Γ—

Rapamycin is Not a Caloric Restriction Mimetic

Its effects work through different metabolic pathways.

Share







RapamycinRapamycin

Although rapamycin reliably extends lifespan in a range of organisms, new research shows that it does not achieve this via the same pathways as caloric restriction [1]. Understanding how the two processes differ and interact could help researchers eventually piece together the longevity puzzle.

To do this, we need your support. Your charitable contribution tranforms into rejuvenation research, news, shows, and more. Will you help?

Caloric or dietary restriction (CR) is perhaps the most robust, effective method known to increase lifespan. Its effects were first reported nearly 100 years ago and have been confirmed in many experiments in a wide variety of organisms since then. In the last two decades, rapamycin has emerged as a potential CR mimetic – a drug that can accomplish the same effect without the hassle of counting calories.

Now, a team of researchers in the Netherlands used progeroid mice to investigate whether rapamycin really is a CR mimetic. These Ercc1Ξ”/- mice have defective DNA repair and live for only 4-6 months. Surprisingly, they are more sensitive to caloric restriction than wild-type mice, with their lifespan more than doubling under conditions that lead to only a 30% increase in wild-type mice. This sensitivity makes them ideal for testing a CR mimetic, since even a small effect should be detectable.

When young Ercc1Ξ”/- mice were fed rapamycin-supplemented food, no increase in lifespan was detected. The researchers repeated the experiment in older mice and still found no increase. Likewise, varying the rapamycin dosage didn’t lead to a longer (or shorter) lifespan in Ercc1Ξ”/- mice. Although caloric restriction clearly increases their lifespan, rapamycin seems to have no effect.

The team dug a bit further to see if rapamycin might have been making the mice healthier even if they didn’t live longer. In liver health assays and evaluation of the vascular and nervous system, as well as neurological degeneration, Ercc1Ξ”/- mice fed rapamycin consistently looked similar to those on a control diet and different from those on a CR diet. Finally, the researchers also genetically altered mammalian target of rapamycin (mTOR) signaling in Ercc1Ξ”/- mice and still found no effect on lifespan or healthspan.

Dietary restriction (DR) and rapamycin extend healthspan and life span across multiple species. We have recently shown that DR in progeroid DNA repair-deficient mice dramatically extended healthspan and trippled life span. Here, we show that rapamycin, while significantly lowering mTOR signaling, failed to improve life span nor healthspan of DNA repair-deficient Ercc1βˆ†/βˆ’ mice, contrary to DR tested in parallel. Rapamycin interventions focusing on dosage, gender, and timing all were unable to alter life span. Even genetically modifying mTOR signaling failed to increase life span of DNA repair-deficient mice. The absence of effects by rapamycin on P53 in brain and transcription stress in liver is in sharp contrast with results obtained by DR, and appoints reducing DNA damage and transcription stress as an important mode of action of DR, lacking by rapamycin. Together, this indicates that mTOR inhibition does not mediate the beneficial effects of DR in progeroid mice, revealing that DR and rapamycin strongly differ in their modes of action.

Conclusion

Altogether, these experiments are a pretty clear demonstration that however rapamycin extends lifespan, it isn’t a caloric restriction mimetic, and the two probably affect lifespan via different mechanisms. However, there are lots of studies linking caloric restriction with TOR signaling, so there’s probably some crosstalk between the various pathways. The fact that rapamycin doesn’t seem to work in Ercc1Ξ”/- mice but has worked well in lots of other organisms suggests that its effect might be mediated via DNA repair mechanisms. While rapamycin no longer offers hope as a substitute for the hard work of caloric restriction, we now have the benefit of two reliable, different longevity treatments to compare and investigate.

We would like to ask you a small favor. We are a non-profit foundation, and unlike some other organizations, we have no shareholders and no products to sell you. We are committed to responsible journalism, free from commercial or political influence, that allows you to make informed decisions about your future health.

All our news and educational content is free for everyone to read, but it does mean that we rely on the help of people like you. Every contribution, no matter if it’s big or small, supports independent journalism and sustains our future. You can support us by making a donation or in other ways at no cost to you.

Study: Waist-to-Hip Ratio Predicts Mortality Better Than BMI

A new study suggests that waist-to-hip ratio (WHR) has a more linear correlation with all-cause mortality than either body mass...

Restoring Heart Regeneration With a Metabolic Switch

In a recent article in Nature, researchers have restored cardiac regeneration to adult mice by disabling fatty acid oxidation, discovering...

Human Clinical Trials of NMN for Safety and Effectiveness

In a recent paper, researchers reviewed the literature for human clinical trials that address NMN's safety and anti-aging effects [1]....

Lifespan News – Elon Musk and the Living Forever Curse

On this episode of Lifespan News, Ryan O'Shea ruminates on Elon Musk's statement on living forever being a curse rather...

Literature

[1] BrikisdΓ³ttir MB, Jaarsma D, Brandt RMC, Barnhoorn S, van Vliet N, Imholz S, van Oostrom CT, Nagaraja B, Portilla FernΓ‘ndez E, Roks AJF, Elgersma Y, van Steeg H, Ferreira JA, Pennings JLA, Hoeijamkers JHJ, Vermeij WP, DollΓ© MET. Unlike dietary restriction, rapamycin fails to extend lifespan and reduce transcription stress in progeroid DNA repair-deficient mice. Aging Cell (2020), doi: 10.1111/acel.13302
CategoryNews
About the author

Sedeer el-Showk

Sedeer became a professional science writer after finishing a degree in biology. He also writes poetry and sff, and somehow juggles an ever-growing list of hobbies from programming to knitting to gardening. Eternal curiosity and good fortune have taken him to many parts of the world, but he’s settled in Helsinki, Finland for the moment. He hopes he’ll never stop learning new things.
No Comments
Write a comment:

*

Your email address will not be published.

This site uses Akismet to reduce spam. Learn how your comment data is processed.