New Insights into the Role of Exercise as an Anti-Aging Intervention through eNAMPT-Mediated NAD⁺ Metabolism

Abstract

NAD⁺ (nicotinamide adenine dinucleotide) is involved in various reactions, notably as a regulator in activating sirtuins, which play a role in aging and lifespan. It has been shown that age-associated NAD⁺ decline in tissues triggers functional deterioration perceived as “aging.” Consequently, replenishing NAD⁺ is considered a promising intervention for anti-aging. The synthesis of NAD⁺ primarily depends on a salvage pathway that has NAMPT (nicotinamide phosphoribosyl-transferase) as its rate-limiting step. Recent studies have found that NAMPT in adipose tissue not only produces intracellular NAD⁺ but also releases it into the bloodstream as eNAMPT (extracellular NAMPT), encapsulated in EVs. Further, eNAMPT boosts NAD⁺ production in the hypothalamus, recognized as the metabolic center. This elevation in eNAMPT demonstrates notable anti-aging benefits across the body and contributes to a longer lifespan. Here, we review NAD⁺ metabolism and aging control and provide an overview of eNAMPT, highlighting its potential to link exercise and healthy longevity.