The Aging Protein, AP-1

Interesting new paper.

Author says “ "We followed the activity of the master regulator Activator Protein 1 or AP-1 and found that it progressively activated adult genes, while the activity of ‘early-life’ genes involved in development were dialed down, and this process was shared across cell types.”

“It was ongoing in adulthood, likely because AP-1 is also activated by a number of stress and inflammatory processes as well as by a protein in our blood that increases with age,” Dr. Naval-Sanchez said.


The activity of early-life gene regulatory elements is hijacked in aging through pervasive AP-1-linked chromatin opening


  • Multi-omic analysis of maturation and aging across >45 mouse and human cell types

  • Common transcription factor pattern for chromatin remodeling in maturation and aging

  • Encoded via relative abundance of AP-1, CTCF, and cell identity factor binding sites

  • Remodeling mechanism activated by AP-1, stress, systemic factor, or PRC2 inhibition


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 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.

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This paper more than any other I have seen recently made me think we could be a few years out from a drug developed with aging as the target – as opposed to an existing FDA-approved drug that happens to be observationally linked to longevity and then tested in the ITP. Given the way the 2012 CRISPR-Cas9 science has blossomed into a multitude of editing systems impacting not just DNA but RNA and epigenetics, it seems like we could be a decade out from a pre-IND therapy and 20-25 years out from commercialization.