Gpld1
Gpld1 (glycosylphosphatidylinositol-specific phospholipase D1)
Written by Aaron CuhaReviewed Sep 2026
Also known as: GPLD1, GPI-specific phospholipase D1, Liver exerkine
A liver enzyme released into blood during exercise that transferred the cognitive benefits of running to sedentary aged mice. Higher in active older people; never administered to anyone.
Overview
In 2020 a Science paper reported that plasma from exercised aged mice, transfused into sedentary aged mice, transferred the effects of exercise on adult neurogenesis and cognition. Screening the plasma identified Gpld1, a liver-derived enzyme that cleaves glycosylphosphatidylinositol anchors, as rising after exercise and correlating with improved cognitive function in aged mice. Raising systemic Gpld1 in aged mice, without any exercise, improved age-related regenerative and cognitive impairments. The authors describe a liver-to-brain axis.
A 2026 Cell paper from the same line of work went further mechanistically: it identified GPI-anchored tissue-nonspecific alkaline phosphatase on the brain vasculature as the Gpld1 substrate that matters, showed that mimicking age-related increases in that enzyme impaired blood-brain transport and cognition in young mice, and showed that inhibiting it reproduced the benefits of Gpld1 in old mice and improved outcomes in an Alzheimer disease model.
The human evidence is measurement in small cohorts. The original Science paper reported that Gpld1 concentrations in blood were higher in active, healthy older humans. A 2025 GeroScience study recruited healthy men and women aged 65 to 85 classified as inactive or highly active, verified activity with accelerometry, and measured circulating GPLD1 alongside cognitive testing and brain MRI at a single visit; the registered study, NCT04645134, enrolled 25 people and is an observational cross-sectional cohort.
No human has received Gpld1. There is no registered interventional trial.
Mechanism of action
In mice, Gpld1 is a liver-derived enzyme released into plasma after exercise that cleaves glycosylphosphatidylinositol anchors, releasing GPI-anchored proteins from cell surfaces. The 2026 Cell work identifies GPI-anchored tissue-nonspecific alkaline phosphatase on brain endothelium as the substrate that carries the cognitive effect: cerebrovascular levels of that enzyme rise with age, mimicking that rise impaired blood-brain transport and cognition in young mice, and inhibiting it restored youthful hippocampal transcriptional signatures and rescued cognition in old mice. Gpld1 has over a hundred putative GPI-anchored substrates, which is the reason identifying the relevant one mattered. None of this has been demonstrated in a human.
Human evidence
Observational only, and small. Circulating GPLD1 has been measured and found higher in physically active older adults, in a 25-person cross-sectional study and in the original 2020 report. No human has been given Gpld1.
- Science 2020: blood Gpld1 concentrations were increased in active, healthy elderly humans. A measurement inside a mouse paper, with no trial design behind it.
- GeroScience 2025 (NCT04645134): 25 healthy adults aged 65 to 85, recruited as either inactive or highly active, activity confirmed by accelerometry, with circulating GPLD1, Mini-Mental State Examination, NIH Toolbox cognition testing and brain MRI at a single visit. Observational and cross-sectional.
- No interventional trial of Gpld1 administration is registered for any indication.
What this does not tell you: Twenty-five people measured at a single visit cannot establish direction, let alone effect. Active older adults differ from inactive ones in many ways, and a higher level of an exercise-released enzyme in people who exercise is close to a tautology. Nothing in the human record shows that raising Gpld1 would improve anything, and nobody has tried. A systemically administered enzyme with over a hundred potential substrates raises obvious specificity questions that the mouse work is only now beginning to resolve.
Reading the research record
Gpld1 is one of the better-characterised exercise factors because the mouse work did the full chain: plasma transfer reproduced the effect, the factor was identified, administering it alone reproduced the effect without exercise, and in 2026 the downstream substrate was named. That is more than most exerkines have.
The translation problem is specific and worth stating rather than glossing. Gpld1 is an enzyme with more than a hundred putative GPI-anchored substrates, so giving it systemically to a person would cleave a great deal besides the one target that carries the cognitive effect. The 2026 Cell paper's identification of tissue-nonspecific alkaline phosphatase on brain endothelium points at a different and more tractable strategy: inhibit the substrate rather than administer the enzyme. That reframing is more likely to produce a drug than Gpld1 itself, and it is also further from anything a person can access today.
