Interacting NAD+ and Cell Senescence Pathways Complicate Antiaging Therapies

During human aging, decrease of NAD(+) levels is associated with potentially reversible dysfunction in the liver, kidney, skeletal and cardiac muscle, endothelial cells, and neurons. At the same time, the number of senescent cells, associated with damage or stress that secretes proinflammatory factors (SASP or senescence-associated secretory phenotype), increases with age in many key tissues, including the kidneys, lungs, blood vessels, and brain. Senescent cells are believed to contribute to numerous age-associated pathologies and their elimination by senolytic regimens appears to help in numerous preclinical aging-associated disease models, including those for atherosclerosis, idiopathic pulmonary fibrosis, diabetes, and osteoarthritis. A recent report links these processes, such that decreased NAD(+) levels associated with aging may attenuate the SASP potentially reducing its pathological effect. Conversely, increasing NAD(+) levels by supplementation or genetic manipulation, which may benefit tissue homeostasis, also may worsen SASP and encourage tumorigenesis at least in mouse models of cancer. Taken together, these findings suggest a fundamental trade-off in treating aging-related diseases with drugs or supplements that increase NAD(+). Even more interesting is a report that senescent cells can induce CD38 on macrophages and endothelial cells. In turn, increased CD38 expression is believed to be the key modulator of lowered NAD(+) levels with aging in mammals. So, accumulation of senescent cells may itself be a root cause of decreased NAD(+), which in turn could promote dysfunction. On the contrary, the lower NAD(+) levels may attenuate SASP, decreasing the pathological influence of senescence. The elimination of most senescent cells by senolysis before initiating NAD(+) therapies may be beneficial and increase safety, and in the best-case scenario reduce the need for NAD(+) supplementation.