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18The diabetes drug metformin is to be clinically tested in aged humans to achieve health 19 span extension, but little is known about responses of old non-diabetic individuals to this 20 drug. By in vitro and in vivo tests we found that metformin shortens life span and limits 21 cell survival when provided in late life, contrary to its positive early life effects. 22 Mechanistically, metformin exacerbates aging-associated mitochondrial dysfunction 23 towards respiratory failure, aggravated by the inability of old cells to upregulate 24 glycolysis in response to metformin, leading to ATP exhaustion. The beneficial dietary 25 restriction effect of metformin on lipid reserves is abrogated in old animals, contributing 26 to metabolic failure, while ectopic stabilization of cellular ATP levels alleviates late life 27 metformin toxicity in vitro and in vivo. The toxicity is also suspended in nematodes 28 carrying diabetes-like insulin receptor insufficiency and showing prolonged resilience to 29 metabolic stress induced by metformin. In sum, we uncovered an alarming metabolic 30 decay triggered by metformin in late life which may limit its benefits for non-diabetic 31 elderly patients. Novel regulators of life extension by metformin are also presented. 32 33 Keywords 34 Aging, metformin, mitochondrial dysfunction, glycolysis, dietary restriction, ATP 35 exhaustion, protein kinase A 36 37 Highlights 38  Late life metformin treatment limits cell survival and shortens lifespan. 39  Metformin exacerbates aging-associated mitochondrial dysfunction causing fatal 1 ATP exhaustion. 2  Old cells fail to upregulate glycolysis as a compensatory response to metformin. 3  The dietary restriction (DR) mimetic response to metformin is abrogated in old 4 animals. 5  PKA and not AMPK pathway instigates the early life DR response to metformin. 6  Stabilization of cellular ATP levels alleviates late life metformin toxicity in vitro 7 and in vivo.8 9 12 (Salani et al., 2014). Metformin is thought to act by inhibiting mitochondrial respiration 13 (Wheaton et al., 2014). Recently, metformin was tested for additional physiological 14 effects and found to extend life span in animal models ranging from nematodes to mice 15 (Martin-Montalvo et al., 2013; Onken and Driscoll, 2010). Extensive clinical use in 16 humans enabled the collection and analysis of data on the longevity of human diabetes 17 patients treated with metformin. The metformin-exposed diabetes cohort was found to 18 be longer lived than untreated healthy subjects (Bannister et al., 2014), in line with 19 potential life-prolonging properties of metformin. 20 Type 2 diabetes is an aging-associated disorder and many patients start 21 metformin treatment in late life. Based on survival analysis of diabetes patients, it was 22proposed that life prolonging effects of metformin may extend also to metabolic-healthy 23 elderly individuals. Considering moderate metformin side effects in diabetes and the 24 potential healthy aging benefits, metformin has emerged as an attracti...

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