Mechanisms of NAD+ Homeostasis in Aging and Disease.

Abstract

Aging is the greatest risk factor for many of society's most prevalent diseases, including diabetes, cancer, cardiovascular disease, and neurodegenerative disorders. A common thread underlying these conditions is the disruption of cellular and metabolic homeostasis. All hallmarks of aging converge on mechanisms that disrupt how cells communicate, interact, and coordinate their functions. Emerging studies have implicated diminished NAD+ levels as a contributor to several hallmarks of aging, underscoring their regulatory role in age-dependent decline. While it remains unclear whether aging drives metabolic decline or if metabolic dysregulation accelerates aging-or both-a growing body of evidence suggests that NAD+ metabolism may be a key link between disrupted communication and metabolic dysfunction. This review integrates current insights into how NAD+ metabolism and signaling influence cellular and organismal aging, emphasizing the nutritional factors that modulate these processes. Together, these perspectives position NAD+ as a unifying framework linking nutrition, metabolic resilience, and the mechanisms of healthy aging and disease.