Rejuvenation Potential of Developmental Genes Downregulated in Aging

Partial reprogramming with Yamanaka factors effectively reverses cellular aging but poses potential oncogenic risks, limiting clinical translation. To identify safer rejuvenation induction factors (RIFs), we integrated five aging datasets and compared them with single-cell transcriptomics data from 811 mouse embryonic cells in preimplatation stages. This analysis identified genes exhibiting an inverse relationship between aging (downregulated) and development (upregulated). We further refined this selection by isolating genes common in the intermediate stage of Yamanaka factor-mediated reprogramming. Based on the molecular characteristics of reprogramming factors, we successfully isolated four RIFs associated with ribosome biogenesis, mitochondrial import, translational regulation, and serine metabolism. The expression of these RIFs in aged fibroblasts effectively reduced senescence markers and increased gene expression patterns inversely associated with aging-associated transcriptional change. Unlike the established Yamanaka factors, these identified RIFs modulate development-associated pathways that decline with aging, without activating pluripotency-associated programs, suggesting a potentially safer rejuvenation strategy.