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Published Online: 17 June 2019

Interacting NAD+ and Cell Senescence Pathways Complicate Antiaging Therapies

Publication: Rejuvenation Research
Volume 22, Issue Number 3


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.

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Information & Authors


Published In

cover image Rejuvenation Research
Rejuvenation Research
Volume 22Issue Number 3June 2019
Pages: 261 - 266
PubMed: 31140365


Published online: 17 June 2019
Published in print: June 2019
Published ahead of production: 29 May 2019


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Andrew R. Mendelsohn [email protected]
Panorama Research Institute, Sunnyvale, California.
Regenerative Sciences Institute, Sunnyvale, California.
James W. Larrick
Panorama Research Institute, Sunnyvale, California.
Regenerative Sciences Institute, Sunnyvale, California.


Address correspondence to: Andrew R. Mendelsohn, Regenerative Sciences Institute, 1230 Bordeaux Drive, Sunnyvale, CA 94089 [email protected]

Author Disclosure Statement

No competing financial interests exist.

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