Sirtuin signaling as therapeutic targets of immunosenescence

Aging is characterized by immunosenescence, encompassing, immune aging and inflammaging. Because immune competence is a critical determinant of lifespan and healthspan, targeting immunosenescence has become a major objective of geroscience. In this context, sirtuins have emerged as compelling therapeutic candidates.

This review examines the role of sirtuin signaling in immunosenescence, focusing on its links with nicotinamide adenine dinucleotide (NAD)+ metabolism, oxidative stress, and inflammatory pathways. Pharmacological strategies aimed at enhancing sirtuin activity, including natural and synthetic activators as well as NAD+ precursors, are critically discussed.

Sirtuin signaling represents a biologically plausible strategy for targeting immunosenescence, as it integrates metabolic, mitochondrial, epigenetic, and inflammatory pathways involved in the age-related remodeling of innate and adaptive immunity. However, sirtuin modulation remains investigational rather than an established therapeutic approach. Although NAD⁺ precursors and sirtuin activators have yielded encouraging preclinical findings, robust evidence of clinically meaningful effects in humans is still lacking. Further progress will require validated biomarkers of immunosenescence, appropriately selected study populations, adequately powered randomized trials incorporating functional and clinically relevant immune endpoints, and long-term safety assessment. At present, mTOR-directed interventions appear closer to clinical translation, whereas NAD⁺- and sirtuin-based approaches remain promising complementary strategies requiring further investigation.