An organismal view of newborn cell dynamics in mammalian aging

Abstract

Aging remodels tissue composition, yet static single-cell atlases cannot show which renewal processes drive this change across the organism. To address this gap, we applied TrackerSci to 21 mouse tissues at young, adult, and aged stages in both sexes, linking in vivo EdU labeling to single-nucleus chromatin accessibility. This produced approximately 3 million profiles of newborn cells matched to global cell populations from the same tissues and ages. Newborn-cell abundance varied widely across tissues and generally declined with age. Beyond abundance, the cell-type composition of newborn cells differed from that of the tissue as a whole. Reflecting this difference, they showed distinct chromatin states, including known renewal compartments and candidate progenitor or proliferation-active states. With age, they also shifted along inferred differentiation trajectories, with stalled-differentiation patterns emerging in multiple lineages. At the population level, age-related changes in newborn-cell abundance partially explained the broader shifts in cell-type composition during aging. Renewal-rate analysis further showed that age-related cell-type declines were driven by reduced replacement, while expansions reflected altered cell-state transitions. Together, these findings show how newborn cell dynamics across the whole organism reveal the routes by which aging remodels cellular composition.