Metformin treatment initiated late in life impairs systemic energy homeostasis and reduces life span by acting in synergy with age-linked mitochondrial dysfunction

ABSTRACT: Metformin is a type 2 diabetes medication which extends life span across species when given from young adulthood onwards; late life effects of metformin are not well understood. Here we used C. elegans to investigate the outcome of metformin treatment initiated late in life. We found that, contrary to young age administration, old age metformin treatment interferes with energy homeostasis and shortens life span by aggravating age-associated mitochondrial dysfunction. Nematode mutants defective in mitochondrial respiration, mitochondrial biogenesis and mitochondrial quality control were highly susceptible to metformin killing already at young age while insulin receptor deficient nematodes carrying healthier mitochondria were protected from late life metformin toxicity. In the mammalian cell culture model of replicative senescence metformin killing correlated with loss of mitochondrial membrane potential and strong reduction of systemic ATP levels. Reduced ATP levels and depletion of lipid stores consistent with energy deficit were observed also in nematodes following late life metformin treatment. At the molecular level young animals responded to metformin by inducing adaptive stress responses and longevity-assurance pathways while old nematodes demonstrated a protein expression signature consistent with lipid turnover and energy deficit. Ectopic ATP supplementation was sufficient to alleviate metformin toxicity in human skin fibroblasts highlighting the key contribution of energy deficit to the detrimental effect of metformin. Also, co-exposure with rapamycin, known to stabilize cellular ATP levels under conditions of mitochondrial failure, significantly reduced metformin-inflicted lethality in both cells and old animals. In summary we uncovered a novel negative synergism between metformin treatment and mitochondrial dysfunction which gains importance late in life and may limit therapeutic benefits of metformin for older patients; these side effects can partially be overcome by co-treatment with agents stabilizing cellular ATP levels such as rapamycin.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive

ORGANISM(S): Caenorhabditis Elegans

SUBMITTER: Joanna Kirkpatrick  

LAB HEAD: Maria Ermolaeva

PROVIDER: PXD011579 | Pride | 2020-09-21

REPOSITORIES: Pride