Aging-related inflammation driven by cellular senescence enhances NAD consumption via activation of CD38⁺pro-inflammatory macrophages

Abstract

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.

Where Metabolism Meets Senescence: Focus on Endothelial Cells

“…Low levels of NAD + were also reported in several tissues (Massudi et al, 2012;Zhu et al, 2015), and supplementation of NAD + precursors increased life span in different species (Fang et al, 2016;Zhang et al, 2016). Interestingly, SCs were shown to induce the SASP-mediated expression of CD38 -an ectoenzyme with a high NADase activity -in non-senescent cells, such as endothelial cells and bone marrow-derived macrophages (Chini et al, 2019;Covarrubias et al, 2019). CD38 inhibitors rescued NAD + decline and ameliorated a number of age-related metabolic outcomes in mice (Tarrago et al, 2018).…”

The possible pathophysiology mechanism of cytokine storm in elderly adults with COVID-19 infection: the contribution of “inflame-aging”

“…However, the mortality rate for obese elderly adults with COVID-19 was approximately 14% [72]. In addition to obesity, Covarrubias and colleagues found that during aging senescent cells significantly accumulate in visceral white adipose tissue and inflammatory cytokines found in the supernatant from senescent cells, which are induced macrophages to proliferate and to express CD38, as a T cell activation marker [73]. Alicka and colleagues in 2020 found that adipose-derived stem cells from older groups exhibited increased gene expression of pro-inflammatory gene and miRNAs (such as IL-8, IL-1β, TNF-α, miR-203b-5p, and miR-16-5p), and apoptosis markers (such as p21, p53, caspase-3, caspase-9) [69].…”

Role of immune cells in the removal of deleterious senescent cells

“…Furthermore, eliminating this subset of so-called senescent-like or pseudo senescent macrophages with an M2 phenotype induces a striking resolution of inflammation [69]. Recent work also shows that the SASP can promote macrophage proliferation and increased expression of CD38, which enhances the consumption of NAD by macrophages and might explain the age-related decline in NAD levels [70].…”