Transient non-integrative nuclear reprogramming promotes multifaceted reversal of aging in human cells

Abstract

Aging is characterized by a gradual loss of function occurring at the molecular, cellular, tissue and organismal levels [1][2][3] . At the chromatin level, aging is associated with the progressive accumulation of epigenetic errors that eventually lead to aberrant gene regulation, stem cell exhaustion, senescence, and deregulated cell/tissue homeostasis 3 . The technology of nuclear reprogramming to pluripotency, through over-expression of a small number of transcription factors, can revert both the age and the identity of any cell to that of an embryonic cell by driving epigenetic reprogramming 2,4,5 . Recent evidence has shown that transient transgenic reprogramming can ameliorate age-associated hallmarks and extend lifespan in progeroid mice 6 .However, it is unknown how this form of 'epigenetic rejuvenation' would apply to physiologically aged cells and, importantly, how it might translate to human cells. Here we show that transient reprogramming, mediated by transient expression of mRNAs, promotes a rapid reversal of both cellular aging and of epigenetic clock in human fibroblasts and endothelial cells, reduces the inflammatory profile in human chondrocytes, and restores youthful regenerative response to aged, human muscle stem cells, in each case without abolishing cellular identity. Our method, that we named Epigenetic Reprogramming of Aging (ERA), paves the way to a novel, potentially translatable strategy for ex vivo cell rejuvenation treatment. In addition, ERA holds promise for in vivo tissue rejuvenation therapies to reverse the physiological manifestations of aging and the risk for the development of age-related diseases.

Differentiation reveals the plasticity of age-related change in murine muscle progenitors

“…Importantly, our experiments demonstrate that only a fraction of age-related changes in progenitors persist through differentiation, whereas differentiation simultaneously reveals age-related changes unseen in progenitors. Dedifferentiation to a pluripotent state has been reported to reverse many hallmarks of aging [48,57,89,59,71,54], indicating that cell identity changes can mask age-related change in an extreme context. Our results further demonstrate that age-related changes can be modulated during the physiologically relevant cell identity changes in differentiation, suggesting that previous results in induced pluripotent systems are not a special case.…”

How can aging be reversed? Exploring rejuvenation from a damage‐based perspective

“…This process might involve restoring original stem cell function through reprogramming differentiated cells to stem cells or the provision of specific signaling molecules that support stem cell functions by reprogramming differentiated cells in the stem cell niche. Recently, a study involving human muscle cells revealed a possibility that, by transiently expressing reprogramming factor (OSKM plus Lin28 and Nanog) mRNAs, one can restore young regenerative capacity and methylation age in human muscle stem cells without changing their identity, yet restore muscle physiological function of these muscle stem cells 88 . This study, along with the previous work on partial reprogramming, suggests a possibility that there are indeed different states that represent age‐related transitions from those of developmental differentiation.…”

Restoring aged stem cell functionality: Current progress and future directions

“…Functionally, transplants of the aged, treated MuSCs generated myofibers with a greater cross-sectional area than those generated by young MuSCs. 64,65 Another avenue for reprogramming focuses not on generating adult stem cells by reprogramming back to iPSCs, but rather on transcription-mediated reprogramming of differentiated cells to adult tissue-specific stem cells. These reprogramming assays have been done in HSCs, 66,67 MSCs, 68,69 NSCs, 70 intestinal progenitor cells, 71 and skeletal muscle progenitors.…”