Chronic 1% metformin treatment is nephrotoxic in mice, but this dose may nonetheless confer health benefits if given intermittently rather than continuously. Here, we examined the effects of 1% metformin given every-other week (EOW) or two consecutive weeks per month (2WM) on survival of 2-year-old male mice fed standard chow. EOW and 2WM mice had comparable life span compared with control mice. A significant reduction in body weight within the first few weeks of metformin treatment was observed without impact on food consumption and energy expenditure. Moreover, there were differences in the action of metformin on metabolic markers between the EOW and 2WM groups, with EOW metformin conferring greater benefits. Age-associated kidney lesions became more pronounced with metformin, although without pathological consequences. In the liver, metformin treatment led to an overall reduction in steatosis and was accompanied by distinct transcriptomic and metabolomic signatures in response to EOW versus 2WM regimens. Thus, the absence of adverse outcomes associated with chronic, intermittent use of 1% metformin in old mice has clinical translatability into the biology of aging in humans.

慢性1％二甲双胍治疗对小鼠有肾毒性，但是如果间歇而非连续给药，该剂量仍可带来健康益处。在这里，我们检查了每隔一周（EOW）或每月连续两个星期（2WM）给予1％二甲双胍对2岁大的饲喂普通食物的雄性小鼠的存活率的影响。与对照小鼠相比，EOW和2WM小鼠的寿命相当。在二甲双胍治疗的最初几周内，体重显着降低，而对食物消耗和能量消耗没有影响。此外，EOW和2WM组之间二甲双胍对代谢指标的作用存在差异，EOW二甲双胍可带来更大的益处。与二甲双胍相比，与年龄相关的肾脏病变更为明显，尽管没有病理后果。在肝脏里 二甲双胍治疗可导致脂肪变性总体减少，并伴随着针对EOW与2WM方案的独特转录组和代谢组学特征。因此，在老年小鼠中不存在与长期间歇性使用1％二甲双胍有关的不良后果，就具有可转化为人类衰老生物学的临床意义。