Molecular hallmarks of heterochronic parabiosis at single cell resolution

Abstract

Slowing or reversing biological ageing would have major implications for mitigating disease risk and maintaining vitality. While an increasing number of interventions show promise for rejuvenation, the effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. We performed single-cell RNA-sequencing on 13 organs to reveal cell type specific responses to young or aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, hematopoietic stem cells, hepatocytes, and endothelial cells from multiple tissues appear especially responsive. On the pathway level, young blood invokes novel gene sets in addition to reversing established ageing patterns, with the global rescue of genes encoding electron transport chain subunits pinpointing a prominent role of mitochondrial function in parabiosis-mediated rejuvenation. Intriguingly, we observed an almost universal loss of gene expression with age that is largely mimicked by parabiosis: aged blood reduces global gene expression, and young blood restores it. Altogether, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity.

Heterochronic parabiosis reprograms the mouse brain transcriptome by shifting aging signatures in multiple cell types

“…To this end, we identified the primary cell types exhibiting these changes and revealed the common and cell-type-specific aging-induced signatures and transcriptional programs that were rescued following parabiosis in the old brains and/or disrupted in the young brains. As corroborated by recent reports, our data provide evidence that heterochronic parabiosis effectively modulates multiple manifestations of canonical aging hallmarks, including altered intercellular communication 79 , loss of proteostasis 115 , defects in mitochondrial dysfunction 68,116–118 and cellular senescence 37,107,119,120 .…”

“…Collectively, our gene expression matrices provide unprecedented data that can be further explored to form working hypotheses for follow-up studies. Similar to other recent reports 118,123,133 , our study advances fundamental understanding of the mechanisms underlying the aging process and potential interventions that go beyond descriptive studies of cell states. Our work extends current knowledge regarding the effects of heterochronic parabiosis on the aging process and supports the key role of the brain vasculature in mediating these effects.…”

Forward single‐cell sequencing into clinical application: Understanding of ageing and rejuvenation from clinical observation to single‐cell solution

“…Palovics et al. investigated inter‐organ and inter‐cellular heterogeneity of transcriptomic profiles in response to heterochronic parabiosis, an approach to exchange blood from young to old or vice versa, and provided solid evidence and new insights for understanding systemic responses and molecular networks among blood‐borne factors and cells at single‐cell solution 20 . Deep understanding of heterochronic parabiosis can characterise biological functions and the therapeutic potential of blood‐borne circulating factors in the body, multiple organs and organelle interactions of ageing.…”

“…Deep understanding of heterochronic parabiosis can characterise biological functions and the therapeutic potential of blood‐borne circulating factors in the body, multiple organs and organelle interactions of ageing. scRNA‐seq data of 20 organs demonstrated that responses to young and aged blood is cell type‐specific in heterochronic parabiosis, where adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes were most responsive 20 . scRNA‐seq showed that transcriptomic alterations of skeletal stem cells in ageing were accompanied by transformation of the bone marrow niche and functional decline 21 .…”

The cell as a bag of RNA

“…wealth of insight into the diversity of cell types in these organisms, how related cell types across different tissues are similar or different, how cells change with age, and what are the evolutionary relationships between different cell types across organisms. For example, the Tabula Muris Senis has helped us understand at a global level how gene expression changes with age, which cell types are most affected, and which of these aspects are reversible via rejuvenation approaches such as parabiosis [33,39]. As another example, the Tabula Drosophila has helped reveal how gene expression depends on sex, and has identified which cell types have the highest levels of sex-biased gene expressionthis is a launching pad to help understand how these differences meet the distinct developmental and physiological needs of males and females [31].…”