Less is more: early short-course rapamycin effective in sustained anti-aging effects

By Dr. Liji Thomas, MDSep 1 2022Reviewed by Danielle Ellis, B.Sc.

Rapamycin is a licensed drug used in cancer treatment. It can inhibit cell growth in post-transplant patients by suppressing the immune response. Currently, much interest is being shown in this macrolide compound because of its ability to delay aging and extend the lifespan of several animal models when given lifelong.

A new study shows that a brief treatment period could have the same anti-aging efficacy and duration of effect but without the potentially serious adverse effects of chronic administration.

Introduction

Rapamycin is an inhibitor of the enzyme TORC1. In mouse models, rapamycin has slowed cognitive decline, cancers, cardiovascular aging, and immune impairments related to age. Earlier experiments have used long-term protocols of rapamycin administration at various dosage levels.

The adverse effects of rapamycin have been a concern, driving researchers to examine the feasibility of lower doses or short-term treatment. Late in life, short courses of the drug have not only led to improved immune responses in older people but, in mice, to an elongation of the lifespan. The question is whether this type of treatment simulates lifelong treatment results and whether early-life treatment for short periods can give comparable benefits.

The study carried out by a research group at the Max Planck Institute for Biology of Ageing in Cologne, Germany, published in the journal Nature Aging, reports the effects of treatment with rapamycin in fruit flies at various ages and for differing durations.

What did the study show?

Lifespan prolongation

As expected from earlier mouse studies, rapamycin treatment in late life (at 30 or 45 days of life) increased the lifespan of the fruit flies, but only in females. At day 60, corresponding to extreme old age, rapamycin did not prolong life when only one in five flies were still alive. In other words, the later the treatment began, the less prolonged the lifespan.  

Interestingly, if treatment was begun on day 30 and continued lifelong, the effect was less than if it began in early life (days 1-30) and continued lifelong. Moreover, the marked extension in lifespan when rapamycin was started early in life and continued lifelong was replicated when the drug was stopped at day 30. Thus, with early life onset, lifelong administration was no longer necessary. The researchers dubbed this effect “rapamycin memory” – “rapamycin in only the first 15 d of adult life recapitulated the full lifespan extension achieved by chronic treatment.”

Again, treatment between days 15 and 30 led to slightly less of an increase in the lifespan compared to lifelong treatment.

How was this effect brought about? The scientists think it could be via the reduction of intestinal stem cells (ISCs) following short-term exposure to rapamycin. ISCs are actively dividing cells that increase with age in female flies. They help repair intestinal damage but are also associated with later-life intestinal dysplasia.

Reduced turnover

Interestingly, rapamycin exposure during the first 15 days of adult life reduced ISC numbers comparably to lifelong exposure. The effect persisted; ISCs remained quiescent for up to 45 days after treatment, despite drug levels dropping to normal within 10 days post-treatment.

The result was a reduced gut epithelium turnover rate after either lifelong or brief early treatment with rapamycin because the rapamycin-treated cells were present in the gut till old age. Moreover, apoptosis of enterocytes was inhibited equally and significantly by either early short-course or long-term treatment with rapamycin.

Improved gut health

The gut remained much healthier in old flies after short-term or chronic treatment, with few dysplastic regions. This was accompanied by improved gut barrier function and better gut mucosal integrity.

“These results indicate that brief, early-life rapamycin exposure exerted long-lasting protective effects on the intestine.”

In contrast to the “memory” effect on lifespan, rapamycin appeared to inhibit TORC1 only briefly. The resulting downstream effects, independent of its primary target, caused long-term prolongation of lifespan via the mechanisms described already.

Lifespan prolongation appeared to be mediated by an increase in autophagy, a known downstream effect of TORC1. Rapamycin acutely induces autophagy which persists for a long period after the drug is withdrawn, despite the return of TORC1 levels to normal within 2 days of stopping rapamycin.

To confirm this, the scientists abolished the increase in autophagy induced by rapamycin. This led to the absence of any effect on the lifespan or gut barrier function, irrespective of rapamycin exposure duration.  

This led to the conclusion that “rapamycin memory” was mediated by a brief rise in autophagy in enterocytes, which produced all the features of brief rapamycin treatment.

This was confirmed by manipulating the gene that induces autophagy in flies, with and without using rapamycin. The researchers observed that even a brief increase in autophagy within enterocytes led to a persistent increase in lifespan and intestinal integrity, identical to that induced by chronic or brief rapamycin treatment. Rapamycin exposure did not increase this effect.

They could replicate the effects of brief rapamycin treatment by increasing the expression of the lysosomal alpha-mannidose V (LManV) gene. Such genes are responsible for lysozyme-associated secretory autophagy, a secretion pathway activated by an infection important to gut integrity.

Secretory Paneth cells contain lysozyme, support ISC growth, and proliferation, and are key to gut health. Rapamycin-induced increase in autophagy within these cells resulted in sustained improvement in gut health, preservation of gut mucosal integrity, and regeneration of the gut epithelium six months after stopping the drug.

The benefits of rapamycin seen in flies were conserved in mammals, as shown in mouse experiments. A short course beginning at three months of age in adult mice, lasting three months, was just as effective as long-term treatment.

Lipopolysaccharide binding protein (LBP) is a marker for leaky gut epithelium, allowing bacteria to escape from the gut into circulation. By measuring blood levels of LBP in mouse plasma, they found further evidence that rapamycin produced a chronic change for the better in mammals. That is, it reduced LBP levels in plasma and increased the proportion of tight junctions, which are key to preserving an intact gut mucosal barrier, at six months from the administration.

What are the implications?

In summary, a short course of rapamycin in early adulthood appears to activate rapamycin memory. It prolongs the lifespan of fruit flies, induces prolonged and increased autophagy, and reduces gut dysplastic changes while promoting regeneration. When given early in life, the benefits of rapamycin were comparable to those seen with chronic treatment and appears to last lifelong but with fewer adverse effects. The same effects were also seen in mice, indicating that mammals could also benefit from this drug.

The study also brings the key role of autophagy in averting age-related deterioration of body systems into the limelight. The question remains whether a short exposure to rapamycin in early adult life can slow the aging of cardiovascular, cognitive, and immune systems while increasing the lifespan, in mice, equivalent to lifelong rapamycin administration.

Prof. Linda Partridge, the senior author of the study, comments:

It will be important to discover whether it is possible to achieve the geroprotective effects of rapamycin in mice and in humans with treatment starting later in life, since ideally the period of treatment should be minimized. It may be possible also to use intermittent dosing. This study has opened new doors, but also raised many new questions.”