de Lima Camillo, L. P.; Gam, R.; Maskalenka, K.; LeBlanc, F. J.; Urrutia, G. A.; Mejia, G. M.; Miller, H. E.; Wardlaw, C. P.; Pickles, A.; Everton, L.; Zaksauskaite, R.; Khan, R. B.; Welsh, A.; Gambo, S.; Gallardo, S.; Oliynyk, Z.; Varankar, S. S.; Epstein, A. E.; Bendall, A.; Mowatt, J.; Ives, D.; Swain, B. M.

Ageing is a key driver of the major diseases afflicting the modern world. Slowing or reversing the ageing process would therefore drive significant and broad benefits to human health. Previously, the Yamanaka factors (OCT4, SOX2, KLF4, with or without c-MYC: \"OSK(M)\") have been shown to rejuvenate cells based on accurate predictors of age known as epigenetic clocks. Unfortunately, OSK(M) induces dangerous pluripotency pathways, making it unsuitable for therapeutic use. Recent work has focused on minimising the danger of the cocktail, but safety concerns remain. Here we present \"SB000\", the first single gene intervention to rejuvenate cells from multiple germ layers with efficacy rivalling the Yamanaka factors. Cells rejuvenated by SB000 retain their somatic identity, without evidence of pluripotency or loss of function. These results reveal that decoupling pluripotency from cell rejuvenation does not remove the ability to rejuvenate multiple cell types. This discovery paves the way for cell rejuvenation therapeutics that can be broadly applied across age-driven diseases.