Age-Related Melatonin Decline: Interactions Among Mitochondrial Dysfunction, Pineal Aging, Circadian Disruption, and the Gut Microbiome

Abstract

This review article summarizes the roles of mitochondria, melatonin, circadian rhythms, and the microbiota/microbiome in aging and cellular senescence, both at the cellular level and in the whole organism. Mitochondria are central to cellular energy metabolism, intercellular signaling, and regulation of programmed cell death. Numerous age-related diseases have been linked to mitochondrial dysfunction [1]. Mitochondrial quality control (MQC)—the processes that maintain mitochondrial homeostasis—is therefore critical for health and for delaying age-related disorders. Melatonin, which is synthesized and metabolized within mitochondria, also reaches mitochondria via transport from the pineal gland in a circadian manner. Its actions on mitochondria are essential for the preservation of MQC, while additional anti-aging effects of melatonin extend beyond mitochondrial function. Because pineal melatonin production is under circadian regulation, circadian rhythms also directly influence mitochondrial quality control. In mammals, aging follows a parallel and interconnected sequence: (1) pineal gland aging, (2) decline in melatonin production, (3) circadian rhythm disruption, (4) mitochondrial dysfunction, and (5) age-related alterations in the microbiome. In this review, we highlight the interdependence of melatonin decline, circadian dysregulation, and mitochondrial dysfunction as key drivers of aging at cellular, subcellular, and organismal levels.