The human record here is 25 people measured once. That is worth reporting accurately because the Science paper's human sentence, that Gpld1 is higher in active elderly humans, is frequently repeated as though it were a trial result. It is a cross-sectional association.
The evidence, charted
Fig. 1 · evidence composition
2of 4 citations (50%) are in people
Counted from the citation list on this page. The Human count is the same number shown in the badge at the top. Both understate any literature larger than the sources we cite.
Fig. 2 · evidence over time
Evidence spans 4 distinct years, 2020 to 2026, counted from the citation list on this page.
Fig. 3 · legal status at a glance
US
Not approved
UK
Approved
AU
Approved
CA
Not approved
Approved in 2 of 4, prescription route in 0, not approved in 2. A jurisdiction's classification is a regulatory fact, not a verdict on the science; see Legal status below for the full text and any notes.
Fig. 4 · dose response
No human dose response curve exists
We draw this figure where the data supports it. For this compound in humans it does not, so the panel stays empty rather than borrowing an animal curve and implying it transfers.
Key studies & citations
- Animal2020
Blood factors transfer beneficial effects of exercise on neurogenesis and cognition to the aged brain
Mouse, with a human measurement component. Plasma from exercised aged mice transferred the effects of exercise on adult neurogenesis and cognition to sedentary aged mice. Plasma Gpld1, a liver-derived GPI-degrading enzyme, rose after exercise and correlated with improved cognition; increasing systemic Gpld1 in aged mice improved age-related regenerative and cognitive impairments without exercise. Gpld1 concentrations in blood were also increased in active, healthy elderly humans. NIH funded.
Science - Animal2026
Liver exerkine reverses aging- and Alzheimer's-related memory loss via vasculature
Mouse. GPI-anchored tissue-nonspecific alkaline phosphatase on the brain vasculature was identified as the Gpld1 substrate mediating cognitive rejuvenation. Mimicking age-related increases in cerebrovascular levels of that enzyme impaired blood-brain transport and cognition in young mice and blunted Gpld1's benefit in aged mice, while inhibiting it restored youthful hippocampal transcriptional signatures and rescued cognition. In an Alzheimer disease model, raising Gpld1 or inhibiting the enzyme reduced amyloid beta pathology and improved cognition.
Cell - Human2025
Associations between physical activity, brain health, cognitive function, and circulating GPLD1 in healthy older (65-85 years) individuals
Healthy men and women aged 65 to 85 with body mass index 20 to 35, recruited as either inactive or highly active by a rapid activity assessment score and verified by accelerometry. Circulating GPLD1 was measured from fasting blood at a single clinical visit alongside Mini-Mental State Examination, the NIH Toolbox Cognition Battery, and brain MRI and functional MRI. Cross-sectional and observational: it measures association, not effect.
GeroScience - Human2021
Physical Activity and Cognitive Function in Older Adults: A Novel Role for GPLD1
Registry record for the human GPLD1 work. Sponsor Pennington Biomedical Research Center, observational cohort with a cross-sectional time perspective, 25 participants enrolled, start 1 April 2021, listed as completed. An observational study of 25 people, not an intervention.
ClinicalTrials.gov
Frequently asked questions
Can Gpld1 give you the benefits of exercise?
In aged mice, raising systemic Gpld1 without any exercise improved age-related regenerative and cognitive impairments, which is the finding that generated the interest. No human has received it, so the question is open in people, and higher Gpld1 in active older adults is a cross-sectional association measured in 25 people.
Is there a human trial?
Only an observational one. NCT04645134 at Pennington Biomedical Research Center enrolled 25 healthy adults aged 65 to 85 and measured circulating GPLD1 alongside cognition and brain imaging at a single visit. No interventional trial of Gpld1 is registered anywhere.
What does Gpld1 actually do?
It is a liver enzyme that cleaves glycosylphosphatidylinositol anchors, releasing anchored proteins from cell surfaces. A 2026 Cell paper identified the relevant target as GPI-anchored tissue-nonspecific alkaline phosphatase on brain blood vessels, and found that inhibiting that enzyme reproduced Gpld1's benefits in old mice. That mechanism is established in mice only.