (abnormal lipid and glucose levels, elevated heart rate and increased risk of skin infection).
All of which is interesting. But for mere mortals who want a long and healthy life without the risk of rapamycin's side-effects the advice remains the same: eat wisely, drink moderately, exercise regularly, sleep well. And stub that cigarette out.
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