The fine line between lifespan extension and shortening in response to caloric restriction

Caloric restriction (CR) is generally linked to lifespan extension in various organisms and may limit age-associated diseases. Processes through which caloric restriction promotes lifespan include obesity-countering weight loss, increased DNA repair, control of ribosomal and telomeric DNA repeats, mitochondrial regulation, activation of antioxidants, and protective autophagy. Several of these protective cellular processes are linked to the suppression of TOR (target of rapamycin) or the activation of sirtuins. In stark contrast, CR fails to extend or even shortens lifespan in certain settings. CR-dependent lifespan shortening is linked to weight loss in the non-obese, mitochondrial hyperactivity, genomic inflexibility, and several other processes. Deciphering the balance between positive and negative effects of CR is critical to understanding its ultimate impact on aging. This knowledge is especially needed in order to fulfil the promise of using CR or its mimetic drugs to counteract age-associated diseases and unhealthy aging.