Discovering New Mechanisms of Action for Metformin

Metformin is a terrible approach to slowing aging in comparison to, say, mTOR inhibition. Slowing aging in this way, by manipulating the operation of an aged cellular metabolism without repairing the underlying damage that causes aging, is in turn a terrible approach to the treatment of aging. Yet metformin attracts a great deal of interest. I believe that most people simply don't care about effect size and reliability. Most popular science materials don't discuss these points, thus putting every intervention on the same footing in the minds of much of the public. Yet effect size and reliability are the very heart of the matter.

The animal data on metformin shows it to be unreliable when it comes to effects on life span; results from different studies and different groups are quite varied. The one large human study to examine mortality and life span looked at people with type 2 diabetes, not healthy individuals. It is known that metformin disrupts the operation of mechanisms needed for benefits to health to arise from regular exercise - a significant issue. Lastly, even if taking the human data at face value, the effect size is really just not large enough to care about. Nothing in the research noted here changes any of this.

Previously, the only biochemical pathway that was known to be activated by metformin was the AMPK pathway, which researchers discovered stalls cell growth and changes metabolism when nutrients are scarce, as can occur in cancer. But the scientists believed more pathways than AMPK might be involved. The scientists developed a novel screening platform to examine kinases, the proteins that transfer phosphate groups, which are critical on/off switches in cells and can be rapidly flipped by metformin. Using this technology, the researchers were able to decode hundreds of regulatory "switch-flipping" events that could affect healthy aging.

The results revealed that metformin turns on unexpected kinases and pathways, many independent of AMPK. Two of the activated kinases are called Protein Kinase D and MAPKAPK2. These kinases are poorly understood, but are known to have some relation to cellular stress, which could connect them to the health-span- and life-span-extending effects observed in other studies. In fact, metformin is currently being tested in multiple large-scale clinical trials as a health-span- and life-span-extending drug, but the mechanism for how metformin could affect health and aging has not been clear. The current study indicates that Protein Kinase D and MAPKAPK2 may be two players in providing these therapeutic effects, and identifies new targets and cellular processes regulated by AMPK that may also be critical to metformin's beneficial effects.

"The results broaden our understanding of how metformin induces a mild stress that triggers sensors to restore metabolic balance, explaining some of the benefits previously reported such as extended healthy aging in model organisms taking metformin. The big questions now are what targets of metformin can benefit the health of all individuals, not just type 2 diabetics."



Many of us, including myself, believe that the benefits of Metformin are most significant for those who are not physically active and that rigorous physical activity makes Metformin unnecessary for those of us who do it.

Posted by: Abelard Lindsey at December 4th, 2019 9:59 AM

Would Berberine, which many people use as a substitute for metformin, be just as bad (not recommended) ?

Posted by: August33 at December 4th, 2019 12:29 PM

"Metformin is a terrible approach to slowing aging in comparison to, say, mTOR inhibition. Slowing aging in this way, by manipulating the operation of an aged cellular metabolism without repairing the underlying damage that causes aging, is in turn a terrible approach to the treatment of aging."

Senolytics meanwhile only have mouse studies showing efficacy, and the cold, hard truth is that basically everything that we try in mice for age related diseases fails to translate into humans; we cure cancer thousands of times in mice for every new cancer drug that makes it to market.

Consequently the safe bet is and always has been that senolysis doesn't extend lifespan/healthspan in humans. The early trials of senolytics in humans have not yet demonstrated any significant health benefits from them at all, even as evidence that they selectively clear senescent cells in humans just like in mice grows. That's not to say that avenue of research should be abandoned; a diverse range of approaches and strategies MUST be employed not simply in regards to aging but in pharmaceuticals in general.

Looming over all of this is the fact that 85% of all INDs fail to pass trials, and the number is closer to 95-99% if we specifically look at drugs for diseases of aging. Of the enormous and growing list of companies involved in longevity, perhaps a single drug (maybe two) will come of it in the next 10 years, and it will be approved for an endpoint that isn't aging, meaning an additional 5 years of trials will be required for it to be approved to use as an anti-aging drug.

That incidentally hinges on aging being a valid endpoint by the time the current generation of longevity biotech companies are culled down to the handful that make it to market. That's not happening without TAME, and the sooner a trial shows any sort of modification of human aging, the sooner the wider industry* will start exploring anti-aging.

* I have to roll my eyes at claims that longevity is its own industry; it's not, it walks, talks, and quacks like BioPharma, the only difference is the specific strategy.

Posted by: Dylan Mah at December 5th, 2019 1:25 AM


Posted by: JohnD at December 5th, 2019 4:31 PM

"Targeting Aging with Metformin", it's the first clinical trial given the go ahead by the FDA that's explicitly targeting aging*, it's intended as a proof of concept for future trials of anti-aging drugs.

* Or rather a de facto description of aging, not everyone agrees with that definition but the intention to treat aging is not lost on the FDA.

Posted by: Dylan Mah at December 6th, 2019 9:56 AM
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