Melatonin regulates aging and neurodegeneration through energy metabolism, epigenetics, autophagy and circadian rhythm pathways

Abstract

Brain aging is linked to certain types of neurodegenerative diseases and identifying new therapeutic targets has become critical. Melatonin, a pineal hormone, associates with molecules and signaling pathways that sense and influence energy metabolism, autophagy, and circadian rhythms, including insulin-like growth factor 1 (IGF-1), Forkhead box O (FoxOs), sirtuins and mammalian target of rapamycin (mTOR) signaling pathways. This review summarizes the current understanding of how melatonin, together with molecular, cellular and systemic energy metabolisms, regulates epigenetic processes in the neurons. This information will lead to a greater understanding of molecular epigenetic aging of the brain and anti-aging mechanisms to increase lifespan under healthy conditions.

Figure 1

Mechanism of melatonin in controlling normal nervous system aging, neuropathological aging and longevity. The multiple mechanisms of action of melatonin include the following: 1. regulating the circadian rhythm, including several clock genes (Per1, Per2, Nampt, CLOCK, and BMAL1); 2. epigenetics, including sirtuins and FoxOs (forkhead box O); and 3. autophagy, including mTOR (mammalian target of rapamycin) and Atg (autophagy-related proteins). Melatonin regulates several molecules and signaling pathways that sense and influence energy metabolism, including insulin/IGF1, Akt (protein kinase B), and PI3K (phosphoinositide 3 kinase). These pathways regulate normal nervous system aging. Age-related neuronal energy deficits contribute to the pathogenesis of several neurodegenerative disorders, such as Alzheimer’s disease and Parkinson’s disease. The anti-aging properties of melatonin regulate energy metabolism, leading to longevity.