PARP-CD38-Driven NAD⁺ Loss in Immune Aging: An Emerging Mechanistic Framework

Immune aging is characterized by inflammaging, progressive immune decline, and compromised tissue surveillance. Although researchers have recognized an association between PARP hyperactivation and immune aging (emerging and context-dependent), a unifying framework for how PARP members beyond PARP1 orchestrate immune dysfunction via NAD⁺ metabolism is lacking. We propose a context-dependent PARP-CD38-NAD⁺-inflammaging hierarchy. PARP1 is the most abundant nuclear PARP, responsible for 85-90% of nuclear PARP activity and dominant NAD⁺ consumption under acute DNA damage; CD38, the principal NAD⁺ glycohydrolase, is upregulated in inflamed aged tissues; NAD⁺ is compartmentalized (cytosolic, mitochondrial) with distinct regulators (NAMPT, NMNAT1/2/3, SLC25A51). Recent human data challenge the universal NAD⁺ decline hypothesis, showing that an 85% muscle NAD⁺ reduction does not impair function, and whole-blood NAD⁺ is age-invariant. Thus, NAD⁺ decline is tissue- and compartment-specific; blood NAD⁺ is not a reliable biomarker. Beyond PARP1, PARP2 (cardiomyocyte aging in mouse), PARP3 (intestinal aging), PARP16 (vascular aging), and PARP9/14 (Alzheimer's models) act as tissue-specific regulators, but their roles in human immune aging remain unquantified. PARP inhibitors and NAD⁺ precursors show promise but face risks: genomic instability, hematopoietic toxicity, senescence promotion, and inconsistent efficacy. Unresolved questions, whether PBMC PARP activity predicts immune aging, sex differences, and whether partial inhibition reduces NAD⁺ consumption without compromising DNA repair. By rethinking PARPs as context-dependent integrators, we provide a framework for immunogerontology.