A Mechanism for Developmental Programming to Contribute to Degenerative Aging
The consensus view of the evolution of aging is that it is a consequence of selection pressure for reproductive fitness operating more strongly in early life. This allows for the selection of cellular biochemistry that works well in youth but malfunctions in later life. The more specific and less widely held hyperfunction or quasi-programmed view of aging envisages degenerative aging as a consequence of the continued activity of developmental programs. It is interesting to here see researchers proposing a specific hyperfunction-like mechanism for dysfunction in aging, linking reactivation of developmental gene expression regulation to aging.
A mechanistic connection between aging and development is largely unexplored. Through profiling age-related chromatin and transcriptional changes across 22 murine cell types, analyzed alongside previous mouse and human organismal maturation datasets, we uncovered a transcription factor binding site (TFBS) signature common to both processes. Early-life candidate cis-regulatory elements (cCREs), progressively losing accessibility during maturation and aging, are enriched for cell-type identity TFBSs. Conversely, cCREs gaining accessibility throughout life have a lower abundance of cell identity TFBSs but elevated activator protein 1 (AP-1) levels.
We implicate transcription factor (TF) redistribution toward these AP-1 TFBS-rich cCREs, in synergy with mild downregulation of cell identity TFs, as driving early-life cCRE accessibility loss and altering developmental and metabolic gene expression. Such remodeling can be triggered by elevating AP-1 or depleting repressive H3K27me3. We propose that AP-1-linked chromatin opening drives organismal maturation by disrupting cell identity TFBS-rich cCREs, thereby reprogramming transcriptome and cell function, a mechanism hijacked in aging through ongoing chromatin opening.