Mechanisms of lifespan extension and preventive effects of calorie restriction on tumor development: Possible link between central neuroendocrine system and peripheral metabolic adaptation

Abstract

Restriction of food intake (calorie restriction [CR]) in laboratory animals extends their lifespan and delays the onset of various age-associated diseases, including cancer development. Recent studies revealed that the molecular mechanisms underlying CR-mediated anti-aging effects may be regulated by a confined number of signal transduction pathways that are triggered by neuropeptide Y (NPY) neurons in the neuroendocrine system. On the other hand, possible peripheral regulators of the beneficial effects of CR involve a transcriptional regulator complex, the hepatocyte nuclear factor 4α/peroxisome proliferator-activated receptor gamma coactivator 1-α (HNF-4α/PGC-1α) complex. This complex could regulate not only glucose and lipid metabolism, but also DNA damage responses in the liver. Therefore, maintenance of optimal glucose and lipid levels to prevent metabolic syndrome, and activation of the DNA damage response for suppression of tumor development, may depend on the HNF-4α/PGC-1α complex. Hence, small molecules modulating the activity of this complex could be an important target for development of CR mimetics (CRM), which mimic the beneficial effects of CR without actual food restriction.