iPSCs: On the Road to Reprogramming Aging

Aging is characterized by irreversible loss of physiological integrity, often accompanied by an organism's loss of function and increased vulnerability to death. Defects in the mechanisms preserving cellular homeostasis over time may give rise to accelerated aging. Somatic cell reprogramming of aged cells can be associated with rejuvenation, erasing certain age-associated features, and illustrating the reversibility potential of aging. Here, we focus on recent advances in the generation of human induced pluripotent stem cells from progeroid syndromes and late-onset diseases such as Alzheimer's or Parkinson's. These cellular models have contributed to a better understanding of such pathologies, as well as to the development of novel therapeutic approaches. We also discuss different strategies to identify and target age-associated reprogramming barriers to facilitate the treatment of age-related disorders.

TrendsSomatic cell reprogramming from normal, abnormal, or aged cells is a highly inefficient process. Despite this impediment, reprogramming aged cells is possible, illustrating aging reversibility.Modeling aging in a dish is challenging, facing the difficulties of recapitulating normal aging as well as late-onset phenotypes that critically contribute to age-related diseases such as neurodegenerative disorders.iPSCs derived from progeroid syndromes and/or progerin overexpression during in vitro iPSC differentiation constitute feasible experimental approaches to induce late-onset phenotypes.NF-κB hyperactivation during aging impairs cell reprogramming through a DOT1L histone methyltransferase-dependent mechanism. DOT1L inhibition extends the longevity of progeroid mice, establishing a parallel between reprogramming enhancement and organism rejuvenation.Cell reprogramming is feasible in vivo, at least in mice, paving the way for future approaches aimed at enhancing tissue homeostasis through the endogenous expression of Yamanaka factors or other transdifferentiation cocktails.