On the Prospects for Intermittent Late-Life Use of Rapamycin

Researchers here discuss the evidence for intermittent use of rapamycin, an mTOR inhibitor that has undesirable side-effects, to be a path forward to producing benefits in older people. We should probably weigh the animal evidence for this class of therapy against the recent failure of a phase III trial for a related form of mTOR inhibition designed to bypass the side-effects of rapamycin. The beneficial effect sizes in humans may be too small to be worth the cost and time of development at the end of the day, and this is somewhat characteristic of interventions, such as mTOR inhibition, that upregulate cellular stress responses such as autophagy. The effect sizes scale down with increased species life span. This is perhaps best illustrated by calorie restriction, an intervention that also acts through increased autophagy. While the practice of calorie restriction can extend life span by up to 40% in short-lived mice, it adds a few years at best in long-lived humans.

Rapamycin is arguably the best-studied pharmaceutical intervention for reliable lifespan and healthspan extension in a wide array of model organisms. These consistent results are encouraging for those eager to develop interventions for prolonging human lifespan or healthspan. Until recently publications of rapamycin treatment in animal models focused on near lifelong treatment, a scenario that is unrealistic to apply to improving the human condition. However, this is beginning to change. A few groups have endeavored to address this by administering rapamycin to mammalian model organisms beginning at mid- to late-life. Results so far have been encouraging - even when delivered late in life, rapamycin can improve both health- and lifespan in mice.

To bring the field even closer to a limited duration regimen that continues to benefit the organism in late life, some groups have published that both intermittent or transient rapamycin treatment can improve lifespan or organ function. Our own work has demonstrated that 8 weeks of rapamycin delivered late in life in mice can confer an improvement in diastolic heart function. This effect persisted for a further 8 weeks post-treatment, even after the metabolic changes due to acute treatment reverted back to pre-treatment levels. That rapamycin could be useful for larger mammals was given credence through a study of dog cardiac outcomes: 10 weeks of rapamycin administered to middle-aged companion dogs was sufficient to improve measures of both systolic and diastolic cardiac function.

A critical goal of any pharmaceutical treatment is to minimize off-target effects. Rapamycin's use in the clinic has been extensive, and side-effects have been reported, though they generally resolve when the drug is removed. Efforts to reduce these off-target responses in humans have ranged from co-treatment with another drug, reducing the dose of rapamycin, and changing the dosing schedule to a more intermittent or transient one. Altering the delivery of rapamycin from continuous to intermittent may help in animal models as well; it was found that the positive effects of an intermittent rapamycin treatment can be separated from its side effects. At 2mg/kg per day, every five days, beginning at 20 months of age in mice, rapamycin could increase medial and maximal lifespan without detrimental effects on glucose homeostasis. This was also in the absence of metabolic effects seen in models using higher/longer-term doses of rapamycin. Intermittent treatment may, therefore, help to balance the minimization of off-target effects with the desired continual boost to health-span.

Link: https://doi.org/10.18632/aging.102947


Perhaps the magic of rapamycin is from it's effect on targets other than mtor.

Posted by: Lee at March 23rd, 2020 1:19 PM

Rapamycin always gets lumped together with CR, being claimed to be a CR mimetic, however there has been mounting evidence in the last couple years that it works quite differently, so therefore one should not assume that the benefits will scale the same way CR does. This paper by Gladyshev showed that Rapamycin's transcriptomic profile was markedly different from CR and other CR mimetics such as resveratrol.
https://www.sciencedirect.com/science/article/abs/pii/S1550413119303729 (paywall)

I saw a couple other similar papers as well, but don't have the time at the moment to track them down.

Posted by: Chris Linnell at March 23rd, 2020 6:46 PM
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