short-term expression of OSKM in mice can reverse some aspects of the ageing process

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In vitro cellular reprogramming through the expression of the four transcription factors OCT4, SOX2, KLF4 and MYC (OSKM) has been shown to ameliorate age-associated cellular phenotypes, including gene expression profiles, telomere length and oxidative stress. Whether reprogramming can have beneficial effects in vivo remains to be explored. Ocampo et al. now show that short-term expression of OSKM in mice can reverse some aspects of the ageing process.

A truncated form of lamin A known as progerin causes Hutchinson–Gilford progeria syndrome (HGPS), which is characterized by premature ageing in humans. The authors used a mouse model of HGPS and generated progeria mice carrying inducible OSKM transgenes. Short-term expression of OSKM in fibroblasts isolated from these mice reversed several molecular and cellular changes that are associated with ageing. For example, these cells had fewer histone γ-H2AX foci (a marker of DNA double-strand breaks) and reduced levels of the DNA damage response protein p53 binding protein 1 (TP53BP1), lower expression of age-related stress-response genes and senescence-associated genes, and reduced production of reactive oxygen species (indicative of improved mitochondrial function).

Short-term induction of OSKM also improved nuclear envelope architecture, which is a main driver of premature ageing in HGPS. Moreover, the levels of histone H3 Lys 9 trimethylation (H3K9me3) and H4K20me3, which are usually altered during ageing, were restored to a younger state. Interestingly, the authors found that an increase in H3K9me3 levels preceded the amelioration of DNA damage and nuclear envelope defects and was necessary for them to occur, indicating that epigenetic remodelling may be a main driver of the amelioration of age-associated phenotypes.

So, does a temporary induction of OSKM confer benefits to the organism? As reprogramming in vivo has been previously shown to induce the formation of teratomas and the development of cancer, the authors established a safe protocol for the in vivo induction of OSKM. They found that repeated cycles of short-term induction prevented the formation of tumours and reduced the mortality seen following continuous OSKM expression. Using this cyclic protocol, the authors treated progeria mice throughout their lives, starting at 8-weeks of age. Strikingly, the appearance of treated mice was improved, and although mice progressively lost body weight, both median and maximal lifespan were substantially increased. Moreover, adult stem cell populations in the muscle and hair follicles were replenished, and cardiovascular alterations and histological changes (in the skin, spleen, kidneys and stomach) that occur during ageing were reversed. Furthermore, the epigenetic changes that were seen in vitro, as well as the reduction in the expression of stress- and senescence-associated genes, were also seen in several organs of the treated mice.

Last, the authors investigated whether partial reprogramming could have beneficial effects in wild-type organisms. Ageing is associated with a loss of proliferative capacity of pancreatic β-cells, which can lead to pancreatic dysfunction as well as a loss of skeletal muscle mass (sarcopenia). The authors observed that cyclic expression of OSKM in 12-month-old mice promoted the expansion of the β-cell population, enhanced their recovery from pancreatic injury and ameliorated glucose tolerance following pancreatic injury. Furthermore, treated 12-month-old mice had a greater muscle regeneration capacity following injury.

Together, these observations suggest that partial reprogramming by cyclic short-term induction of OSKM can revert or slow down the decline in regenerative capacity and the loss of tissue homeostasis that occur during ageing. This system could be exploited to study ageing-related diseases and further elucidate the role of epigenetics in ageing.