Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain
Open accessAbstract
Plasma transfers exercise benefit in mice: Exercise has a broad range of beneficial healthful effects. Horowitz et al. tested whether the beneficial effects of exercise on neurogenesis in the brain and improved cognition in aged mice could be transferred in plasma (blood without its cellular components) from one mouse to another (see the Perspective by Ansere and Freeman). Indeed, aged mice that received plasma from young or old mice that had exercised showed beneficial effects in their brains without hitting the treadmill. The authors identified glycosylphosphatidylinositol-specific phospholipase D1 as a factor in plasma that might, in part, mediate this favorable effect. Science , this issue p. 167 ; see also p. 144
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The liver secretes neuroprotective molecules such as fibroblast growth factor 21 (FGF21) and glycosylphosphatidylinositol-specific phospholipase D1 (Gpld1), which are reported to prevent neuronal apoptosis, improve neurogenesis, and even prolong the lifespan of mice.
“In addition, the liver secretes neuroprotective molecules such as fibroblast growth factor 21 (FGF21) and glycosylphosphatidylinositol-specific phospholipase D1 (Gpld1), which are reported to prevent neuronal apoptosis,222 improve neurogenesis223 and even prolong the lifespan of mice.224”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [223]
GPDL1 reverses age-related declines in neurogenesis and cognition in old mice.
“GPDL1 rescues the age-related loss in neurogenesis and cognition in old mice12”
From Exercise plasma boosts memory and dampens brain inflammation via clusterin (2021) · cites this paper as [12]
GPDL1 is an exercise-induced plasma protein reported to improve cognition in old mice and is also produced in the liver.
“Notably, GPDL1–which is an exercise-induced plasma protein that has been reported to improve cognition in old mice12–is also produced in the liver.”
From Exercise plasma boosts memory and dampens brain inflammation via clusterin (2021) · cites this paper as [12]
Sample size was determined from previous literature to estimate an optimal n for studies on runner plasma effects on neuroplasticity and behaviour.
“Sample size was determined using previous literature4,10,12 to estimate an optimal n for our studies on the RP effects on neuroplasticity and behaviour.”
From Exercise plasma boosts memory and dampens brain inflammation via clusterin (2021) · cites this paper as [12]
The benefits of GPLD1 and other exerkines on brain structure and function may relate to peripheral effects such as complement signalling or coagulation.
“Hence, the benefit of GPLD1 (REF.148) and other exerkines on brain structure and function might relate to its peripheral effects, such as the complement signalling cascade149,158, or coagulation159.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [148]
Transferring plasma from exercising aged mice to sedentary aged mice enhances adult hippocampal neurogenesis and memory function.
“Exchanging plasma from exercising aged mice to sedentary aged mice enhances adult hippocampal neurogenesis and memory function148.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [148]
GPLD1 does not cross the blood-brain barrier.
“Investigations into the underlying mechanisms indicate that GPLD1 does not cross the blood-brain barrier148.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [148]
Since 2020, studies transferring plasma from exercised animals to sedentary animals have produced subsequent improvements in cognitive function, supporting a transferable factor for cognitive improvement.
“Since 2020, several studies have transferred plasma from exercised animals into sedentary animals, with subsequent improvements in cognitive function, supporting the presence of a transferable factor in improving cognitive function148,149.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [148]
Evidence is accumulating that factors released from non-neuronal tissue and delivered to the brain via the vasculature may have important roles in synaptic plasticity, memory function and mood regulation.
“Evidence is now accumulating that factors released from non-neuronal tissue148–152 and delivered via the vasculature to the brain might have important roles in synaptic plasticity, memory function and mood regulation150.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [148]
In humans, blood GPLD1 concentrations were higher in active healthy older adults (n=20, >66 years) than in sedentary counterparts.
