Transient non-integrative expression of nuclear reprogramming factors promotes multifaceted amelioration of aging in human cells

TLDR

Aging is marked by progressive loss of function across molecular, cellular, tissue, and organismal levels, driven in part by accumulating epigenetic errors that disrupt gene regulation, stem cell function, senescence, and tissue homeostasis, and nuclear reprogramming to pluripotency has been shown to reverse cellular age and identity, with transient reprogramming improving age‑related hallmarks and lifespan in progeroid mice. The study aims to determine whether transient expression of nuclear reprogramming factors can rejuvenate naturally aged human cells. Transient expression of nuclear reprogramming factor mRNAs rapidly and broadly ameliorated cellular aging in human cells, resetting the epigenetic clock, reducing inflammatory profiles in chondrocytes, and restoring youthful regenerative responses in aged muscle stem cells, all without loss of cellular identity.

Abstract

Abstract Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels. At the chromatin level, aging associates with progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis. Nuclear reprogramming to pluripotency can revert both the age and the identity of any cell to that of an embryonic cell. Recent evidence shows that transient reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice. However, it is unknown how this form of rejuvenation would apply to naturally aged human cells. Here we show that transient expression of nuclear reprogramming factors, mediated by expression of mRNAs, promotes a rapid and broad amelioration of cellular aging, including resetting of epigenetic clock, reduction of the inflammatory profile in chondrocytes, and restoration of youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity.