A Mechanism for Developmental Programming to Contribute to Degenerative Aging
The consensus view on the evolution of aging suggests that it is driven by selection pressure for reproductive fitness, leading to cellular changes that work well in youth but malfunction in later life. A less common perspective, the hyperfunction or quasi-programmed view, proposes that degenerative aging stems from continued activity of developmental programs. Researchers are now exploring a specific hyperfunction-like mechanism linking reactivation of developmental gene regulation to aging.
A mechanistic link between aging and development is an uncharted territory. By analyzing age-related chromatin and transcriptional changes across various murine cell types, researchers have discovered a common transcription factor binding site (TFBS) signature that connects both processes. They found that early-life candidate cis-regulatory elements (cCREs) lose accessibility as maturation and aging progress, while cCREs gaining accessibility throughout life exhibit distinct molecular changes.
The redistribution of transcription factors towards AP-1 TFBS-rich cCREs, in conjunction with downregulation of cell identity TFs, leads to altered gene expression and cellular functions. This remodeling can be induced by manipulating AP-1 levels or repressive H3K27me3. The study proposes that AP-1-linked chromatin opening disrupts cell identity TFBS-rich cCREs, driving organismal maturation and subsequently contributing to aging through ongoing chromatin remodeling.
