Epigenetic changes induced by partial reprogramming of aged cells

National Institute On Aging

Investigators

Abstract

Age is the major risk factor for many human diseases. Multiple studies have demonstrated that cellular reprogramming to pluripotency reverses cellular age. In this proposal, we will utilize a non-integrative transient reprogramming protocol based on a cocktail of mRNAs expressing OCT4, SOX2, KLF4, c-MYC, LIN28, and NANOG (OSKMLN) to induce partial reprogramming at large scale on aged human fibroblasts from the GESTALT study. The partial reprogramming regimen includes two steps: de-differentiation and re-differentiation. We thus hypothesize that the old human fibroblasts will be easier to reprogram into a youthful state by simply expressing re-differentiation factors. To find the potential re-differentiation factors, we will first test if aged human fibroblasts show the same de-differentiated state as aged mouse cells. We will then map and compare the chromatin landscape at various stages of the partial reprogramming process to specify the re-differentiation factors. With the same non-integrative reprogramming protocol, we will then treat aged fibroblasts with the cocktail of mRNAs expressing re-differentiation factors to test if it can ameliorate age-associated phenotypes. We expect that this collaborative work will illuminate a deeper mechanistic understanding of how reprogramming factors rejuvenate aged cells and pave the way for safer anti-aging interventions.