The latest meta analysis comparing the old fashioned dietary restriction with Rapamycin and Metformin was released in June, just over two weeks ago.

The results are indeed surprising to the longevity community, as we will see in the article below.

As you may already know, dietary restriction, whether in the form of caloric restriction or time restricted eating, has been shown for decades to increase lifespan across multiple species, including humans. In simple words, giving your body regular breaks from constant eating flips it from “growth mode” to “repair mode.”

When fuel is scarce, cells pause non-stop growth signals and instead:

1. Clean up junk: They break down and recycle worn-out proteins and cell parts.

2. Fix damage: Extra energy goes into repairing DNA and other wear-and-tear.

3. Boost power plants: Mitochondria run more efficiently, so fewer harmful by-products build up.

Together, these housekeeping jobs slow the ageing process, so animals and humans tend to stay healthier and live longer.

 

The issue with dietary restriction is that it’s not an easy job. It’s not easy building a habit of intermittent fasting or counting your calories.

But what if there were a pill that could help increase lifespan to the same extent?

This is why searching for an alternative to caloric restriction is important to the longevity community.

Over the last decade, there were two medication postulated to help with this:

• Rapamycin – an mTOR inhibitor, originally an immunosuppressant.
• Metformin – the world’s most-used diabetes drug, activates AMPK and indirectly nudges mTOR.

The studies in humans lack, but there are a few quality studies in other animals, ranging from lab rats to lemurs.

 

The meta analsysis publised in the Aging Cell journal analysed 167 previous studies ranging from case reports to randomised control trials.

The majority, about 80% of the subjects were lab mice, but there were also rats, fish and a few studies looked at dog lifespan expansion.

However, there were no human studies.

Researchers in the meta analysis asked two core questions:

1. Does DR still work when we pool all the different species together?

2. Do rapamycin or metformin copy those benefits?

Here is what they found:

Study Results

1. DR Remains the Gold Standard

“Across the board, DR extended lifespan by roughly 17 percent—sometimes more, sometimes less, but always in the positive direction.”

2. Rapamycin ≈ DR

“When you average everything together, rapamycin boosted lifespan about 20 percent, and statistically was indistinguishable from DR after bias correction.”

• Median-based estimates showed the clearest edge; mean-based estimates were more conservative but still positive.

• The effect was robust even after removing short-lived control animals.

3. Metformin Under-whelms

“Metformin’s overall curve overlapped zero. Some strains saw tiny gains, others none at all, and the pooled verdict was ‘weak support’.”

Side effects

Although the meta analysis concluded that in animals (excluding humans) there might be beneficial effects to taking Rapamycin long term, they did not look at any potential side effects.

With Rapamycin and most drugs, really, side effects and interaction with other medication or even supplements, is a major concern.

In the press lately, Bryan Johnson, whom you might know as one of the longevity gurus took metformin at various doses for the past 5 years and concluded that the benefits do not outweigh side effects.

Recurrent skin infections, mouth ulcers, glucose elevations, lipid abnormalities, and increased resting HR. These are all known side effects of rapamycin, but the medication will affect everyone in different ways, as is always the case so it’s not possible to predict who will tolerate and who won’t.

Metformin on the other hand is a medication with a much better side effect profile. Its main side effect is that it can sometimes cause nausea or stomach issues, often mild. Most of these resolve if you switch formulation from the standard to modified release, which is what we tend to do in primary care if someone who is started on metformin complains of intolerable side effects and would like an alternative.

There is also currently an ongoing trial called the TAME trial, which is ongoing and it’s also looking at its effect on lifespan, but there are no results from this yet.

So, anyway, out of the two Rapamycin is the more dangerous medication so to speak, as it can cause more significant side effects so any off-label use would require proper medical supervision.

Take Home Messages

So what are some Practical Take-Home messages?

1. Dietary restriction works NOW.

If you can sustain a 10–30 % calorie reduction, or a well-structured intermittent-fasting plan, then your longevity odds should improve. Start with a dietitian, certified nutritionist even or get in contact with your family doctor first to avoid malnutrition.

1. Rapamycin Is Promising but Experimental

Early human data says safe at low intermittent doses, but we still lack long-term morbidity or mortality endpoints. So it wouldn’t be a medication I would recommend. Then there are also the side effects which can make taking it very daunting and even cause more harm than good, especially if it causes you an increased heart rate and dysregulation in lipds or glucose levels.

3. Metformin Remains a Great Diabetes Drug, Not a Universal Longevity Hack

Unless you’re insulin-resistant, evidence for lifespan gain is weak. The TAME study may clarify this when the study finally completes.

One thing is certain, in that Basic Pillars like Movement, Sleep, Low-inflammatory diet (Mediterranean diet) and Social connection still deliver the highest certainty-to-benefit ratio.

In our Longevity programs, we put an emphasis on the four pillars and always focus on science backed interventions, rather than pure biohacking and exposing ourselves or our patients to the unknown and potentially harmful effects.

To find out more about our longevity services or to book a consultation either remotely or in our London clinic, please get in touch.