Health benefits of late-onset metformin treatment every other week in mice

Abstract

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.

Determination of metformin bio-distribution by LC-MS/MS in mice treated with a clinically relevant paradigm

“…Metformin treatments of 0.1% and 1% w/w in diet yielded serum concentrations of 0.45 and 5 mM, respectively, which are considerably higher than the plasma concentrations seen in humans treated with metformin [32]. Even intermittent treatment of 1% metformin in diet given every-other-week or 2 consecutive weeks per month produced serum metformin concentration many folds higher than the recommendation of maximum plasma metformin concentration of 2,500 ng/ml (~19 μM) from the considerations of lactic acidosis [12,33]. Table 3.…”

Metformin activates KDM2A to reduce rRNA transcription and cell proliferation by dual regulation of AMPK activity and intracellular succinate level

“…Recently, it was reported that metformin treatment for more than 24 h decreased the intracellular levels of several metabolites in the TCA cycle 45–47 , including α-KG and succinate. However, the changes of metabolites soon after the metformin treatment have not been reported yet.…”

Late life metformin treatment limits cell survival and shortens lifespan by triggering an aging-associated failure of energy metabolism

“…Collectively, we identified important age-specific effects of metformin which may limit therapeutic benefits of this drug for non-diabetic elderly patients. In fact, observations consistent with a reversal of metformin benefits at old age (Alfaras et al, 2017) and a negative impact of late life metformin exposure on adaptive, motor and cognitive abilities (Konopka et al, 2019; Thangthaeng et al, 2017) have recently emerged from descriptive studies performed in mice and humans. In this context, our work provides for the first time the definite molecular and genetic evidence linking age-specific adverse effects of metformin to reduced longevity assurance capacity and impaired metabolic plasticity of non-diabetic old subjects.…”

“…Via literature research of animal studies providing evidence of longevity modulation by metformin, we discovered that the pro-survival effect of this drug was mostly studied in young animals or animals exposed to metformin from young adulthood. The few studies performed in older animals (56-60 week old mice, average lifespan 96 weeks; 8 day old nematodes, average lifespan 14-21 days), either failed to detect life extension by metformin (Alfaras et al, 2017; Anisimov et al, 2011) or revealed toxicity that was partially attributed to the metformin overdose (Cabreiro et al, 2013; Martin-Montalvo et al, 2013; Thangthaeng et al, 2017). Strikingly, a dose of 50mM metformin which triggered strongest lifespan extension in a seminal study performed in young C. elegans , was moderately toxic when given to middle aged (adulthood day 8) nematodes (Cabreiro et al, 2013; Onken and Driscoll, 2010).…”