{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,29]],"date-time":"2026-10-29T00:04:44Z","timestamp":1793232284049,"version":"4.5.0"},"posted":{"date-parts":[[2026,8,7]]},"group-title":"Molecular Biology","reference-count":88,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T00:00:00Z","timestamp":1786060800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"award":["P01AG092325"],"award-info":[{"award-number":["P01AG092325"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["U54 AG079758"],"award-info":[{"award-number":["U54 AG079758"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"award":["R21AG101323"],"award-info":[{"award-number":["R21AG101323"]}],"id":[{"id":"https:\/\/ror.org\/049v75w11","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R35GM142495"],"award-info":[{"award-number":["R35GM142495"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,7]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                <jats:p>Aging is driven by multiple interacting processes, suggesting that effective strategies to promote healthy aging may require simultaneous targeting of more than one underlying mechanism. Here we identify a strategy that couples restoration of nicotinamide adenine dinucleotide (NAD+) homeostasis with selective targeting of senescent cells, two mechanistically linked features of aging. Senescent cells express elevated intracellular levels of nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme in the nicotinamide (NAM) salvage pathway for NAD+ biosynthesis. Despite increased NAMPT abundance, isotope-tracing studies revealed decreased NAD+ biosynthesis and consumption, indicating that elevated NAMPT abundance was not accompanied by a corresponding increase in NAD+ metabolic flux. Treatment with the NAMPT activator SBI-0802162 engaged the spare enzymatic capacity of NAMPT in senescent cells and produced a marked rise in intracellular NAD+ that, when sustained, disrupted their transcriptional program and selectively reduced the viability of senescent cells but not proliferating cells. In mice, SBI-0802162 reduced circulating NAM levels, suggesting that sustained NAMPT activation may be limited by substrate availability. This observation prompted the development of a combination approach using SBI-0802162 together with dietary NAM supplementation. Co-administration of SBI-0802162 and NAM robustly increased tissue NAD+, suppressed select age-associated inflammatory signatures and markers of cellular senescence in a tissue-specific manner. These molecular effects occurred alongside preserved physical performance in aged mice and reductions in food intake and body weight, which were observed whether SBI-0802162 was present in the chow or administered by oral gavage. Together, these findings establish a mechanistically integrated approach to target two convergent features of aging, NAD+ dysregulation and senescent cell accumulation, and support combined NAMPT activation and NAM supplementation as a strategy to promote healthy aging.<\/jats:p>","DOI":"10.64898\/2026.08.06.743365","type":"posted-content","created":{"date-parts":[[2026,8,7]],"date-time":"2026-08-07T13:10:11Z","timestamp":1786108211000},"source":"Crossref","is-referenced-by-count":1,"title":["NAMPT activation uncovers a senescence-specific vulnerability and promotes healthy aging in combination with NAM"],"prefix":"10.64898","author":[{"given":"Michael","family":"Alcaraz","sequence":"first","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"},{"name":"Graduate School of Biomedical Sciences, Sanford Burnham Prebys Medical Discovery Institute, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raghuveer","family":"Ramachandra","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rouven","family":"Arnold","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcos","family":"Garcia-Teneche","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adarsh","family":"Rajesh","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Haddadin","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mey","family":"Taing","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Lei","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Armin","family":"Gandhi","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Theophilos","family":"Tzaridis","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Miller","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jessica","family":"Proulx","sequence":"additional","affiliation":[{"name":"Sanford Burnham Prebys Medical Discovery Institute, Cancer Genome and Epigenetics Program, La Jolla, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amirhossein Nayeri","family":"Rad","sequence":"additional","affiliation":[{"name":"Ludwig Boltzmann Institute for Traumatology. 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