To date, the benefits of in vivo reprogramming are limited by the occurrence of detrimental side effects. A new study in Nature Aging reports a safer method for in vivo reprogramming in mice.

Aging is a complex process characterized by the accumulation of molecular, cellular and organ damage, leading to loss of function and increased vulnerability to disease and death. Although aging has long been considered an inevitable process, several strategies are emerging to delay and potentially even reverse it. One of these potential approaches is the restoration of youthful characteristics, or rejuvenation. The forced expression of the four transcription factors Oct4, Sox2, Klf4 and c‐Myc (OSKM) can induce dedifferentiation of somatic cells and ameliorate age-associated phenotypes in mice. However, continuous OSKM expression can also lead to cancer development, teratoma formation and early mortality.

To better understand the causes of the above adverse effects, the team of researchers at the University of Lausanne characterized the phenotype of two well-studied reprogrammable mouse lines. The researchers induced OSKM expression in the 2-month-old 4Fj and 4Fs-B mice by continuously treating them with doxycycline in drinking water. After a few days, the mice displayed signs of hepatic and intestinal dysfunction, associated with decreased activity, body weight loss and premature death (median survival of 5 days and 10 days for 4Fj and 4Fs-B mice, respectively). However, the mice showed neither tumor nor teratoma formation, which suggests that hepatic and intestinal dysfunctions, not tumor or teratoma formation, are the major causes of early mortality in the reprogrammed mice.

To confirm these findings, the researchers generated a new transgenic mouse strain that expresses OSKM in the whole body, with the exception of the liver and the intestine. The mice showed none of the adverse effects associated with in vivo reprogramming, including body weight loss or abnormal activity, and could sustain longer continuous induction of in vivo reprogramming (median survival of 30 days) than 4Fj and 4Fs-B mice.

This new 4F Non-Liver/Intestine mouse model opens new avenues for safer and longer-term induction of in vivo reprogramming and for the study of organismal regeneration and rejuvenation as a strategy to improve human health and lifespan.

Original reference: Parras, A., Vílchez-Acosta, A., Desdín-Micó, G. et al. Nat. Aging https://doi.org/10.1038/s43587-023-00528-5 (2023)