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Key findings:

  • Dietary restriction - from intermittent fasting to cutting calories - consistently extended lifespan across all vertebrate species analysed in this study.
  • Rapamycin increased lifespan to the same extent as dietary restriction.
  • Metformin showed no clear longevity benefit although it is widely used for type 2 diabetes.
  • Lifespan gains were the same for males and females, and did not depend on the type of diet restriction.

The anti-aging drug Rapamycin (sirolimus) has the same life-extending effect as eating less, according to new research from the University of East Anglia and University of Glasgow.

Dietary restriction has long been considered one of the most reliable methods for increasing lifespan across species.

But if fasting for hours sounds unpleasant, science may suggest another route to achieving a longer and healthier life.

A new study published today reveals compelling evidence that Rapamycin, a compound originally developed as an immunosuppressant, offers comparable life-extending benefits in eight species of vertebrates, not including humans. [Note: this study did not include the most recent, successful marmoset study that has yet to be published: Breaking: 15% Healthy Lifespan improvement via Rapamycin seen in Marmosets ]

Co-lead researcher Dr Zahida Sultanova, from UEA’s School of Biological Sciences, said: “Dietary restriction - for example through intermittent fasting or reduced calorie intake - has been the gold standard for living longer. But it’s difficult for most of us to maintain long-term.

“We wanted to know if popular anti-aging drugs like Rapamycin or Metformin could offer similar effects without the need to cut calories.”

The research team looked at data from 167 studies of lifespan across eight vertebrate species including fish, mice, rats and primates – in this, the largest study of its kind.

They investigated the effect of dietary restriction on longevity - as well as that of Rapamycin and Metformin, both of which have been touted as life-extending drugs.

The team found that Rapamycin extends lifespan almost as consistently as eating less, while the Type 2 diabetes medicine, Metformin, does not.

We found that eating less still came out on top as the most consistent way to prolong life in all animals but rapamycin was close behind. Metformin, in contrast, showed no clear benefit. The life-extension effect of eating less was the same in both sexes, and it didn’t matter whether the diet plan involved eating smaller portions or intermittent fasting.

That makes rapamycin one of the most exciting leads for new anti-ageing therapies. Ageing might not be considered a disease, but it is a risk factor behind many diseases from cancer to dementia. If we slow that underlying process, the benefit will be extra years of quality life and lower healthcare bills as the world’s population grows older.

https://www.eurekalert.org/news-releases/1087826

More information: Open Access Paper Rapamycin, not metformin, mirrors dietary restriction-driven lifespan extension in vertebrates: a meta-analysis, Aging Cell (2025).

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#2

Does this imply metformin is neutral, or negative in lifespan impact?

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#3

Metformin is useful, but not by itself (unless you are diabetic). If you pair Metformin (or Acarbose or SGLT2i) with Rapamycin, you get an enhancement of Rapamycin’s benefits. Metformin counteracts some of Rapamycin’s negatives making it even more potent.

However, if you are not diabetic or not taking Rapamycin, you probably shouldn’t take Metformin.

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#4

This is what I was thinking. I’m using berberine but I’m thinking of swapping to metformin on the day before, day of and 2 days after rapamycin dosing as it doesn’t interact with CYP3A4 and there is some evidence it is a beneficial combination. I’ll use berberine other days though I might end up using metformin permanently depending on how I react to it.

Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice | Aging
“In genetically heterogeneous HET3 mice, we found that chronic administration of encapsulated rapamycin by diet caused a measurable defect in glucose metabolism in both male and female mice as early as 1 month after treatment. In female mice, this defect was alleviated over time by simultaneous treatment with metformin, also by diet, such that females treated with both drugs where indistinguishable from control mice during glucose tolerance tests”

Interesting effect on weight though I’d like to see a more thorough breakdown of fat vs muscle vs bone mass:
“After 9 months of treatment, eRapa males weighed significantly less than all other groups including eRapa+Met mice suggesting that metformin abolishes this effect of rapamycin. Females treated with rapamycin, either eRapa or eRapa+Met, weighed significantly less than control and Met-treated females starting at 3 months of treatment and continuing through 9 months (Figure 1). The masses of most fat depots were reduced in mice fed rapamycin at this 9 month point, as were hind-limb skeletal muscle mass in males and kidney mass reduced in female mice fed rapamycin (Supplementary Table 1). Metformin had no effect on tissue mass at this time point except for a small reduction in hind limb muscle mass in females.”

“Our main finding here is that a multi-drug approach utilizing metformin can alleviate common metabolic deficits associated with chronic rapamycin treatment as a pro-longevity therapeutic.”

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#5

I stopped taking metformin due to its potential in hurting muscle gains, and it didn’t do much for my crazy glucose spikes.

I’m taking dapagliflozin, acarbose and rapa, and my spikes are in check.

My a1c is always good

In my case, is there any reason to consider metformin again?

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#6

For centuries, humans have searched for ways to extend life. Alchemists never found the philosopher’s stone, but scientists have consistently shown that a longer life can be attained by eating less – at least in certain lab animals. But can we find a way to live longer while still enjoying our food?

Compounds that mimic the biological effects of dieting could be the answer, and the two most popular diet-mimicking drugs are rapamycin and metformin. In a new study, my colleagues and I found that rapamycin prolongs life almost as consistently as eating less, whereas metformin does not.

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#7

Hi all – I’m considering adding Metformin (500mg twice daily with meals) to my stack and would appreciate any feedback, especially from those with experience combining it with Rapamycin and Acarbose.

Current Core Protocol:

  • Rapamycin: 18mg fortnightly (single dose)
  • Acarbose: 200mg with every meal
  • Metabolic background: Very mild insulin resistance (confirmed via Glucose-Insulin Tolerance Test), likely genetic

Primary Goal for Metformin:
Targeting potential anti-cancer benefits via:

  • Blunting post-prandial glucose spikes
  • Lowering overall circulating glucose
  • Nudging metabolism further toward ketone utilization

Relevant Context:
I’m already on a comprehensive longevity and cardiovascular protocol, including:

  • Lipid management: Rosuvastatin + Ezetimibe + Bempedoic Acid
  • Other additions: Lithium Orotate and various supplements targeting cardiovascular and mitochondrial health
  • Also incorporating twice-yearly fasting combined with IV ozone therapy, primarily for metabolic and anti-cancer benefits
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#8

I’ll share that metformin did not drastically lower my post prandial glucose spikes. Replacing it with dapagliflozin made a much bigger difference, for me.

I also take acarbose and rapamycin

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#9

The Economist Magazine on Rapamycin…

Do longevity drugs work?

Animal studies suggest rapamycin is as effective as long-term fasting

Both rapamycin and metformin have drawn the attention of the “live for ever” brigade because they inhibit what is known as the mtor pathway (indeed, mtor stands for “mechanistic target of rapamycin”). Overactivation of this in old age is associated with hallmarks of ageing such as inflammation. Conversely, fasting suppresses mtor activity. That promotes autophagy, a phenomenon in which cells clear out their accumulated crud, which is reckoned lifespan-enhancing. Moreover, both substances also have the advantages of having undergone safety trials as part of approval for their on-label uses, and of being off-patent, and therefore cheap.

Being off-patent, however, cuts both ways. It means commercial sponsors for human clinical trials are hard to find, since they cannot monopolise sales. As a result the Targeting Ageing with Metformin (tame) trial, a proposal sponsored by the American Federation for Aging Research, a charity, and approved by the Food and Drug Administration in 2015, remains in abeyance for lack of funds. Rapamycin, by contrast, has been tested in what is known as the pearl (Participatory Evaluation of Ageing with Rapamycin for Longevity) trial, which began in July 2020. But this found no strong evidence that it worked.

Animal tests have proved more definitive. The new paper, published in Aging Cell by Edward Ivimey-Cook of Glasgow University and his colleagues, gathers all the vertebrate-trial evidence that the authors could find. This amounts to 167 studies on eight species, ranging from fish to monkeys. The answers seem clear-cut. To no one’s surprise, calorie restriction works. So, to a pretty-much equal extent, does rapamycin. But metformin does not.

