NAD⁺ as a central metabolic hub Regulating the hallmarks of aging: Mechanisms and therapeutic implications.

Abstract

The increasing global burden of age-related diseases necessitates interventions that target the unified biological processes of aging, as outlined by the expanding framework of fourteen interconnected hallmarks. This review establishes nicotinamide adenine dinucleotide (NAD⁺) as the central metabolic hub that coordinately regulates this entire network. We systematically elucidate the bidirectional mechanistic links between NAD⁺ metabolism and each hallmark, demonstrating how its age-related decline-driven by impaired biosynthesis and heightened consumption-propagates dysfunction across genomic, epigenetic, mitochondrial, proteostatic, and communicative processes. A large body of evidence supports that NAD⁺ can counter functional decline in models of neurodegenerative diseases, cardiometabolic diseases, and musculoskeletal aging However, a critical synthesis of evidence reveals a paradoxical, context-dependent role for NAD⁺, particularly in oncology, where it can sustain the pro-tumorigenic senescence-associated secretory phenotype (SASP) and fuel established cancers. This duality, along with tissue-specific metabolic nuances, underscores the fundamental limitation of indiscriminate "blind supplementation." Consequently, we advocate for a necessary paradigm shift towards "precision NAD⁺ modulation." Building on the integrated mechanistic analysis, we critically examine the therapeutic implications and challenges across major age-related diseases. Looking ahead, we propose that advancing the field requires embracing a "NAD⁺ systems biology" perspective. Design next-generation interventions that precisely balance tissue-specific NAD⁺ synthesis and consumption. This paradigm is essential for translating the promise of NAD⁺ biology into safe and effective strategies for extending human healthspan.