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A metformin and rapamycin drug combination against aging

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Jamila Sep 11, 2020
Could metformin and rapamycin be used together as an anti-aging drug combo?

Metformin and rapamycin can both increase the lifespan of various animals independently, their power has been shown time and time again across a magnitude of research studies.

Rapamycin is an immunosuppressant drug used to prevent organ rejection after a transplant. Rapamycin exerts its geroprotective effects by inhibiting mTOR signaling. In one study, the lifespan of mice increased by 60% when treated with a high dose of rapamycin for 3 months. Even though rapamycin can improve the lifespan of various animals, it can cause insulin resistance in the long run which can be an issue!

Metformin is a drug used to treat diabetes, it reduces blood glucose levels and prevents insulin resistance. This drug exerts its geroprotective abilities by boosting the activity of the adenosine monophosphate-activated protein kinase (AMPK) pathway. In terms of lifespan studies, worms that were given 50 mM metformin had improved their lifespans by 36%. Metformin may be able to tackle insulin resistance that arises from rapamycin usage.

I haven't seen any studies so far that have assessed the geroprotective effects of these two key anti-aging drugs together. Sometimes the combination of different anti-aging interventions can amplify the anti-aging effect and further improve the lifespan. So I thought this may be the case for rapamycin and metformin too.

Some ideas:
  1. Can a metformin and rapamycin drug combination improve lifespan?
  2. Can this drug combination improve the hallmarks of aging? like the epigenetic age?
  3. Would these drugs amplify the geroprotective effects or negate each other?

[1]Cabreiro F, Au C, Leung K-Y, Vergara-Irigaray N, Cochemé HM, Noori T, et al. Metformin Retards Aging in C. elegans by Altering Microbial Folate and Methionine Metabolism. Cell [Internet]. 2013 Mar;153(1):228–39. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0092867413002675

[2]Melemedjian, Ohannes K., et al. "Targeting adenosine monophosphate-activated protein kinase (AMPK) in preclinical models reveals a potential mechanism for the treatment of neuropathic pain." Molecular pain 7 (2011): 1744-8069.

[3]Bitto, Alessandro, et al. "Transient rapamycin treatment can increase lifespan and healthspan in middle-aged mice." elife 5 (2016): e16351.

[4]Lamming, Dudley W. "Inhibition of the mechanistic target of rapamycin (mTOR)–rapamycin and beyond." Cold Spring Harbor perspectives in medicine 6.5 (2016): a025924.

[5]Castillo-Quan, Jorge Iván, et al. "A triple drug combination targeting components of the nutrient-sensing network maximizes longevity." Proceedings of the National Academy of Sciences 116.42 (2019): 20817-20819.

