Rejuvenation rankings from CRISPRi screens change with the aging cohort and track cell growth programs

Ranking gene knockdowns by how well they reverse an aging expression signature is a common way to find rejuvenation targets, but the stability of these rankings has not been tested. We built TRACE, an open-source set of tests, to score 18,746 knockdown profiles from five CRISPR interference (CRISPRi) screens in four human cell lines. Rankings built from fibroblasts of 111 donors and from Genotype-Tissue Expression (GTEx) fibroblasts were unrelated ({rho} = -0.05). In an exploratory test, the 200 strongest age genes of the first cohort changed in the opposite direction in GTEx ({rho} = -0.55), but this was not significant after correction and shrank when GTEx batch was modeled. Raw scores followed the broad programs inside each signature: strongly for proliferation with the fibroblast signature, weakly for stress with a GTEx-derived signature. Proliferation alone matched the fibroblast scores' agreement with senescence labels. TRACE runs on other aging cohorts and screens.