Gerosuppressant Metformin: less is more

Further expanding the major findings of the landmark study by Harrison and colleagues showing that late-life pharmacological inhibition of the enzyme mammalian Target Of Rapamycin (mTOR) –a conserved integrator of nutrient and growth factor signaling-is sufficient to significantly extend lifespan in mice on rapamycin feeding [1], Selman and colleagues have recently revealed that loss of the ribosomal S6 protein kinase S6K1 –a downstream target and effector of mTOR-can similarly provide health and longevity effects without detrimental effects when targeted pharmacologically [2]. As previously observed in calorie restriction (CR)-related interventions that similarly delayed aging in Caenorhabditis elegans, rodents and rhesus monkeys [3], long-lived S6K1 knockout animals exhibit a reduced body size [2]. Pro-longevity features in animals lacking S6K1, including hyperactivation of the metabolic rheostat adenosine monophosphate (AMP)-activated protein kinase (AMPK) and transcriptional alterations of key genes involved in the regulation of glucose and lipid metabolism, paradoxically imitate those observed in reliable models of human progeria in which certain aspects of aging are manifested precociously or in exacerbated form [4]. We have learned that, in their attempt to re-allocate resources from growth to life extension, rapidly aging progeroid mice with nuclear envelope abnormalities –which could also be a central cause of normal aging-metabolically adopt CR-like strategies (i.e. activation of AMPK and inhibition of mTOR/S6K1 leading to extensive activation of autophagic catabolism) aimed to slowdown cellular division-dependent accumulation of Commentaries and Editorials genomic damage [5]. While it is obvious that systemic CR-like metabolic responses fail to repair nuclear architecture defects and rather accelerate death in progeroid mice, it is also obvious that, upon activation of AMPK in animals lacking S6K1, CR-like metabolic responses successfully accomplish an anti-aging mechanism while significantly decreasing body size [2]. Less (AMPK-sensed anabolism) is More (lifespan) If activation of AMPK (and/or inhibition of mTOR/S6K1) constitutes the best metabolic response to avoid that a normal growth rate would compromise somatic integrity in progeroid animals [4, 5], it is reasonable to suggest that the occurrence of AMPK upregulation upon loss of S6K1 would lead also to reductions in cell growth/division rates in order to avoid that bioenergetic stresses might trigger cell death. In this regard, we should acknowledge that metabolic requirements are identical in all proliferating (normal, cancer, and stem) cells and, proliferative metabolism is successfully adapted in all of them to facilitate and ensure the rapid uptake and efficient incorporation of nutrients into the biomass needed to produce new cell …