Skin & Muscle

Metformin and Leucine Cocktail Prevents Muscle Atrophy and Cell Senescence: New Study

Scientists show that combining metformin and leucine prevents mouse and human muscle fiber atrophy along with mouse muscle cell senescence.

By Bennett M. Sherman

Key Points

  • Combining metformin and leucine thwarts the atrophy of mouse and human muscle fibers.
  • Metformin and leucine work synergistically to alleviate mouse muscle fibers of senescent markers.

As we get older, muscle deterioration and atrophy can drive low physical activity and ultimately, our loss of independence. A recent study in aged mice has shown that combining the diabetes medication metformin with the essential amino acid leucine can protect against diminished muscle function. How a metformin and leucine cocktail prevents muscle decline and whether it alleviates muscle cell senescence – a state where cells stop dividing and release inflammatory molecules – hadn’t been explored.

Published in Aging, Drummond and colleagues from the University of Utah show that metformin and leucine combined prevents human and mouse muscle fiber atrophy. The researchers go on to demonstrate that the metformin and leucine cocktail reduces muscle senescent cell abundance. These findings tie muscle atrophy with senescent cell accumulation and point to using metformin and leucine together to prevent age-related muscle atrophy.

Metformin and Leucine Combined Prevent Muscle Atrophy and Reduce Senescent Cells

To demonstrate that the metformin and leucine combination prevents age-related atrophy, Drummond and colleagues isolated mouse muscle fibers. To trigger atrophy, they deprived the muscle fibers of nutrients (serum deprivation). When metformin and leucine were added to the muscle fibers with atrophy-inducing serum deprivation, muscle fiber size was significantly preserved. These findings suggest that the metformin and leucine cocktail can prevent muscle loss and atrophy in aged muscle fibers.

To find whether metformin and leucine combined rescues aged human muscle from atrophy, Drummond and colleagues utilized muscle fibers from an aged human donor. Although metformin and leucine didn’t stop muscle fiber size decline, the compounds significantly improved the myogenic index – a measurement of muscle formation. These data suggest that metformin and leucine have potential to counteract age-related atrophy and that their benefits against atrophy may translate to humans.

(Petrocelli et al., 2023 | Aging) Metformin and leucine combination prevents atrophy in mice and shows potential against atrophy in human muscle fibers. H) Compared to healthy mouse muscle fibers treated with horse serum (2% HS; white bar), atrophy inducing serum deprivation (SD; red bar) significantly reduced muscle fiber area (% Myotube Area). Metformin and leucine treatment significantly increased muscle fiber area, thus preventing atrophy (blue bars). E) Compared to healthy human muscle fibers treated with horse serum (2% HS; white bar), those with atrophy-inducing serum deprivation (SD; red bar) display a lower indicator of muscle growth. The Methionine and leucine combination (MET+LEU; blue bar) rescues growth under atrophy-inducing conditions


To find how the compounds work at the cellular level to prevent atrophy, Drummond and colleagues measured a marker of cell senescence in mouse muscle fibers. They found that metformin and leucine prevented the atrophy-associated accumulation of the senescent marker. They looked at the marker of senescence – senescence-associated ꞵ galactosidase – and found that atrophied muscle fibers treated with metformin and leucine exhibit significantly less of the senescence marker. Adding the senescent cell-eliminating drugs dasatinib and quercetin to atrophy-induced muscle fibers preserved their size, adding further support that senescence plays a key role in age-related muscle atrophy. These results tie the accumulation of senescence markers to age-related atrophy and suggest that metformin and leucine act synergistically to reduce senescent muscle cells and prevent muscle decline.

(Petrocelli et al., 2023 | Aging) The metformin and leucine combination reduces a marker for senescent cells and the combination of dasatinib and quercetin prevents atrophy. H) Mouse muscle fibers with atrophy-inducing serum deprivation (SD; red bar) display elevated levels of the marker for cell senescence compared to healthy muscle fibers treated with horse serum (2% HS; white bar). Methionine and leucine treatment under atrophy-inducing conditions reduced the senescent cell marker (MET+LEU; blue bar). L) Serum deprivation conditions (SD; red bar) drives lower muscle fiber size (% Myotube Area) compared to healthy muscle fibers (2% HS). Methionine and leucine (MET+LEU; blue bar) and dasatinib and quercetin (D+Q; purple bar) restored muscle fiber size.

Other Senolytics May Give Similar Muscle-Preserving Effects

This study supports that cellular senescence within muscle fibers triggers the decline of muscle to the point of atrophy. This idea makes sense since senescent cells release inflammatory products into their surroundings that affect nearby cells, causing them to enter a senescent state. An overabundance of senescent cells would then trigger high levels of inflammatory molecules along with overall muscle tissue dysfunction. Interestingly, other results in the study showed that the senescent cell-eliminating drugs dasatinib and quercetin had a similar effect in preventing atrophy, adding further support tying senescence to muscle atrophy. These results may also mean that using other senolytics like fisetin could have similar benefits in preserving muscle function as we age.

Metformin is available with a prescription as an antidiabetic drug for around $18.83 for a month’s supply of 750 mg tablets. Leucine is available for between $5 and $15 for a month’s supply of 500 mg capsules.

Model and Dosage

Model: 22-23-month-old C57Bl6 male mice and muscle tissue from a healthy, 66-year-old human male

Dosage: 25 µM of metformin and 125 µM of leucine


Petrocelli JJ, de Hart NMMP, Lang MJ, Yee EM, Ferrara PJ, Fix DK, Chaix A, Funai K, Drummond MJ. Cellular senescence and disrupted proteostasis induced by myotube atrophy are prevented with low-dose metformin and leucine cocktail. Aging (Albany NY). 2023 Mar 20;15. doi: 10.18632/aging.204600. Epub ahead of print. PMID: 36947713.

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