Nature Communications 14(1) (2023) The naked mole rat (NMR), Heterocephalus glaber, the longest-living rodent, provides a unique opportunity to explore how evolution has shaped adult stem cell (ASC) activity and tissue function with increasing lifespan. Using cumulative BrdU labelling and a quantitative imaging approach to track intestinal ASCs (Lgr5+) in their native in vivo state, we find an expanded pool of Lgr5+ cells in NMRs, and these cells specifically at the crypt base (Lgr5+CBC) exhibit slower division rates compared to those in short-lived mice but have a similar turnover as human LGR5+CBC cells. Instead of entering quiescence (G0), NMR Lgr5+CBC cells reduce their division rates by prolonging arrest in the G1 and/or G2 phases of the cell cycle. Moreover, we also observe a higher proportion of differentiated cells in NMRs that confer enhanced protection and function to the intestinal mucosa which is able to detect any chemical imbalance in the luminal environment efficiently, triggering a robust pro-apoptotic, anti-proliferative response within the stem/progenitor cell zone. Nature Portfolio CC BY 4.0 International http://creativecommons.org/licenses/by/4.0/ Adult stem cell activity in naked mole rats for long-term tissue maintenance application/pdf eng doi:10.1038/s41467-023-44138-6 https://phaidra.vetmeduni.ac.at/o:3002 2023 article Mice; Humans; Animals; Longevity; Intestinal Mucosametabolism; Intestines; Adult Stem Cellsmetabolism; Receptors, G-Protein-Coupledmetabolism; Mole Rats Montazid, Shamir (University of Oxford) Irshad, Shazia (University of Oxford) Hayee, Bu'Hussain (King's College) Ziolkowski, Piotr (Wroclaw Medical University) Gazinska, Patrycja (Polish Center for Technology Development) Rost, Fabian (Technische Universität Dresden) Altrock, Philipp M. (Max Planck Institute for Evolutionary Biology) Bansal, Mukesh (Bristol Myers Squibb) Wernisch, Bettina (University of Veterinary Medicine Vienna) Penn, Dustin J. (University of Veterinary Medicine Vienna) Thrumurthy, Sri G. (King's College) Johnson, Brian (University of California) Tomlinson, Ian (University of Oxford) Gao, Nan (Rutgers University) Bandyopadhyay, Sheila (Rutgers University) Hart, Daniel W. (University of Pretoria) Bennett, Nigel C. (University of Pretoria) East, James E. (John Radcliffe Hospital) Bodmer, Walter F. (University of Oxford) Koth, Jana (University of Oxford) Tessitore, Annamaria (Novo Nordisk Research Centre Oxford) Han, Jiangmeng (Rutgers University) Liu, Yue (Rutgers University)