Multi-omic rejuvenation and life span extension on exposure to youthful circulation

Heterochronic parabiosis (HPB) is known for its functional rejuvenation effects across several mouse tissues. However, its impact on biological age and long-term health is unknown. Here we performed extended (3-month) HPB, followed by a 2-month detachment period of anastomosed pairs. Old detached mice exhibited improved physiological parameters and lived longer than control isochronic mice. HPB drastically reduced the epigenetic age of blood and liver based on several clock models using two independent platforms. Remarkably, this rejuvenation effect persisted even after 2 months of detachment. Transcriptomic and epigenomic profiles of anastomosed mice showed an intermediate phenotype between old and young, suggesting a global multi-omic rejuvenation effect. In addition, old HPB mice showed gene expression changes opposite to aging but akin to several life span-extending interventions. Altogether, we reveal that long-term HPB results in lasting epigenetic and transcriptome remodeling, culminating in the extension of life span and health span. Heterochronic parabiosis ameliorates age-related diseases in mice, but how it affects epigenetic aging and long-term health was not known. Here, the authors show that in mice exposure to young circulation leads to reduced epigenetic aging, an effect that persists for several months after removing the youthful circulation.

Automated summary

Heterochronic parabiosis (HPB) is a technique that has rejuvenation effects on mouse tissues, reducing biological age and improving long-term health. In this study, mice exposed to young circulation through HPB showed reduced epigenetic aging, and this effect lasted even after the removal of youthful circulation. The transcriptomic and epigenomic profiles of these mice indicated a global rejuvenation effect. Furthermore, gene expression changes in the old HPB mice resembled those seen in interventions that extend lifespan. Overall, HPB results in lasting changes in epigenetic and transcriptomic profiles, leading to an extension of lifespan and health span.