Rejuvenating senescent and centenarian human cells by reprogramming through the pluripotent state

TLDR

Direct reprogramming of somatic cells into iPSCs offers patient‑specific stem cells for therapy, yet cellular senescence has been viewed as a barrier to iPSC derivation. The study shows that cellular senescence does not limit reprogramming and that age‑related cellular physiology can be reversed using an optimized protocol. iPSCs derived from senescent and centenarian cells reset telomere length, gene expression, oxidative stress, and mitochondrial metabolism to levels indistinguishable from hESCs, can redifferentiate into fully rejuvenated cells, and thus provide a foundation for regenerative medicine in aged patients.

Abstract

Direct reprogramming of somatic cells into induced pluripotent stem cells (iPSCs) provides a unique opportunity to derive patient-specific stem cells with potential applications in tissue replacement therapies and without the ethical concerns of human embryonic stem cells (hESCs). However, cellular senescence, which contributes to aging and restricted longevity, has been described as a barrier to the derivation of iPSCs. Here we demonstrate, using an optimized protocol, that cellular senescence is not a limit to reprogramming and that age-related cellular physiology is reversible. Thus, we show that our iPSCs generated from senescent and centenarian cells have reset telomere size, gene expression profiles, oxidative stress, and mitochondrial metabolism, and are indistinguishable from hESCs. Finally, we show that senescent and centenarian-derived pluripotent stem cells are able to redifferentiate into fully rejuvenated cells. These results provide new insights into iPSC technology and pave the way for regenerative medicine for aged patients.