Inducible chronic NAD deficiency in mice reveals multi-systemic phenotypical, metabolic, and transcriptional changes
Year: 2026
Type: article
Abstract: Nicotinamide adenine dinucleotide (NAD) is a metabolic cofactor regulating energy metabolism, epigenetics, DNA repair, and signaling. Although NAD declines with vitamin B3 deficiency, disease, and aging, systemic consequences of chronic depletion remain unclear. Here, we characterize an in vivo model of inducible NAD deficiency using acquired niacin dependency (ANDY) mice, in which NAD synthesis becomes dependent on dietary niacin. On a niacin-free diet, ANDY mice developed widespread tissue NAD depletion and sex-independent multisystem abnormalities, including kyphosis, reduced bone, lean, and fat mass, impaired exercise capacity, fur browning, frailty, cataracts, disrupted energy homeostasis, and shortened lifespan. NAD depletion was accompanied by tissue inflammation and cellular senescence. Transcriptomic analyses revealed broad metabolic remodeling and only partial overlap with chronological aging. Senolytic treatment partially improved functional decline without restoring NAD. In contrast, dietary niacin repletion reversed phenotypic, biochemical, senescence-associated, and transcriptional abnormalities, demonstrating that recovery of tissue NAD levels restored systemic function. The authors show that chronic NAD deficiency causes widespread metabolic, physical, and cellular changes, including senescence and inflammation, while dietary niacin restores NAD levels and reverses most of these effects.
Source: Nature Communications
Authors: Andres Benitez-Rosendo, Morgan B. Feuz, Claudia C. S. Chini, Gina M. Warner, Gina L. Ciccio Lopez, Gustavo H. Souza, Katrina Rae Bueser, Sonu Kashyap, Laura Colman, Katie L. Thompson, Delaram Zamani Mazdeh, Sierra A. Lopez, Laura B. Miller, Alexie E. Zwerdling, Miles K. Wandersee, Thais R. Peclat, Sara Peixoto Rabelo, Karina S. Kanamori, Fernanda C. Pereira, Heidi S. Cordeiro, Jessica L. Strange, Naiara C. Lucredi, Luiza Palmieri Serrano, Rakesh Kaundal, Jason D. Doles, Jennifer L. Rowsey, Joshua N. Farr, Sundeep Khosla, Ralph G. Meyer, Mirella L. Meyer-Ficca, Eduardo N. Chini
Language: English
Subfield: Geriatrics and Gerontology
Field: Medicine
Domain: Health Sciences
Open Access status: gold
Estimated APC paid: $6,990
Funders: Mayo Clinic, Glenn Foundation for Medical Research, Utah State University, Utah Agricultural Experiment Station, Center for Strategic Scientific Initiatives, National Cancer Institute, Fondation pour la Recherche Médicale, National Institutes of Health, University Research Coordination Office, De La Salle University, National Institute on Aging, National Cancer Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
OpenAlex ID: W7214065663
FWCI:
Cites:
Cited by:
Related to: