Mitophagy and DNA damage signaling in human aging

Aging is associated with multiple human pathologies. In the past few years mitochondrial homeostasis has been well correlated with age-related disorders and longevity. Mitochondrial homeostasis involves generation, biogenesis and removal of dysfunctional mitochondria via mitophagy. Mitophagy is regulated by various mitochondrial and extra-mitochondrial factors including morphology, oxidative stress and DNA damage. For decades, DNA damage and inefficient DNA repair have been considered as major determinants for age-related disorders. Although defects in DNA damage recognition and repair and mitophagy are well documented to be major factors in age-associated diseases, interactivity between these is poorly understood. Mitophagy efficiency decreases with age leading to accumulation of dysfunctional mitochondria enhancing the severity of age-related disorders including neurodegenerative diseases, inflammatory diseases, cancer, diabetes and many more. Therefore, mitophagy is being targeted for intervention in age-associated disorders. NAD(+) supplementation has emerged as one intervention to target both defective DNA repair and mitophagy. In this review, we discuss the molecular signaling pathways involved in regulation of DNA damage and repair and of mitophagy, and we highlight the opportunities for clinical interventions targeting these processes to improve the quality of life during aging.