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The ageing systemic milieu negatively regulates neurogenesis and cognitive function
Open accessAbstract
In the central nervous system, ageing results in a precipitous decline in adult neural stem/progenitor cells and neurogenesis, with concomitant impairments in cognitive functions. Interestingly, such impairments can be ameliorated through systemic perturbations such as exercise. Here, using heterochronic parabiosis we show that blood-borne factors present in the systemic milieu can inhibit or promote adult neurogenesis in an age-dependent fashion in mice. Accordingly, exposing a young mouse to an old systemic environment or to plasma from old mice decreased synaptic plasticity, and impaired contextual fear conditioning and spatial learning and memory. We identify chemokines--including CCL11 (also known as eotaxin)--the plasma levels of which correlate with reduced neurogenesis in heterochronic parabionts and aged mice, and the levels of which are increased in the plasma and cerebrospinal fluid of healthy ageing humans. Lastly, increasing peripheral CCL11 chemokine levels in vivo in young mice decreased adult neurogenesis and impaired learning and memory. Together our data indicate that the decline in neurogenesis and cognitive impairments observed during ageing can be in part attributed to changes in blood-borne factors.
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“Recent findings from parabiosis models (left) have shown that exposure to young blood restores neurogenesis, learning and memory and neuronal functions in older mice via increase in growth factors and endothelial remodeling in older mice(Baruch et al, 2014;Katsimpardi et al, 2014;Villeda et al, 2011).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Villeda et al, 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“parabiosis experiments have demonstrated that the decline in neural and muscle stem cell function in old mice can be reversed by systemic factors from young mice”
From The Hallmarks of Aging (2013) · cites this paper as Villeda et al., 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“the rejuvenation strategies based on the use of blood-borne systemic factors identified in parabiosis experiments (Conboy et al., 2005; Loffredo et al., 2013; Villeda et al., 2011).”
From The Hallmarks of Aging (2013) · cites this paper as Villeda et al., 2011
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“Exposure to pro-aging circulating factors present in the blood of aged mice induces neuroinflammation and triggers age-related cognitive decline in young rodents27,28.”
From MT1-MMP inhibition rejuvenates ageing brain and rescues cognitive deficits in obesity (2025) · cites this paper as [27]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“Elevated circulating cytokine/chemokine levels, particularly CCL11, can also limit neurogenesis and contribute to cognitive impairment (Villeda et al., 2011).”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Villeda et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“CCL11 efficiently crosses the blood brain barrier56, has been implicated in neuroinflammatory disorders and SARS-CoV-2 (COVID-19) cognitive impairment57,58, and impairs neurogenesis54,58,59.”
From Senescent-like microglia limit remyelination through the senescence associated secretory phenotype (2025) · cites this paper as [54]
The cited source says what the claim attributes to it.
In the citing paper
“CCL11/Eotaxin1 is a chemokine that selectively recruits eosinophils, is elevated with age in humans and mice52–54, and has been shown to promote senescence55.”
From Senescent-like microglia limit remyelination through the senescence associated secretory phenotype (2025) · cites this paper as [54]
The cited source says what the claim attributes to it.
In the citing paper
“Excitingly, proof of principle exists for rejuvenation through blood-borne systemic factors (Conboy et al., 2005; Loffredo et al., 2013; Villeda et al., 2011).”
From The Hallmarks of Aging (2013) · cites this paper as Villeda et al., 2011
The cited source says what the claim attributes to it.
In the citing paper
“CCL11 (eotaxin) has been associated with lower neurogenesis and improper learning and memory in mice. 66”
From Three Tiers to biological escape velocity: The quest to outwit aging (2022) · cites this paper as [66]
The check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“and similarly, we did not see a difference in CCL11 [25].”
From Rejuvenation of three germ layers tissues by exchanging old blood plasma with saline-albumin (2020) · cites this paper as [25]
Experimental — accuracy not yet measuredIn the citing paper
“a chemokine whose serum and cerebrospinal fluid levels increase with age and correlate with reduced neurogenesis,40”
From Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease (2015) · cites this paper as [40]
In the citing paper
“In agreement with previous studies,40 eotaxin-1 levels increased with age in the total cohort.”
From Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease (2015) · cites this paper as [40]
In the citing paper
“Eotaxin-1 levels increase throughout life and this increase is correlated with reduced neurogenesis.40”
From Whole-genome sequencing suggests a chemokine gene cluster that modifies age at onset in familial Alzheimer's disease (2015) · cites this paper as [40]
In the citing paper
“Exposing a young mouse to plasma from old mice impairs synaptic plasticity, neurogenesis and cognition,310,311 suggesting that aged blood contributes to brain ageing.”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [310]
In the citing paper
“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 [310]
In the citing paper
“These observations suggest that the SASP from peripheral blood negatively impacts neurogenesis and cognitive functions. 63”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [63]
In the citing paper
“This elevation of SASP components in AD patients correlates with CSF tau levels, inflammation, and cognitive impairment.”
From Senescence, brain inflammation, and oligomeric tau drive cognitive decline in Alzheimer's disease: Evidence from clinical and preclinical studies (2024) · cites this paper as [63]
In the citing paper
“Elevated CCL11 in the plasma and cerebrospinal fluid seen in aging mice and humans are associated with declining neurogenesis, neurodegenerative disease, and cognitive decline and may contribute to driving neovascularisation in AMD via interaction with CCR3 [1, 93, 123].”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [123]
In the citing paper
“Elevated CCL11 in the plasma and cerebrospinal fluid seen in aging mice and humans are associated with declining neurogenesis, neurodegenerative disease, and cognitive decline and may contribute to driving neovascularisation in AMD via interaction with CCR3 [1, 93, 123].”
From Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain (2022) · cites this paper as [123]
In the citing paper
“This surgical intervention also enhances rates of neurogenesis, remyelination and other measures of neural function in the old parabiont, suggesting that changes in stem cell function in the aging central nervous system are also affected by blood-borne factors165–167.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [165]
In the citing paper
“This surgical intervention also enhances rates of neurogenesis, remyelination and other measures of neural function in the old parabiont, suggesting that changes in stem cell function in the aging central nervous system are also affected by blood-borne factors165–167.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [165]
In the citing paper
“Elevated levels of CCL11 found in mice after respiratory infection with either SARS-CoV-2 or H1N1 influenza, and in humans with cognitive symptoms after COVID, can cause deficient hippocampal neurogenesis as shown here and previously (Villeda et al., 2011), and induces microglial reactivity specifically in the hippocampus.”
From Mild respiratory COVID can cause multi-lineage neural cell and myelin dysregulation (2022) · cites this paper as Villeda et al., 2011
In the citing paper
“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 [65]
In the citing paper
“Based on early work from our laboratories that ushered in a new era of the use of the technique of parabiosis in aging research, it is clear that systemic factors originating from distant tissues in the body are able to either promote or reverse cell and tissue aging phenotypes.63,64,65”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [65]
In the citing paper
“blood factors that can influence NSC ageing and rejuvenation include inflammatory cytokines (for example, CXCL11) (likely circulating in the blood), circulating enzymes produced by the liver and complement factors (likely circulating in the blood146–148)”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [148]
In the citing paper
“Conversely, younger mice heterochronically paired with older mice showed reduced cell proliferation in the dentate gyrus and impaired neurogenesis.”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Villeda et al, 2011
In the citing paper
“Additional evidence for the role of blood-borne systemic factors in aging-induced impairments was provided by Villeda et al (2011) who showed that older mice that share a blood supply with younger mice show increased neurogenesis, enhanced LTP and improved cognitive functioning.”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Villeda et al, 2011
In the citing paper
“In particular, aging-associated increase in systemic levels of CCL11 was associated with impaired neurogenesis and learning deficits, which were reversed by systemic and intrahippocampal administration of neutralizing anti-CCL11 antibody in the aged mice (Villeda et al, 2011).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Villeda et al, 2011
In the citing paper
“Furthermore, plasma transfer from younger mice into the aged was sufficient to replicate the findings from the parabiosis experiments, elucidating the role of blood-borne soluble factors, and not blood cells, in reversing aging-associated impairments in the brain (Villeda et al, 2011).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Villeda et al, 2011
In the citing paper
“Recent findings from parabiosis models (left) have shown that exposure to young blood restores neurogenesis, learning and memory and neuronal functions in older mice via increase in growth factors and endothelial remodeling in older mice(Baruch et al, 2014;Katsimpardi et al, 2014;Villeda et al, 2011).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Villeda et al, 2011
In the citing paper
“Recent findings from parabiosis models (left) have shown that exposure to young blood restores neurogenesis, learning and memory and neuronal functions in older mice via increase in growth factors and endothelial remodeling in older mice(Baruch et al, 2014;Katsimpardi et al, 2014;Villeda et al, 2011).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Villeda et al, 2011
In the citing paper
“Recent findings from parabiosis models (left) have shown that exposure to young blood restores neurogenesis, learning and memory and neuronal functions in older mice via increase in growth factors and endothelial remodeling in older mice(Baruch et al, 2014;Katsimpardi et al, 2014;Villeda et al, 2011).”
From Microglia Priming with Aging and Stress (2017) · cites this paper as Villeda et al, 2011
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Metadata
- Authors
- Villeda, S. A., Luo, J., Mosher, K. I., Zou, B., Britschgi, M., Bieri, G., Stan, T. M., Fainberg, N., Ding, Z., Eggel, A., Lucin, K. M., Czirr, E., Park, J.-S., Couillard-Després, S., Aigner, L., Li, G., Peskind, E. R., Kaye, J. A., Quinn, J. F., Galasko, D. R., Xie, X. S., Rando, T. A., & Wyss-Coray, T.
- Affiliations
- Stanford Medicine (US)
- AfaSci (United States) (US)
- Paracelsus Medical University (AT)
- University of Washington (US)
- Oregon Health & Science University (US)
- University of California San Diego (US)
- VA Palo Alto Health Care System (US)
- ORCID
- Venue
- Nature
- Published
- 2011-08-31
- Volume
- 477
- Issue
- 7362
- Pages
- 90-94
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3170097
- OpenAlex
- W1969905245
- Cited by
- 1,763
- References
- 33
- Citations by year
- 2026: 74 · 2025: 110 · 2024: 118 · 2023: 142 · 2022: 159 · 2021: 135 · 2020: 146 · 2019: 109 · 2018: 117 · 2017: 117 · 2016: 127 · 2015: 116 · 2014: 100 · 2013: 100 · 2012: 81
- FWCI
- 30.59
- 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 Institutes of Health (DP1OD000392)
- National Institute on Aging (P30 AG 08017, R01AG027505, P30AG008017, P50AG005136, F31AG034045)
- National Institute of Mental Health (R01MH078194)
- National Institute of Allergy and Infectious Diseases (T32AI007290)
- National Institute of Neurological Disorders and Stroke (F31NS066676)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR056849)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- aging, adult neurogenesis, cognitive decline, heterochronic parabiosis, blood-borne factors, eotaxin, chemokines, beta2-microglobulin, neural stem/progenitor cells, synaptic plasticity, learning and memory, plasma proteomics, cerebrospinal fluid
- MeSH terms
- Aging, Animals, Female, Learning, Learning Disabilities, Male, Memory Disorders, Mice, Inbred C57BL, Parabiosis, Plasma, Time Factors, Chemokines, Mice, Chemokine CCL11, Neurogenesis
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