β2-microglobulin is a systemic pro-aging factor that impairs cognitive function and neurogenesis
Open accessAbstract
Aging drives cognitive and regenerative impairments in the adult brain, increasing susceptibility to neurodegenerative disorders in healthy individuals. Experiments using heterochronic parabiosis, in which the circulatory systems of young and old animals are joined, indicate that circulating pro-aging factors in old blood drive aging phenotypes in the brain. Here we identify β2-microglobulin (B2M), a component of major histocompatibility complex class 1 (MHC I) molecules, as a circulating factor that negatively regulates cognitive and regenerative function in the adult hippocampus in an age-dependent manner. B2M is elevated in the blood of aging humans and mice, and it is increased within the hippocampus of aged mice and young heterochronic parabionts. Exogenous B2M injected systemically, or locally in the hippocampus, impairs hippocampal-dependent cognitive function and neurogenesis in young mice. The negative effects of B2M and heterochronic parabiosis are, in part, mitigated in the hippocampus of young transporter associated with antigen processing 1 (Tap1)-deficient mice with reduced cell surface expression of MHC I. The absence of endogenous B2M expression abrogates age-related cognitive decline and enhances neurogenesis in aged mice. Our data indicate that systemic B2M accumulation in aging blood promotes age-related cognitive dysfunction and impairs neurogenesis, in part via MHC I, suggesting that B2M may be targeted therapeutically in old age.
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During ageing, the levels of pro-ageing factors such as CCL11 and β2-microglobulin in the blood gradually increase, which damages synapse, neurogenesis and cognition.
“During ageing, the levels of pro-ageing factors such as C-C motif chemokine ligand 11 (CCL11) and β2-microglobulin (B2M) in the blood gradually increase, which damages synapse, neurogenesis and cognition.310,320,321”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [320]
Neutralizing antibody treatment or gene editing to lower circulating levels of CCL11 and β2-microglobulin alleviates neuroinflammation and age-related cognitive decline.
“Neutralizing antibody treatment or gene editing to lower circulating levels of CCL11 and B2M alleviates neuroinflammation and age-related cognitive decline.320,392”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [320]
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- Authors
- Smith, L. K., He, Y., Park, J.-S., Bieri, G., Snethlage, C. E., Lin, K., Gontier, G., Wabl, R., Plambeck, K. E., Udeochu, J., Wheatley, E. G., Bouchard, J., Eggel, A., Narasimha, R., Grant, J. L., Luo, J., Wyss-Coray, T., & Villeda, S. A.
- Affiliations
- University of California, San Francisco (US)
- Stanford Medicine (US)
- University Hospital of Bern (CH)
- QB3 (US)
- Corresponding author
- Villeda, Saul A
- ORCID
- Venue
- Nature Medicine
- Published
- 2015-07-06
- Volume
- 21
- Issue
- 8
- Pages
- 932-937
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC4529371
- OpenAlex
- W1832678746
- Cited by
- 500
- References
- 42
- Citations by year
- 2026: 36 · 2025: 49 · 2024: 51 · 2023: 67 · 2022: 62 · 2021: 38 · 2020: 49 · 2019: 39 · 2018: 34 · 2017: 41 · 2016: 27 · 2015: 7
- FWCI
- 14.73
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Bern Open Repository and Information System (University of Bern) (submittedVersion)
- Funders
- National Institutes of Health (DP5OD012178, UL1TR000004)
- National Institute on Aging (AG027505, 1F31-AG050415, R01AG027505, F31AG050415, R01AG045034)
- National Institute of Mental Health (T32MH020016)
- National Institute of General Medical Sciences (T32GM008568)
- National Center for Advancing Translational Sciences
- Eunice Kennedy Shriver National Institute of Child Health and Human Development (T32HD007470)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- beta2-microglobulin, aging, cognitive decline, neurogenesis, hippocampus, heterochronic parabiosis, MHC class I, TAP1, neurodegeneration
- MeSH terms
- ATP Binding Cassette Transporter, Subfamily B, Member 2, Adult, Aged, Aged, 80 and over, Aging, Animals, beta 2-Microglobulin, Cognition, Humans, Major Histocompatibility Complex, Mice, Inbred C57BL, Middle Aged, ATP-Binding Cassette Transporters, Mice, Neurogenesis
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