Rapamycin: the molecule from Easter Island

The story begins in 1972 with a soil sample from Rapa Nui, Easter Island. From it, researchers isolated a bacterium that produced a substance with antifungal activity. It was named after the place it was found: rapamycin. As an antifungal it was of little use, but it turned out to dampen the immune system, and so the substance came onto the market in the late nineties as an immunosuppressant after kidney transplantation.

The story could have ended there. Instead, basic research found out what the molecule actually acts on, and named the target protein after it: mTOR, mechanistic target of rapamycin. mTOR is the cell’s central nutrient sensor. It reports whether amino acids, energy and growth signals are present, and then switches the cell to growth and protein synthesis. If it is inhibited, the cell tips into the opposite mode: autophagy, recycling, repair. Precisely the state, in other words, that caloric restriction and fasting also trigger – those interventions that since the 1930s have been the only ones reliably to extend the lives of laboratory animals.

If there was ever a pharmacological candidate for ageing itself, it is this one.

The mouse data are extraordinary

In 2009 the Interventions Testing Program of the American National Institute on Aging published in Nature a result that changed ageing research. Genetically heterogeneous mice that received rapamycin in their feed from the age of 600 days lived significantly longer. Converted, this starting point corresponds to a human of around sixty. The effect therefore occurred even though half of life was already over.

Then came the dose-response curve. In the 2014 follow-up study, median lifespan rose at the highest dose tested by 23 per cent in male and 26 per cent in female animals, and maximum lifespan also increased. Further work showed that even a time-limited administration works: three months of treatment in old mice, then nothing more, and the survival curve shifts all the same.

The Interventions Testing Program tests in parallel at three institutes following a shared protocol. This kind of independent multiple replication is rare in ageing research. Rapamycin has passed it, and repeatedly. That is why it is still regarded among geroscience researchers as the reference substance against which everything else has to be measured.

What has actually been measured in humans

The first serious human finding came in 2014 from a group around Joan Mannick. Older volunteers received a rapamycin derivative in low dose for six weeks, after which the flu vaccination was administered. The antibody response improved by around twenty per cent. That is not life extension, but it is a direct measurement of one of the most reliable ageing markers there is: the declining adaptive immune response. A follow-up study found fewer respiratory infections.

The most important study in healthy adults so far is PEARL, a decentralised, double-blind, placebo-controlled investigation over 48 weeks. 114 participants received five or ten milligrams of a compounded rapamycin, or placebo, weekly. The results deserve close reading, because they are regularly cited too optimistically in the longevity scene.

The primary endpoint, the reduction of visceral fat tissue, was not reached. Safety was unremarkable: adverse events occurred with comparable frequency in all groups, and laboratory values remained within the normal range. Among the secondary endpoints, women in the ten-milligram group showed a significant increase in lean mass, on average about five per cent after 48 weeks, along with less pain and better scores in quality-of-life questionnaires. Men in this group gained on average a good one per cent in bone mineral content.

The dose used is worth mentioning. The authors convert their five and ten milligrams of the compounded preparation into approximately 1.4 and 2.9 milligrams respectively of commercially available rapamycin per week. That is a fraction of what transplant recipients receive daily. The hypothesis behind it: a partial, intermittent inhibition of mTORC1 triggers the repair programmes without producing the immunosuppression that occurs with a chronic full dose.

The dog as the decisive witness

Perhaps the most important ongoing study concerns neither mice nor humans. Within the Dog Aging Project, TRIAD is the first rigorous test of a pharmacological intervention against biological ageing with lifespan as the endpoint to be carried out outside the laboratory in any species. Planned are 580 dogs aged seven and over and weighing at least twenty kilograms, one year of rapamycin or placebo, followed by two years of observation. The project is financed among other things by a seven-million-dollar grant from the National Institutes of Health; completion is scheduled for November 2029.

Dogs are the ideal intermediate step. They live in our households, share our environment, develop comparable age-related diseases and die early enough for one to live to see the result. Preliminary work from the same project suggests that low-dose rapamycin improves the cardiac function of older dogs.

What is happening in the USA

Rapamycin is a generic, it is approved, and doctors in the USA may prescribe off label. That is precisely what is happening. Telemedicine providers and specialised longevity practices prescribe weekly low doses to healthy people; the PEARL group had previously conducted a survey among 333 users. There is therefore a real practice of use, comprising several thousand people, that runs far ahead of the evidence.

And here precision is needed, because an image circulates in this scene that cannot be sustained: that users look decades younger. There are no controlled data for that. What there is are self-reports, before-and-after pictures and surveys without a control group. In the only randomised long-term study in healthy people, not even the primary endpoint changed.

What counts in the consultation

For the community pharmacy this is no longer an exotic topic, because the question does come up. It comes from customers who listen to podcasts, order from abroad or are looking for a second opinion.

In Switzerland, sirolimus is approved for transplant medicine indications. Any use for ageing prevention is off label, prescription-only, not covered by health insurance and takes place outside any guideline. That is not a judgement but the starting point of every conversation.

Three points are above all pharmacologically relevant. First, the interactions: rapamycin is metabolised via CYP3A4 and P-glycoprotein, so azole antifungals, macrolides, certain calcium channel blockers and grapefruit – and conversely enzyme inducers such as St John’s wort – influence the levels considerably. Second, the effects known from transplant medicine, which stem from chronic full dosing: immunosuppression, hyperlipidaemia, hyperglycaemia, aphthae and delayed wound healing. Whether they remain relevant at a weekly low dose is precisely the open question; the presumption is no, the proof is lacking. Third, the practical consequences: live vaccines, planned operations and infections are situations in which such self-medication has to be known to the treating physician.

And then there is the point that should not be relativised: there are no long-term data on use in healthy people over decades. The longest controlled observation lasted 48 weeks.

Why the enthusiasm is nonetheless justified

One can read this text as a sobering account. That would be a misunderstanding.

Ageing research lived for decades on candidates that worked in worms and then disappeared. Rapamycin is the great exception. It works in yeast, worms, flies and mammals, it works in independent laboratories following a shared protocol, it works in old animals, it works intermittently, and its molecular point of attack is one of the best-understood signalling pathways in cell biology. In humans there is clean randomised evidence that a related substance partially reverses an age-related immune weakness. And in a few years a study with almost six hundred dogs will show whether this can be transferred to a mammal that shares our sofa.

That is no small matter. It is the most promising attempt so far to address ageing itself as a treatable process, rather than one age-related disease after another.

What is missing is not the idea. What is missing are the years. And the only serious attitude to this is: watch with enthusiasm, advise attentively, and wait for the results before anticipating them.