Molecular hallmarks of heterochronic parabiosis at single-cell resolution
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Abstract
The ability to slow or reverse biological ageing would have major implications for mitigating disease risk and maintaining vitality1. Although an increasing number of interventions show promise for rejuvenation2, their effectiveness on disparate cell types across the body and the molecular pathways susceptible to rejuvenation remain largely unexplored. Here we performed single-cell RNA sequencing on 20 organs to reveal cell-type-specific responses to young and aged blood in heterochronic parabiosis. Adipose mesenchymal stromal cells, haematopoietic stem cells and hepatocytes are among those cell types that are especially responsive. On the pathway level, young blood invokes new 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. 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 in select cell types. Together, these data lay the groundwork for a systemic understanding of the interplay between blood-borne factors and cellular integrity. A transcriptomics study demonstrates cell-type-specific responses to differentially aged blood and shows young blood to have restorative and rejuvenating effects that may be invoked through enhanced mitochondrial function.
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Geroprotective strategies such as long-term exercise and exposure to youthful bodily fluids mitigate accumulation of IgG and senescent cells in aging tissues.
“By contrast, established geroprotective strategies such as long-term exercise and exposure to youthful bodily fluids,17”
From Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging (2024) · cites this paper as [48]
The introductory passage (section labelled Abstract; page unavailable) describes exposure to young blood through heterochronic parabiosis as a rejuvenation method with beneficial effects in mice. The Cell type-specific responses section reports changes associated with young blood, but the cited paper does not establish that long-term exercise or youthful bodily fluids mitigate IgG accumulation or senescent-cell accumulation in aging tissues. (LLM, conf=0.82)
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- Authors
- Pálovics, R., Keller, A., Schaum, N., Tan, W., Fehlmann, T., Borja, M., Kern, F., Bonanno, L., Calcuttawala, K., Webber, J., McGeever, A., The Tabula Muris Consortium, Almanzar, N., Antony, J., Baghel, A. S., Bakerman, I., Bansal, I., Barres, B. A., Beachy, P. A., Berdnik, D., Bilen, B., Brownfield, D., Cain, C., Chan, C. K. F., Chen, M. B., Clarke, M. F., Conley, S. D., Demers, A., Demir, K., de Morree, A., Divita, T., du Bois, H., Ebadi, H., Espinoza, F. H., Fish, M., Gan, Q., George, B. M., Gillich, A., Gòmez-Sjöberg, R., Green, F., Genetiano, G., Gu, X., Gulati, G. S., Hahn, O., Haney, M. S., Hang, Y., Harris, L., He, M., Hosseinzadeh, S., Huang, A., Huang, K. C., Iram, T., Isobe, T., Ives, F., Jones, R. C., Kao, K. S., Karnam, G., Kershner, A. M., Khoury, N., Kim, S. K., Kiss, B. M., Kong, W., Krasnow, M. A., Kumar, M. E., Kuo, C. S., Lam, J., Lee, D. P., Lee, S. E., Lehallier, B., Leventhal, O., Li, G., Li, Q., Liu, L., Lo, A., Lu, W.-J., Lugo-Fagundo, M. F., Manjunath, A., May, A. P., Maynard, A., McKay, M., McNerney, M. W., Merrill, B., Metzger, R. J., Mignardi, M., Min, D., Nabhan, A. N., Ng, K. M., Nguyen, P. K., Noh, J., Nusse, R., Patkar, R., Peng, W. C., Penland, L., Pollard, K., Puccinelli, R., Qi, Z., Rando, T. A., Rulifson, E. J., Segal, J. M., Sikandar, S. S., Sinha, R., Sit, R. V., Sonnenburg, J., Staehli, D., Szade, K., Tan, M., Tato, C., Tellez, K., Torrez Dulgeroff, L. B., Travaglini, K. J., Tropini, C., Tsui, M., Waldburger, L., Wang, B. M., van Weele, L. J., Weinberg, K., Weissman, I. L., Wosczyna, M. N., Wu, S. M., Xiang, J., Xue, S., Yamauchi, K. A., Yang, A. C., Yerra, L. P., Youngyunpipatkul, J., Yu, B., Zanini, F., Zardeneta, M. E., Zee, A., Zhao, C., Zhang, F., Zhang, H., Zhang, M. J., Zhou, L., Zou, J., Luo, J., Pisco, A. O., Karkanias, J., Neff, N. F., Darmanis, S., Quake, S. R., & Wyss-Coray, T.
- Affiliations
- Stanford Medicine (US)
- Chan Zuckerberg Biohub San Francisco (US)
- Saarland University (DE)
- VA Palo Alto Health Care System (US)
- Stanford University (US)
- University of California, San Francisco (US)
- University of Pittsburgh (US)
- Princess Máxima Center (NL)
- Jagiellonian University (PL)
- Canadian Institute for Advanced Research (CA)
- Harvard University (US)
- Corresponding author
- Keller, Andreas
- Darmanis, Spyros
- Quake, Stephen R.