“These findings are supported in humans, as concentrations of GPLD1 in blood were higher in active, healthy older adults (n = 20, >66 years old) than in their sedentary counterparts148.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [148]
Plasma proteomic analysis identified GPLD1, a novel hepatokine that increases after exercise and correlates with improved cognitive function in aged mice.
“Upon further investigation, plasma proteomic analysis led to the identification of a novel hepatokine, glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1), which increases after exercise and correlates with improved cognitive function in aged mice.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [148]
Transfer of plasma from exercised aged mice to sedentary aged mice can confer benefits on the ageing brain, including improvements in cognitive function.
“This paper demonstrated that transfer of plasma from exercised aged mice to sedentary aged mice can confer benefits on the ageing brain, including improvements in cognitive function.”
From Exerkines in health, resilience and disease (2022) · cites this paper as [148]
Blood factors that can influence NSC ageing and rejuvenation include inflammatory cytokines such as CXCL11, circulating enzymes produced by the liver and complement factors.
“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 [147]
Blood levels of the liver enzyme glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) increase in response to exercise.
“Second, blood levels of the liver enzyme glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) increase in response to exercise, and the administration of GPLD1 to aged mice enhanced performance on cognitive tests147.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [147]
Transfer of plasma from exercised mice to non-exercised aged mice enhances neurogenesis and cognitive function.
“Transfer of plasma from exercised mice to non-exercised aged mice enhanced neurogenesis and cognitive function146,147.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [147]
Administration of GPLD1 to aged mice enhances performance on cognitive tests.
“Second, blood levels of the liver enzyme glycosylphosphatidylinositol-specific phospholipase D1 (GPLD1) increase in response to exercise, and the administration of GPLD1 to aged mice enhanced performance on cognitive tests147.”
From Ageing and rejuvenation of tissue stem cells and their niches (2023) · cites this paper as [147]
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Aged hematopoietic stem cells are refractory to bloodborne systemic rejuvenation interventions
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Self-citationAge-related loss of neural stem cell O-GlcNAc promotes a glial fate switch through STAT3 activation
White, C. W., Fan, X., Maynard, J. C., Wheatley, E. G., Bieri, G., Couthouis, J., Burlingame, A. L., & Villeda, S. A. (2020) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2007439117 · Cited by 98 · see citing works
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Can exercise training teach us how to treat Alzheimer's disease?
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Late‐life physical activity relates to brain tissue synaptic integrity markers in older adults
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Putative neural consequences of captivity for elephants and cetaceans
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Exerkines, Nutrition, and Systemic Metabolism
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- Authors
- Horowitz, A. M., Fan, X., Bieri, G., Smith, L. K., Sanchez-Diaz, C. I., Schroer, A. B., Gontier, G., Casaletto, K. B., Kramer, J. H., Williams, K. E., & Villeda, S. A.
- Affiliations
- University of California, San Francisco (US)
- Department of Anatomy, University of California, San Francisco, CA, USA.
- Corresponding author
- Villeda, Saul A.
- ORCID
- Venue
- Science
- Published
- 2020-07-10
- Volume
- 369
- Issue
- 6500
- Pages
- 167-173
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- PMC
- PMC7879650
- OpenAlex
- W3041860193
- Cited by
- 496
- References
- 58
- Citations by year
- 2026: 68 · 2025: 89 · 2024: 100 · 2023: 94 · 2022: 69 · 2021: 57 · 2020: 19
- FWCI
- 23.61
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- National Institute on Aging (AG053382, AG055797, AG058752, AG023501)
- 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
- physical activity, brain aging, adult neurogenesis, cognitive function, plasma transfer, glycosylphosphatidylinositol, aged mice, age-related cognitive impairment
- MeSH terms
- Aging, Animals, Blood Circulation, Brain, Cognition, Liver, Phospholipase D, Physical Conditioning, Animal, Regeneration, Signal Transduction, Glycosylphosphatidylinositols, Mice, Neurogenesis, Cognitive Dysfunction
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.
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