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General comments

Subash Chapagain
Subash Chapagain8 months ago
Combinatorial drug administration can indeed prove to be highly effective in a variety of cases as exemplified by a lot of combined treatments against diseases as deadly as cancer. It is plausible to propose a combination of life-span prolonging drugs like rapamycin and metformin, even more so when findings from animal studies have suggested that metformin can alleviate the glucose intolerance caused by rapamycin [1]. However, there are some things that need to seriously considered before going on to a battery of drugs like rapamycin and metformin for their synergistic effects on longevity: 1. Though such drug-based interventions have shown to be promising in animal studies for elongating the life span, the ideal ‘biological scale’ at which ageing and senescence can be clinically targeted is still in question. Therapeutics as such are likely to have differing levels of complexity depending on their targets. Single genes are easiest to target, and the difficulty compounds as we move up into the levels of a pathway to the level of cells. It becomes much onerous when we try to salvage a cell from becoming senescent. Similarly, overactive (cancer-prone) cells can be targeted to kill based on one single receptor/gene; however, salvaging neurons from death (eg as in case of various dementias) is a harder therapeutic task. Since the drugs rapamycin (still under clinical investigation) and metformin are likely to act on multiple levels of these pathways, we might need to objectively design control points for being as specific as we can on our targets. When we use the combinatorial advantage, we must be even more careful. 2. In a study that investigated the combinatorial effect of Rapamycin+Metformin in autophagy and proteostasis in skeletal myotubes in vitro, the Met+Rap treatment seemingly activated autophagy of cytosolic proteins to a noticeable extent. The combination also reduced mitochondrial protein: DNA synthesis ratio. However, when cytosolic protein: DNA breakdown ratios were compared, there were no changes with respect to control. Hence, more decisive conclusions are yet to be made to decide whether the actual mechanism that this combination works by when it comes to maintaining proteostasis [2]. 3. In some studies, a higher dose of metformin has been linked to the development of some solid tumours in humans. Colorectal, breast cancer and pancreatic cancer are some of the ailments linked to metformin. It needs to be quantified if these effects will subside or exacerbate when administered with rapamycin, before moving on to the therapeutic applications[3]. 4. Though there are some common molecular routes (mainly through mTOR signalling eventually to AMPK activation) that both metformin and rapamycin convergently work, it has been found that metformin can act in an AMPK independent manner, possibly via Nuclear Pore Complex (NPC) or late endosomal interactions. If this is substantiated, what would be the effect on this mode of metformin action in combination with rapamycin? This needs to be answered [4]. 5. There is one significant difference in action between rapamycin and metformin. Rapamycin increases autophagy in a large magnitude over apoptosis than done by metformin. This is much helpful in regards to the extension of cellular life but could prove to be problematic in usage when cells are predisposed to cancer-causing conditions [5]. Such cases with comorbidities should be objectively scrutinized before proceeding on to human applications. References: 1. Weiss R, Fernandez E, Liu Y, Strong R, Salmon AB. Metformin reduces glucose intolerance caused by rapamycin treatment in genetically heterogeneous female mice. Aging (Albany NY). 2018; 10:386–401. 10.18632/aging.101401 2. Wolff CA, Reid JJ, Musci RV, et al. Differential Effects of Rapamycin and Metformin in Combination With Rapamycin on Mechanisms of Proteostasis in Cultured Skeletal Myotubes. J Gerontol A Biol Sci Med Sci. 2020;75(1):32-39. doi:10.1093/gerona/glz05 3. Adak T, Samadi A, Ünal AZ, Sabuncuoğlu S. A reappraisal on metformin. Regulatory Toxicology and Pharmacology. 2018;92:324-332 4.Kim J, Lee H-Y, Ahn J, Hyun M, Lee I, Min K-J, et al. NHX-5, an Endosomal Na+/H+ exchanger, is associated with metformin action. The Journal of Biological Chemistry. 2016;291:18591-18599
Jamila 8 months ago
Thanks for the great comment. The specific dosage for a combination therapy would definitely need to be scrutinized so that the treatment is effective by having geroprotective capabilities but it also needs to be safe and have no severe side effects. Metformin does have its own set of established side-effects which are usually gastrointestinal related like diarrhea, stomach pain, and nausea. Lactic acidosis is a rare but severe complication of metformin usage. But apparently, the risk of metformin-induced lactic acidosis is quite low. (https://www.sciencedirect.com/science/article/pii/S1548559519301442) In the study kindly linked by Juran, it showed that both female and male mice that had the combination treatment (rapamycin and metformin) had significantly reduced metformin levels compared to the mice that were just given metformin. So it seems from this study that a combination treatment of metformin and rapamycin (0.1% and 14ppm) may actually reduce metformin blood levels at these specific dosages. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892694/). The rapamycin and metformin combination treatment has also shown protective effects against dye-induced retinal damage. The researchers believe that these protective effects were mediated by the induction of autophagy. (https://link.springer.com/article/10.1007/s00417-019-04548-z)
J.8 months ago
I ran on some articles that can help in developing the story. The most interesting one was the opinion paper on all the reversible side-effects caused by rapamycin treatment, compared to the irreversible effects of aging (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6814615/). Also, one paper showed that scientists have partially confirmed that metformin reduces glucose intolerance caused by rapamycin in female mice (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892694/). What could also be a solution, a parallel story with same beginning and the same goal, is that the problem of insulin resistance can possibly be solved by metformin and rapamycin mimetics found in silico (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5723685/).
Jamila 8 months ago
Thanks for the comment; you’ve linked really helpful studies! It’s quite interesting, in the paper about the drug combination reducing glucose intolerance in female mice. I wonder what caused the gender differences observed in this particular study. I say this because even in some lifespan studies, I’ve noticed gender differences where sometimes maybe the female has an improved response to the lifespan intervention in question but not the male mice (and the same vice versa). (https://www.cell.com/cell-metabolism/pdf/S1550-4131(16)30237-6.pdf) In the study that you linked, the researchers suggest that sex differences may have arisen due to differences in the way rapamycin is metabolized in male and female mice. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5892694/) oo yes, it seems that there are many possible compounds that could be used instead of rapamycin and metformin because of in silico techniques, it’s amazing! Chances are they might be better than rapamycin and metformin and way safer!! Let’s see what happens.
J.8 months ago
I am glad if you found something helpful. Yes, that's really intriguing, especially because it happens only in the case of rapamycin, as they state. The reason could be the metabolism because there is also proof that the rapamycin blood concentrations were higher in female mice. (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4207939/). Is it because of the different "food intake, resorption of the drug, tissue distribution, metabolism of the drug, or a combination of these factors", it will be interesting to find out. That being said reminded me of a brainstorming session on rapamycin blood concentrations (https://brainstorming.com/sessions/why-people-taking-same-dose-of-rapamycin-have-different-blood-rapamycin-concentrations/29). Maybe, Shubhankar could contribute here.