Cellular Survivorship Bias as a Mechanistic Driver of Muscle Stem Cell Aging

Aging is characterized by a significant impairment in the ability of muscle stem cells (MuSCs) to efficiently contribute to muscle regeneration. Here we uncover a novel cause of this aging-associated stem cell dysfunction - a cell-specific survivorship bias that prioritizes stem cell persistence at the expense of functionality. We show here that, with age, muscle stem cells upregulate a tumor suppressor, NDRG1, which, by blunting the mTOR pathway, increases their long-term survival potential but comes at the cost of their ability to promptly activate and contribute to muscle regeneration. These findings suggest that delayed muscle regeneration with age may be the result of a tradeoff that favors long term stem cell survival over immediate regenerative capacity. Overall design: In order to determine the extent to which the elevation of NDRG1 might be a causal driver of the impaired activation rate observed in old MuSCs, we generated a MuSC-specific conditional NDRG1 KO mouse model (Pax7CreER/+; NDRG1fl/fl;ROSAeYFP/+ ) to ablate NDRG1 in MuSCs following tamoxifen injection. We next sought to determine the molecular mechanism by which NDRG1 was eliciting its effects in old MuSCs. To this end, we sequenced the transcriptomes of MuSCs from aged WT and NDRG1cKO mice