The Combination of Metformin and Rapamycin Increases Lifespan by 23%

by Nils Osmar. Updated April 4, 2022

According to a 2016 study conducted by the National Institute on Aging Interventions Testing Program, a combination of metformin and rapamycin increases maximal lifespan by 23 percent in lab animals.

I found this study fascinating and am surprised it hasn’t gotten more attention in the anti-aging community. It suggests that the life extension benefit of rapamycin, which has been well documented in mice and appear promising in humans, can be more than doubled by combining it with metformin.

Some other compounds were also tested, but the metformin plus rapamycin, in the correct proportions, showed the most significant life extension. The effect was significant in both male and female mice.

More research would be needed to clarify what the equivalent doses would be in humans. And of course, proving that a compound extends life in mice doesn’t prove it would also do so in humans. (See cautions below.)

You can read the entire study at this link.

From the Study

Here are some quotes from the section looking at rapamycin and metformin:

The National Institute on Aging Interventions Testing Program (ITP) evaluates agents hypothesized to increase healthy lifespan in genetically heterogeneous mice… We report the effects of lifelong treatment of mice with four agents not previously tested: Protandim, fish oil, ursodeoxycholic acid (UDCA) and metformin – the latter with and without rapamycin, and two drugs previously examined: 17‐α‐estradiol and nordihydroguaiaretic acid (NDGA), at doses greater and less than used previously.
Figure 2 shows survival curves of male and female mice that received both Met (1000 ppm) and Rapa (14 ppm) (Met/Rapa) from 9 months of age.
As shown in Table 1, this combination led to a 23% increase in survival compared with controls in both sexes, as well as to significant increases in maximum lifespan (P < 0.001).
Met/Rapa led to a significant increase in lifespan in both sexes at each site separately (Table S1 and Fig. S5, Supporting information) and to significant increases in maximal lifespan except for UT males.
Males given Met/Rapa had a 23% increase in median longevity, higher than the 10% effect produced by Rapa alone in C2006 or the 13% effect in C2009 males.

A later (2018) study called Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice suggests a possible explanation:

As part of the Interventions Testing Program (ITP), the 2011 longevity cohort tested the effect of combined metformin and rapamycin treatment on the lifespan of HET3 mice. … In these recently published data, both female and males in this combined treatment group lived 23% longer than control mice suggesting that combining metformin with rapamycin results in a lifespan extension at least as great as (if not greater than) rapamycin treatment alone.
As an extension of these findings, we used this experimental paradigm to test what effect chronic treatment with both pharmaceuticals has on metabolic function of mice.
We report here that metformin can almost completely abolish glucose intolerance in female HET3 mice treated with rapamycin.

Cautions and Caveats

One caution for those trying to extrapolate from either study to humans is that the comparative doses needed to achieve a similar effect in humans is unclear.
It’s important to note that in some studies, dosing with metformin has actually been shown to shorten the lifespan in some lab animals, particularly when given late in life.
Even in studies in which it’s been found to extend the lifespan, the effect is dose-dependent, with low doses sometimes shortening lifespan. So I’m not suggesting that people take the combination in an attempt to increase their own lifespans..

Dangers and Side Effects

Anyone taking rapamycin or metformin should do so with an awareness of the possible side effects One possible side effect of metformin is the an increased danger of birth defects in male babies. An article in Healio Endocrinology states:

The birth defect frequency for offspring exposed to insulin was the same as the overall rate at 3.3%, and the sex ratio was similar with 51.3% of defects occurring in boys. Those exposed to metformin had a 5.2% birth defect rate with 49.4% of defects occurring in boys, and offspring exposed to sulfonylureas had a 5.1% birth defect rate with 49.3% of defects occurring in boys.

One possible side effect of rapamycin, if dosed incorrectly, is suppression of the immune system. When given to young rats, even low doses of rapamycin interfered with the development of a strong immune response. From the article:

In summary, all these data suggest that there is not a rapamycin dose that can inhibit mTOR for epilepsy without causing any side effects, but 1 mg /kg may be the optimal dose for young rats for suppressing mTOR with relatively few side effects.

Both are promising anti-aging interventions, but neither should be regarded as completely safe.