Read the full story:
https://archive.ph/FTDML

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#10

Rapamycin, by contrast, has been tested in what is known as the PEARL (Participatory Evaluation of Ageing with Rapamycin for Longevity) trial, which began in July 2020. But this found no strong evidence that it worked.

Absence of evidence is not evidence of absence, which some people reading that might misread.

They didn’t mention Brad Stanfield’s double blind exercise + rapa trial that he will be presenting the result in Gstaad later this year, it might’ve detected an effect, or not. I thought the popular opinion was that it was underpowered ex ante as iirc it was a phase 1 trial.

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#11

Anyone combining Rapamycin, Metformin, and a GLP-1 agonist? Been doing that combination for about 9 months. Eating less seems to be helpful.

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#12

Do you have blood test results before and after to see what sort of shift you’ve had?

I’m on rapamycin, berberine and tirzepatide (GLP1/GIP agonist).

Too early on rapamycin to know how that has impacted but my LDL went from 2.4 mmol/L (92.8 mg/dL) down to 1.7 mmol/L (65.74 mg/dL)

I haven’t even touched a cholesterol medication in my life. I’m gonna give ezetimibe a go soon I think.

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#13

pearl (Participatory Evaluation of Ageing with Rapamycin for Longevity) trial, which began in July 2020. But this found no strong evidence that it worked.

Unfortunately, the hugely publicized PEARL clinical trial missed the basics in a study - which is the quality of the material being investigated. That’s step 1.

Non-coated rapamycin is almost equal to no rapamycin being introduced into the body due to the gut acid destruction of the drug. Can’t blame our bodies for reducing the potency of foreign substances that are ingested.

The 1999 ITP rapamycin mouse study highlights this in that trial. The non-coated rapamycin wasn’t reaching the blood. So they took 18 months to fix this and now were treating mice at the equivalent of 65 years. That mistake proved… coated rapamycin had an effect on increasing lifespan in aged mice. Earth shattering results in the field of longevity. Did anyone in PEARL read that study? Obviously not.

TBH I was completely frustrated with the PEARL trial. So much potential and we got very little from it.

Had potential…but provided no real understanding of dose… and okay… rapamycin isn’t dangerous for healthy humans to take in intermittent doses. Like everyone on this site hasn’t figured that one out… me going on almost 5-years continuous use at 6 mg and greater.

IMHO was a complete waste of time and money.

We have discovered more on this site about rapamycin dose … benefits and adverse reactions than the whole PEARL trial provided.

Would I trust these researchers in a part II trial. No!

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#14

“We found that eating less still came out on top as the most consistent way to prolong life in all animals but rapamycin was close behind.”

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#15

Lots of news coverage of this new paper…

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#16

So what you are saying is that you chose the site name well, and there is no reason to change it?

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#17

Right… no plans right now. If/when rapamycin is replaced by something better… perhaps then.

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#18

Are all the studies dietary restriction OR Rapamycin? I’m wondering if there is a way to combine both diet modification and Rapamycin to be significantly better than either alone.

#19

I look at the rapamycin / caloric restriction issue as sort of a Venn diagram with about 80 to 90% overlap. There have not, to my knowledge, been any combination studies of the two. I’ve tried caloric restriction (really, CRON, CR with optimal nutrition), and its hard to do… and the side effects are hard to deal with if you are doing significant CR (you’re cold all the time, libido goes through the floor, etc.).

For me the marginal benefit vs. the marginal cost is pretty heavily weighted towards doing rapamycin alone. Take some sirolimus and you’ve got close to the same level of benefits of CR without the pain and suffering. Your calculus may be different. But we don’t have much in the way of data to go on if you want to combine the two.

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#20

I thoroughly agree with @RapAdmin. Rapamycin is much more pleasant than caloric restriction. There’s also the fact that if you overdo caloric restriction, it can be detrimental to your lifespan and it may not have any effect if you underdo it. Overdoing Rapamycin may be unpleasant (canker sores, hives, etc) but not detrimental to your long-term health.

I will not do caloric restriction with Rapamycin.

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