Evidence map›Paper›PMID 41713415›Full record

ArticleCell2026

Liver exerkine reverses aging- and Alzheimer's-related memory loss via vasculature.

Gregor Bieri, Karishma J B Pratt, Yasuhiro Fuseya, Turan Aghayev, Juliana Sucharov, Alana M Horowitz, Amber R Philp, Karla Fonseca-Valencia, Rebecca Chu, Mason Phan and 5 more

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Cell, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.

0numbers the graph read from it
0cells of the map it votes in
14citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

14 citing papers in PubMed.

  1. Review
  2. Bioenergetics of the combat sports brain: Between risk and resilience.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2026
    Review
  3. Review
  4. Article
  5. Aged circulating CD8Immunity · 2026
    Article
  6. Review
  7. Review
  8. Observational
  9. Article
  10. Review
  11. Article
  12. Review
  13. Review
  14. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

15 authors.

Gregor BieriDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: gregbieri@gmail.com.
Karishma J B PrattDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Yasuhiro FuseyaDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Turan AghayevDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Juliana SucharovDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Alana M HorowitzDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Amber R PhilpDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Karla Fonseca-ValenciaDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Rebecca ChuDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Biomedical Sciences Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA.
Mason PhanDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Laura RemesalDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA.
Shih-Hsiu J WangDepartment of Pathology, Duke University Medical Center, Durham, NC 27710, USA; Department of Neurology, Duke University Medical Center, Durham, NC 27710, USA.
Andrew C YangGladstone Institute of Neurological Disease, San Francisco, CA 94158, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
Kaitlin B CasalettoDepartment of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA; Memory and Aging Center, Department of Neurology, University of California, San Francisco, San Francisco, CA 94143, USA.
Saul A VilledaDepartment of Anatomy, University of California, San Francisco, San Francisco, CA 94143, USA; Pharmaceutical Sciences and Pharmacogenomics Graduate Program, University of California, San Francisco, San Francisco, CA 94143, USA; Department of Physical Therapy and Rehabilitation Science, University of California, San Francisco, San Francisco, CA 94143, USA; Bakar Aging Research Institute, University of California, San Francisco, San Francisco, CA 94143, USA. Electronic address: saul.villeda@ucsf.edu.

Funding

Restorative practice in repairing harm and promoting safe and inclusive practices in the laboratory.T32GM136547 · NIGMS · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI Adrian Erlebacher, Anita Sil · 2020 to 2026
$4.5M
Pro-youthful role of Gpld1 on regenerative and cognitive function in the aged brainR01AG077770 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI SAUL A VILLEDA · 2022 to 2026
$3.2M
Role of exercise-induced blood factors in rejuvenating the aged brainR01AG067740 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI VILLEDA, SAUL A · 2020 to 2024
$2.0M
Leveraging mouse and human models to investigate neuroprotective effects of blood-derived exerkines in Alzheimer's diseaseR56AG082414 · NIA · UNIVERSITY OF CALIFORNIA, SAN FRANCISCO · PI CASALETTO, KAITLIN B, VILLEDA, SAUL A · 2023 to 2023
$1.2M
NIA NIH HHS R01 AG067740NIA NIH HHS R01 AG077770NIA NIH HHS R56 AG082414NIGMS NIH HHS T32 GM136547
6 · The paper itself

Abstract

Blood factors transfer the benefits of exercise to the aged brain independent of physical activity. Here, we show that the liver-derived exercise factor (exerkine) glycosylphosphatidylinositol (GPI)-specific phospholipase D1 (GPLD1), a GPI-degrading enzyme, reverses aging- and Alzheimer's-related memory loss by targeting the brain vasculature. GPLD1 has the potential to cleave over 100 putative GPI-anchored proteins, necessitating the identification of downstream targets that mediate cognitive rejuvenation for translational application. We identified GPI-anchored tissue-nonspecific alkaline phosphatase (TNAP) on the brain vasculature as a GPLD1 substrate. Mimicking age-related increases in cerebrovascular TNAP impaired blood-brain transport and cognition in young mice and mitigated GPLD1-induced cognitive benefits in aged mice. Inhibiting TNAP recapitulated the benefits of GPLD1 in old age, restoring youthful hippocampal transcriptional signatures and rescuing cognition. In an Alzheimer's disease model, increasing GPLD1 or inhibiting TNAP ameliorated Aβ pathology and improved cognitive deficits. We thus identify brain vasculature as a mediator of the cognitive benefits of a liver-to-brain exercise axis.

Indexed as

AgingAlzheimer DiseaseLiverMemory DisordersPhospholipase DAlkaline PhosphataseAnimalsBrainCognitionDisease Models, AnimalHippocampusHumansMaleMiceMice, Inbred C57BLPhysical Conditioning, AnimalAlkaline PhosphatasePhospholipase Dphospholipase D1agingAlzheimer’s diseaseblood-brain barrierblood factorscognitionexerciseGPLD1liverrejuvenationvasculature

Identifiers

PMID41713415
PMCPMC13070421

What Socratic holds

Textmetadata
LicenceTDM
Read underepoch 390

Registered trials

None linked

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.