Decline in tissue NAD levels during aging is linked to aging and its associated diseases. However, the mechanism for aging-associated NAD decline remains unclear. Here we report that pro-inflammatory M1-like macrophages, but not naïve or M2 macrophages, accumulate in metabolic tissues including visceral white adipose tissue and the liver during aging. Remarkably, these M1-like macrophages highly express the NAD consuming enzyme CD38 and have enhanced CD38-dependent NADase activity. We also find that senescent cells progressively accumulate in visceral white adipose tissue during aging and that inflammatory cytokines found in the supernatant from senescent cells (Senescence associated secretory proteins, SASP) induce macrophages to proliferate and to express CD38. These results highlight a new causal link between visceral tissue senescence and tissue NAD decline during aging and represent a novel therapeutic opportunity targeting maintenance of NAD levels during aging.
Introduction:Nicotinamide adenine dinucleotide (NAD) is a redox coenzyme central to energy metabolism and an essential cofactor for non-redox NAD-dependent enzymes including sirtuins and poly-ADP-ribose polymerases (PARPs) 1 . Early in the 20 th century, NAD deficiency was linked to pellagra, a disease characterized by dermatitis, diarrhea, dementia, and eventually death 2 . More recently, a progressive decrease in NAD levels during aging in both rodents and humans has been documented in multiple tissues including the liver, adipose tissue, and muscle 3 . Remarkably, restoration of NAD levels with the NAD precursor vitamins nicotinamide riboside (NR), nicotinamide (NAM) and nicotinic acid (NA), in addition to the biosynthetic NAD precursor nicotinamide mononucleotide (NMN) appear to mitigate aging-associated diseases 3-5 . These observations have stimulated a flurry of research activity aiming to better understand how NAD levels affect the aging process and how or why NAD levels decline during aging, with the goal of developing therapeutics to combat aging-related disease.