Targeted partial reprogramming of age-associated cell states improves markers of health in mouse models of aging.

Abstract

Aging is a complex multifactorial process associated with epigenome dysregulation, increased cellular senescence, and decreased rejuvenation capacity. Short-term cyclic expression of <i>octamer-binding transcription factor 4</i> (<i>Oct4</i>), <i>sex-determining region Y-box 2</i> (<i>Sox2</i>), <i>Kruppel-like factor 4</i> (<i>Klf4</i>), and <i>cellular myelocytomatosis oncogene</i> (<i>cMyc</i>) (<i>OSKM</i>) in wild-type mice improves health but fails to distinguish cell states, posing risks to healthy cells. Here, we delivered a single dose of adeno-associated viruses (AAVs) harboring <i>OSK</i> under the control of the <i>cyclin-dependent kinase inhibitor 2a</i> (<i>Cdkn2a</i>) promoter to specifically partially reprogram aged and stressed cells in a mouse model of Hutchinson-Gilford progeria syndrome (HGPS). Mice showed reduced expression of proinflammatory cytokines and extended life spans upon aged cell-specific <i>OSK</i> expression. The bone marrow and spleen, in particular, showed pronounced gene expression changes, and partial reprogramming in aged HGPS mice led to a shift in the cellular composition of the hematopoietic stem cell compartment toward that of young mice. Administration of AAVs carrying <i>Cdkn2a-OSK</i> to naturally aged wild-type mice also delayed aging phenotypes and extended life spans without altering the incidence of tumor development. Furthermore, intradermal injection of AAVs carrying <i>Cdkn2a</i>-<i><i>OSK</i></i> led to improved wound healing in aged wild-type mice. Expression of <i>CDKN2A</i>-<i>OSK</i> in aging or stressed human primary fibroblasts led to reduced expression of inflammation-related genes but did not alter the expression of cell cycle-related genes. This targeted partial reprogramming approach may therefore facilitate the development of strategies to improve health and life span and enhance resilience in the elderly.