Source: United Kingdom – Executive Government & Departments

June 19, 2025

A meta-analysis published in Aging Cell looks at the effect of Rapamycin, Metformin, and Dietary Restriction on non-human vertebrate lifespan.

Dr David Clancy, Lecturer in Biogerontology, Lancaster University, said:

“Diet restriction seems to extend lifespan significantly but is hard to do, and certainly no fun. So Ivimey-Cook et al decided to look at hundreds of datasets across 8 species of vertebrate which examined lifespan effects of diet restriction (DR), the immune suppressant drug rapamycin and the diabetes drug metformin. Both drugs have been extensively tested for lifespan extension. The closest species to humans were rhesus monkeys (4 studies) and the furthest from humans were fish (4 studies). The most common were mice and rats (210 studies).

“This well-done study showed DR and rapamycin extending lifespan with significant consistency across studies, in both sexes, DR probably a little greater than rapamycin. However metformin did not. That is a pity for the many people now taking off-label metformin for lifespan extension. Let’s hope it doesn’t have any or many adverse effects.

“Rapamycin is used mainly as an immune suppressant in kidney transplant. Oddly it may be slightly toxic to kidneys in humans but has not been tested in non-renal patients, and not over the long term as in these lifespan studies. Early experiments in flies and worms show that it needs the cell process known as autophagy to exert its lifespan extension. This is the process whereby cells ‘clean’ themselves of damaged and misfolded proteins and other damaged biomolecules and cell components and recycle them. Unsurprisingly research is looking for stimulators of autophagy (which DR achieves, and exercise), and is searching for ‘rapalogues’ – molecules similar in action to rapamycin but ideally smaller, less complex molecules with no immune system or other ‘off-target’ effects.”

Prof Dame Linda Partridge, Professorial Fellow, UCL, said:

“This meta-analysis of published studies of the effects on vertebrate animals of dietary restriction (DR) and two licensed drugs, metformin and rapamycin, finds that only DR and rapamycin consistently extend lifespan. They do so to about the same extent and with similar effects in males and females. Dietary restriction is long established as ameliorating many of the adverse effects of ageing, The discovery of lifespan extension from rapamycin is more recent. In mice irapamycin also holds back several ageing-related pathologies. The finding that DR and rapamycin have effects of similar magnitude on lifespan across species implies that rapamycin is a candidate for repurposing for prevention of ageing-related pathologies in humans. Other licensed drugs may be similarly geroprotective, and more work is needed to investigate their potential to prevent deterioration of health in older people. Given that many of the candidate drugs are off patent, public and charity funding may be needed to investigate the potential of these drugs for prevention of age-related diseases.”

Prof Lynne Cox, Associate Professor of Biochemistry, University of Oxford, said:

“Research into ageing understandably attracts a lot of public interest. For most people, retaining their health is more important than the exact length of time they live, but it is also the case that increased lifespan usually reflects better health, and in the scientific laboratory, lifespan (time from birth to death) is clear and easy to measure.

“Dietary restriction (DR, i.e. cutting down on overall food intake, reducing calories or undertaking periods of fasting) has been widely reported to increase lifespan in experimental animals. But it is very hard for people to achieve DR for long periods, and in fact research suggests that it is actually harmful for older adults to cut down on how much they eat.

“Scientists have therefore looked for ways of achieving lifespan extension without having to stick to a highly restrictive diet, using drugs that might mimic DR, particularly rapamycin and metformin. Each drug has been reported to increase lifespan in multiple scientific reports. In this new study, the researchers compare results from 167 scientific papers studying the effect on lifespan of dietary restriction, metformin or rapamycin. They conclude that DR and rapamycin (but not metformin) increase lifespan in all vertebrate species analysed, and that males and females equally benefit.

“The difficulties these researchers encountered when trying to find original raw data highlights a major problem in the ageing field – the lack of transparency and accessibility of lifespan data so that others can cross check and carry out further analysis. They also report far fewer studies on females compared with males – again a major issue with biomedical research.

“The paper is an interesting first-pass analysis, but it doesn’t take into account the really important aspect of drug dosing or duration, which can have huge impacts on healthspan and lifespan; a very high dose of a drug might be toxic, while much lower doses of the drug could be beneficial. Dosing is particularly important with rapamycin which is immunosuppressive at high doses but immunosupportive at low doses. Similarly, metformin either increases or decreases lifespan in mice according to dose. It is therefore vital that the drug dose, duration of treatment, and the age of the individual at which the drug is administered, are all taken into account when analysing lifespan effects.  By drawing together results from so many studies across different vertebrate species, this paper is a step in the right direction but highlights the need for even more studies that provide important information on age, dose and treatment duration, as well as correlations with detailed health measures.”

