Fig. 1: Chronic, low-grade inflammation drives systemic NAD⁺ reduction.

Environmental, exogenous stimuli, including pathogens, allergens, ultraviolet (UV), and toxic substances, and metabolic, endogenous stimuli, including lipids, misfolded proteins, and cellular debris, activate specific immune cells, such as macrophages, microglia, and T lymphocytes. These activated immune cells secrete a variety of inflammatory cytokines. On the other hand, senescent cells, which accumulate over age in multiple tissues, also show the senescence-associated secretory phenotype (SASP), secreting many inflammatory cytokines. The constant exposure to these inflammatory cytokines, often called “inflammaging”, decreases the expression of NAMPT, a key NAD⁺ biosynthetic enzyme, and increases the expression of CD38, a major NAD⁺ glycohydrolase, both resulting in a significant reduction in NAD⁺ levels at a systemic level. Such systemic NAD⁺ reduction leads to cellular and tissue dysfunction, causing age-associated pathophysiologies.