- ORCID
- Pálovics, Róbert
- Keller, Andreas
- Fehlmann, Tobias
- Borja, Michael
- Kern, Fabian
- Webber, James
- McGeever, Aaron
- Almanzar, Nicole
- Antony, Jane
- Baghel, Ankit S.
- Barres, Ben A.
- Beachy, Philip A.
- Bilen, Biter
- Brownfield, Douglas
- Chan, Charles K. F.
- Clarke, Michael F.
- Espinoza, F. Hernán
- Fish, Matt
- Gan, Qiang
- George, Benson M.
- Gillich, Astrid
- Gu, Xueying
- Gulati, Gunsagar S.
- Hahn, Oliver
- Haney, Michael Seamus
- Hang, Yan
- Harris, Lincoln
- He, Mu
- Hosseinzadeh, Shayan
- Huang, Albin
- Huang, Kerwyn Casey
- Iram, Tal
- Isobe, Taichi
- Jones, Robert C.
- Kao, Kevin S.
- Kershner, Aaron M.
- Kim, Seung K.
- Kiss, Bernhard M.
- Krasnow, Mark A.
- Kumar, Maya E.
- Kuo, Christin S.
- Lam, Jonathan
- Lee, Song E.
- Lehallier, Benoit
- Leventhal, Olivia
- Li, Guang
- Li, Qingyun
- Liu, Ling
- Lu, Wan-Jin
- Manjunath, Anoop
- May, Andrew P.
- Maynard, Ashley
- McNerney, M. Windy
- Merrill, Bryan
- Metzger, Ross J.
- Mignardi, Marco
- Nabhan, Ahmad N.
- Ng, Katharine M.
- Nguyen, Patricia K.
- Noh, Joseph
- Patkar, Rasika
- Peng, Weng Chuan
- Penland, Lolita
- Pollard, Katherine
- Puccinelli, Robert
- Qi, Zhen
- Rando, Thomas A.
- Segal, Joe M.
- Sikandar, Shaheen S.
- Sinha, Rahul
- Sonnenburg, Justin
- Szade, Krzysztof
- Tan, Michelle
- Tato, Cristina
- Tellez, Krissie
- Travaglini, Kyle J.
- Tropini, Carolina
- Tsui, Margaret
- Waldburger, Lucas
- Wang, Bruce M.
- Weinberg, Kenneth
- Weissman, Irving L.
- Wosczyna, Michael N.
- Wu, Sean M.
- Yamauchi, Kevin A.
- Yang, Andrew C.
- Youngyunpipatkul, Justin
- Zanini, Fabio
- Zardeneta, Macy E.
- Zee, Alexander
- Zhao, Chunyu
- Zhang, Fan
- Zhang, Hui
- Zhang, Martin Jinye
- Zhou, Lu
- Zou, James
- Luo, Jian
- Pisco, Angela Oliveira
- Karkanias, Jim
- Neff, Norma F.
- Darmanis, Spyros
- Quake, Stephen R.
- Wyss-Coray, Tony
- Venue
- Nature
- Published
- 2022-03-02
- Volume
- 603
- Issue
- 7900
- Pages
- 309-314
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC9387403
- OpenAlex
- W4220972523
- Cited by
- 153
- References
- 52
- Citations by year
- 2026: 32 · 2025: 36 · 2024: 39 · 2023: 29 · 2022: 17
- FWCI
- 10.14
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Jagiellonian University Repository (Jagiellonian University) (submittedVersion, cc-by-nc-nd)
- Infoscience (Ecole Polytechnique Fédérale de Lausanne) (submittedVersion)
- Funders
- U.S. Department of Veterans Affairs (IK6 BX004599)
- Glenn Foundation for Medical Research
- Fondation pour la Recherche Médicale
- NOMIS Stiftung
- National Institutes of Health (AG045034)
- Wu Tsai Neurosciences Institute, Stanford University
- Japan Society for the Promotion of Science (21K07152)
- National Institute on Aging (RF1AG064928, R01AG045034, DP1AG053015, P30AG059307, R01AG072255, P30AG066515)
- National Heart, Lung, and Blood Institute (R00HL127267, R01HL163013)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Single-cell and spatial transcriptomics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Keywords
- heterochronic parabiosis, biological aging, rejuvenation, young blood, cell type-specific gene expression, hematopoietic stem cells, hepatocytes, mitochondrial function, electron transport chain, blood-borne factors
- MeSH terms
- RNA-Seq, Aging, Electron Transport, Hematopoietic Stem Cells, Mitochondria, Organ Specificity, Parabiosis, Rejuvenation, Adipocytes, Hepatocytes, Single-Cell Analysis, Mesenchymal Stem Cells
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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