Prof Neil Mabbott, Personal Chair of Immunopathology, Roslin Institute & Royal (Dick) School of Veterinary Sciences, University of Edinburgh, said:

“Many studies have described how interventions such as dietary restriction can extend lifespans in experimental settings.  However, the impact that some of these approaches have on lifespans has occasionally been inconsistent, or not observed, when repeated in different animal species or laboratories. To address these concerns the authors have analysed over 900 effect sizes across 167 studies to compare the reported effects of three interventions on their ability to extend lifespan.  Their analysis revealed that dietary restriction or treatment with the immunosuppressant drug rapamycin were equally effective in extending lifespans in the animal species used in those studies. 

“This is an interesting and useful study, but more research is now required to uncover how these treatments extend lifespans.  Furthermore, none of the studies the authors compared described effects in humans.  So it is uncertain whether the effects described in animals such as laboratory mice, rats, dogs, macaques, fish and mouse lemurs, are also applicable to humans.

“With advances in health care etc. lifespans across the world are forecast to steadily increase.  While this is obviously to be welcomed, an increased elderly population does bring with it challenges, especially to health care providers.  In this study the authors compared how effective the different interventions were on extending lifespan.  However, rather than simply focusing on lifespan duration, we should also focus our efforts on extending the health-span.  This is the period of our lives in which we live healthily and disease-free.  While this study found consistent effects on lifespan, it is uncertain whether these interventions have a similar impact on the health-span.  Living a lot longer but with the multiple morbidities that can accompany aging is perhaps not the best thing.  Treatments that can improve the duration of those healthy years, will themselves feedback into increased lifespans.”

Prof Ilaria Bellantuono, Co-director of the Healthy Lifespan Institute, University of Sheffield, said:

“This meta-analysis compiles existing data on the effects of dietary restriction (DR), metformin, and rapamycin on lifespan across multiple species, but its findings—particularly regarding DR and rapamycin—should be interpreted with caution. While the authors report no significant differences between these two interventions or between sexes, this may reflect limitations in the underlying data, and its heterogeneity, rather than a true absence of effect. Both rapamycin and DR have demonstrated sex-specific and context-dependent effects on longevity in numerous experimental models, especially in mice. Moreover, the analysis cannot address key translational questions, such as dose dependency and timing of intervention—factors that are particularly important given rapamycin’s known side effects. Perhaps more critically, the study focuses on lifespan rather than healthspan, and it is well established that longer life does not necessarily mean more years in good health. Although the study reinforces general principles about the influence of these interventions on longevity, its relevance to human ageing and therapeutic translation is limited, and claims of equivalence should be treated with caution.”

Dr Laura Sinclair, Postdoctoral Research Associate, University of Exeter, said:

“The team made use of the powerful tool of meta-analysis to look at how dietary restriction, metformin and rapamycin affect longevity across published experimental research studies.

“As one might expect, a drug’s effect on lifespan can be quite difficult to assess in humans, so research often uses model organisms for assessing lifespan, while human studies focus more on age-related diseases. For example, the Targeting Ageing with Metformin (TAME) Trial in the US will use mortality and a combination of age-related disease indications to examine metformin’s effects on ageing and lifespan.

“The team analysed data from lots of experiments from other studies. Most of the experiments that the team studied will have involved giving an animal a treatment and measuring their lifespan compared to a control group of animals not given the treatment. The dietary restriction treatment may have consisted of giving the animal less food, less time to eat and/or less nutrition in their food.

Dietary restriction is well known to increase longevity across many studies in animals, but its effects are difficult to replicate in people in the real world for many reasons.

“When you eat less, lots of nutrition-sensing pathways are affected in your cells. These pathways overlap a lot with cell-controlling pathways that are associated with living longer. It is important to study these pathways as targeting them might help us be able to live healthier in older age. It is also important to consider sex differences as some differences in response between sexes have been observed in other studies.

‘Rapamycin, not metformin, mirrors dietary restriction-2driven lifespan extension in vertebrates: a meta-analysis’ by Ivimey-Cook et al. will be published in Aging Cell at 00:01 UK time on Thursday 19th June, which is when the embargo will lift.

Declared interests

Prof Neil Mabbott “I have no conflicts of interest to declare”

Prof Ilaria Bellantuono “I am consulting for Holland and Barrett.”

Dr Laura Sinclair “My project is currently funded by the charity, Animal-Free Research UK”

Prof Lynne Cox “Lynne Cox is a biochemist at the university of Oxford. She runs the Lab of Ageing and Cell Senescence in Oxford, and has strong research interest in rapamycin and drugs that act in similar ways to preserve healthspan. She has served for the past 3 years as co-director of the UK Ageing research Networks (UKAN) and is currently Program Director of Dynamic Resilience, a $60m global healthspan program co-funded by Wellcome Leap and Temasek Trust.”

Dr David Clancy “No interested to declare”

For all other experts no reply to our request for COIs was receive.