Be it a football team, a book club, or an epigenetics lab, bringing in “young blood” can seriously improve quality in the short term, but does this effect endure? Now, a heterochronic parabiosis study reveals that long-term exposure to young blood induces persistent slowing of DNA methylation-based epigenetic aging and extends healthy lifespans in mice!
A forever young team led by Vadim N. Gladyshev (Harvard Medical School) and James P. White (Duke University School of Medicine) knew that hooking old mice up to the blood of young mice (heterochronic parabiosis) induces functional rejuvenation; however, they needed an invigorating force to develop a means to evaluate any lasting impact on epigenetic age and long-term health. Their “next generation” study exposed old mice to extended heterochronic parabiosis (three months) with young mice, followed by two months of detachment.
Let’s hear from Zhang, Lee, Trapp, and Colleagues on how young blood persistently and systemically slows epigenetic aging:
- Old heterochronic parabiosis mice detached from young mice exhibit improved physiological parameters and extended lifespans compared to matched control isochronic mice
- Heterochronic parabiosis reduces epigenetic age in the blood and liver (measured via RRBS and array data using eight epigenetic clocks), with rejuvenation persisting for up to two months after detachment
- This rejuvenation effect had a greater effect compared to traditional short-term heterochronic parabiosis
- A decrease in epigenetic age compared to non-parabiosed controls suggests that heterochronic parabiosis reverses epigenetic age rather than ameliorating surgery-induced age acceleration
- Transcriptomic/epigenomic profiles of mice undergoing long-term heterochronic parabiosis display an intermediate phenotype between old and young isochronic pairs
- Gene set/pathway analyses reveal enriched tricarboxylic acid cycle, oxidative phosphorylation, mitochondrial biogenesis, and fatty acid metabolism pathways, and depleted IFNγ and inflammatory response pathways
- Longevity-associated genes (including Gstt2, Sirt3, C1qb, and Tert) also display sustained expression changes after long-term parabiosis
- Gene expression changes induced by heterochronic parabiosis in old mice (compared to isochronic controls) negatively correlate with changes induced by aging but positively correlates with changes induced by common lifespan-extending interventions, suggesting a multi-omic, systemic, and sustained biological rejuvenation at the global level
Adapting long-term parabiosis to include detachment supported this first demonstration that exposure to a young circulatory system prompts persistent and systemic slowing of epigenetic aging, which correlates with longer healthy lifespans, improved physiological parameters, and globally rejuvenated epigenomes/transcriptomes. The next step will identify factors that recapitulate the rejuvenation effect to replace the complex and impractical parabiosis procedure.
For more on how bringing in “young blood” persistently and systemically slows epigenetic aging, see Nature Aging, July 2023.