Calorie restriction as an intervention in ageing. (3rd January 2016) - López‐Lluch, Guillermo
Abstract : Calorie restriction modifies several essential pathways in the organisms. Molecular components of this response act by modifying physiological processes such as proliferation, inflammation, mitochondrial physiology and remodelling, autophagy and the expression of antioxidants. In general CR inhibits processes involved in cell proliferation and glycolysis through blocking IGF‐I receptor‐dependent pathways and Target of Rapamycin (TOR). At the same time, CR induces mitochondrial activity by activating AMP‐dependent kinase (AMPK) and sirtuins. This effect is accompanied by a higher activity of Forkhead box proteins (FoxO) that activate both auto/mitophagy and antioxidant expression. Interestingly, this FoxO activation can be induced by both, TOR inhibition and AMPK activation. Nuclear factor erythroid 2‐related factor 2 (NRF2) is also activated by CR and, by this mechanism, the expression of antioxidant proteins is induced. Finally, CR also inhibits Nuclear Factor‐kB activity and reduces the proinflammatory profile found during ageing. Any of these processes contribute individually in the increase in healthspan and longevity found after CR. Abstract: Ageing causes loss of function in tissues and organs, is accompanied by a chronic inflammatory process and affects life‐ and healthspan. Calorie restriction (CR) is a non‐genetic intervention that prevents age‐associated diseases and extends longevity in most of the animal models studied so far. CR produces a pleiotropic effect and improves multiple metabolic pathways, generating benefits to the whole organism. Among the effects of CR, modulation of mitochondrial activity and a decrease in oxidative damage are two of the hallmarks. Oxidative damage is reduced by the induction of endogenous antioxidant systems and modulation of the peroxidability index in cell membranes. Mitochondrial activity changes are regulated by inhibition of IGF‐1 and Target of Rapamycin (TOR)‐dependent activities and activation of AMP‐dependent kinase (AMPK) and the sirtuin family of proteins. The activity of PGC‐1α and FoxO is regulated by these systems and is involved in mitochondria biogenesis, oxidative metabolism activity and mitochondrial turnover. The use of mimetics and the regulation of common factors have demonstrated that these molecular pathways are essential to explain the effect of CR in the organism. Finally, the anti‐inflammatory effect of CR is an interesting emerging factor to be taken into consideration. In the present revision we focus on the general effect of CR and other mimetics in longevity, focusing especially on the cardiovascular system and skeletal muscle.