Human umbilical cord plasma proteins revitalize hippocampal function in aged mice
Open accessAbstract
Ageing drives changes in neuronal and cognitive function, the decline of which is a major feature of many neurological disorders. The hippocampus, a brain region subserving roles of spatial and episodic memory and learning, is sensitive to the detrimental effects of ageing at morphological and molecular levels. With advancing age, synapses in various hippocampal subfields exhibit impaired long-term potentiation, an electrophysiological correlate of learning and memory. At the molecular level, immediate early genes are among the synaptic plasticity genes that are both induced by long-term potentiation and downregulated in the aged brain. In addition to revitalizing other aged tissues, exposure to factors in young blood counteracts age-related changes in these central nervous system parameters, although the identities of specific cognition-promoting factors or whether such activity exists in human plasma remains unknown. We hypothesized that plasma of an early developmental stage, namely umbilical cord plasma, provides a reservoir of such plasticity-promoting proteins. Here we show that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. Tissue inhibitor of metalloproteinases 2 (TIMP2), a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appears in the brain after systemic administration and increases synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. We find that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for previously unknown roles for TIMP2 in normal hippocampal function. Our findings reveal that human cord plasma contains plasticity-enhancing proteins of high translational value for targeting ageing- or disease-associated hippocampal dysfunction.
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In the brain, comparable rejuvenating effects were seen when young human plasma was transferred into old animals.
“In the brain, similar rejuvenating effects were observed by a simpler procedure of young human plasma transferred into old animals268.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [268]
The Abstract reports that young adult human plasma was injected into aged mice and increased expression of a smaller subset of hippocampal plasticity-related genes. But young adult plasma did not significantly improve measured long-term potentiation; the reported improvements in hippocampal function and memory were primarily from umbilical cord plasma. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTIMP2 plays a critical role in mediating human cord plasma-induced beneficial effects on synaptic and cognitive function in aged mice.
“Although how young blood reversed aging-induced cognitive defects is not clear, a recent study suggests that tissue inhibitor of metalloproteinases 2 (TIMP2) plays a critical role in mediating human cord plasma-induced beneficial effects on synaptic and cognitive function in aged mice [522].”
From Molecular and cellular mechanisms underlying the pathogenesis of Alzheimer’s disease (2020) · cites this paper as [522]
The levels of antiageing factors such as GDF11, TIMP2 and CSF2 are reduced; these factors are linked to improved microglial phagocytosis and neurogenesis and reduce the amyloid-β load, thus enhancing cognition.
“In contrast, the levels of antiageing factors, such as GDF11, tissue inhibitor of metalloproteinase 2 (TIMP2) and granulocyte‒macrophage colony stimulating factor (CSF2), are reduced. These factors are linked to improved microglial phagocytosis and neurogenesis and reduce the Aβ load, thus enhancing cognition.72,322–324”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [322]
TIMP2 in umbilical cord plasma enhances synaptic plasticity and improves hippocampus-dependent cognition in aged mice.
“Moreover, TIMP2 in umbilical cord plasma enhances synaptic plasticity and improves hippocampus-dependent cognition in aged mice.322”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [322]
The effect of young blood was also seen after injection of human umbilical cord blood.
“This effect was also seen after injection of human umbilical cord blood (Castellano et al., 2017).”
From Alzheimer Disease: An Update on Pathobiology and Treatment Strategies (2019) · cites this paper as Castellano et al., 2017
Plasma infusions alone are sufficient to exert effects that promote or reverse cell and tissue aging phenotypes.
“including the demonstration that plasma infusions alone are sufficient to exert these effects,65,69”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [69]
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“A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript have recapitulated the effects of plasma, such as the pro-aging B2M and CCL11, and the rejuvenating tissue inhibitor of metalloproteinases 2 (TIMP2) (Castellano et al., 2017; Smith et al., 2015; Villeda et al., 2011).”
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Blood-to-brain communication in aging and rejuvenation
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Asynchronous, contagious and digital aging
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- Authors
- Castellano, J. M., Mosher, K. I., Abbey, R. J., McBride, A. A., James, M. L., Berdnik, D., Shen, J. C., Zou, B., Xie, X. S., Tingle, M., Hinkson, I. V., Angst, M. S., & Wyss-Coray, T.
- Affiliations
- Stanford Medicine (US)
- VA Palo Alto Health Care System (US)
- AfaSci (United States) (US)
- ORCID
- Venue
- Nature
- Published
- 2017-04
- Volume
- 544
- Issue
- 7651
- Pages
- 488-492
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5586222
- OpenAlex
- W2606478035
- Cited by
- 445
- References
- 54
- Citations by year
- 2026: 26 · 2025: 46 · 2024: 49 · 2023: 43 · 2022: 53 · 2021: 46 · 2020: 52 · 2019: 58 · 2018: 44 · 2017: 28
- FWCI
- 21.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (R43AG043203, F31AG040877, AG040877, P50AG047366, AG045034, K99AG051711, R01AG045034, DP1AG053015, R44AG043203)
- National Institute of Neurological Disorders and Stroke (R44NS086343)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- umbilical cord plasma, TIMP-2, hippocampus, aging, cognitive function, synaptic plasticity, long-term potentiation, spatial memory, blood-borne factors, young blood, neurodegeneration, aged mice, brain rejuvenation, immediate early genes, synaptic loss, neuroinflammation, neurogenesis, neurotrophins
- MeSH terms
- Aging, Animals, Blood Proteins, Cognition, Female, Fetal Blood, Hippocampus, Humans, Male, Neuronal Plasticity, Neurons, Long-Term Potentiation, Maze Learning, Tissue Inhibitor of Metalloproteinase-2, Protein Array Analysis, Mice, Spatial Memory
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