biostudies-literatureUnknownYang HIntramural NIH HHSNIA NIH HHSNIH HHSThe dorsolateral prefrontal cortex (DLPFC) underpins higher cognitive functions and is highly susceptible to age-related decline. However, a comprehensive, lifespan-resolved map of its cellular and molecular programs has been lacking. Here, we constructed the first single-nucleus transcriptomic atlas of the human DLPFC, spanning the full lifespan, profiling over 1.3 million nuclei from 284 postmortem samples ranging in age from 0-97 years. This unprecedented resource reveals three distinct transcriptomic phases: dynamic developmental remodeling, midlife stability, and late-life molecular reactivation. Non-linear modeling of age trends uncovers ten distinct trajectories, including a neuronal resilience program peaking in early adolescence and glial aging programs marked by immune activationmedRxiv : the preprint server for health sciences2024.11.06.24316592https://www.ebi.ac.uk/biostudies/studies/S-EPMC12632665biostudies-literatureA lifespan transcriptomic atlas of the human prefrontal cortex at single-cell resolution.PMC12632665ZIC MH002903R01 AG067025R01 AG065582R01 AG08218575N95019C00049Auluck PKMarenco SCasey CVenkatesh SMcClung CALee DShao ZVoloudakis GYu AKHoffman GEWang XMurphy SRArgyriou SYang HAlvia MRoussos PTsankova NMScott MRPsychAD ConsortiumBendl JHong AFullard JFHaroutunian VGirdhar KPjanic MClarence TPrashant NMfalseA lifespan transcriptomic atlas of the human prefrontal cortex at single-cell resolution.The dorsolateral prefrontal cortex (DLPFC) underpins higher cognitive functions and is highly susceptible to age-related decline. However, a comprehensive, lifespan-resolved map of its cellular and molecular programs has been lacking. Here, we constructed the first single-nucleus transcriptomic atlas of the human DLPFC, spanning the full lifespan, profiling over 1.3 million nuclei from 284 postmortem samples ranging in age from 0-97 years. This unprecedented resource reveals three distinct transcriptomic phases: dynamic developmental remodeling, midlife stability, and late-life molecular reactivation. Non-linear modeling of age trends uncovers ten distinct trajectories, including a neuronal resilience program peaking in early adolescence and glial aging programs marked by immune activation2025-01-01T00:00:00Z2025 Oct2026-06-01T03:16:50.909Z2026-06-01T03:10:50.783ZS-EPMC126326654128285910.1101/2024.11.06.24316592