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How the Liver Became Part of the Brain’s Defense Team

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dr Karunia Valeriani Japar

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Keywords: Aerobic Exercise, Alzheimer’s Disease, Blood-Brain Barrier, Brain Health, Brain-Derived Neurotrophic Factor, Cognitive Function, Exerkines, GPLD1, Hepatokines, Irisin, Myokines, Neuroprotection, Physical Activity, Resistance Training, Vascular Health

Over the past several decades, the beneficial effects of physical exercise on brain health have been primarily attributed to enhanced cerebral blood flow and the upregulation of neurotrophic factors such as brain‑derived neurotrophic factor (BDNF). This classical model has framed exercise as a predominantly cardiovascular and neurotrophic intervention, with the brain conceptualized as the main target organ. However, emerging evidence suggests that this view is incomplete. Beyond muscle and brain, a traditionally metabolic organ, the liver appears to play a pivotal and previously underappreciated role in mediating the neuroprotective effects of exercise.

In 2026, experimental work published in Cell demonstrated that endurance exercise induces the secretion of a liver‑derived “exerkine” capable of remodelling the cerebral microvasculature and strengthening the integrity of the blood–brain barrier (BBB). In aged and Alzheimer’s‑model mice, upregulation of this hepatokine improved BBB function and was accompanied by measurable gains in learning and memory performance. These findings extend the concept of exercise‑induced plasticity beyond neuronal circuits to include the vascular and barrier systems that regulate brain exposure to circulating factors, inflammation, and metabolic stress.

Concurrently, a growing body of literature has characterized additional exercise‑responsive mediators, including myokines and hepatokines such as irisin and glycosylphosphatidylinositol‑specific phospholipase D1 (GPLD1). These circulating factors have been shown to increase hippocampal BDNF expression, enhance synaptic plasticity, and improve cognitive outcomes in preclinical models, thereby supporting the existence of a broader muscle–liver–brain communication axis. Rather than acting in isolation, skeletal muscle and liver appear to form an integrated endocrine network that transduces mechanical work into biochemical signals with direct consequences for neural function and resilience.

Taken together, these data support a conceptual shift: under appropriate exercise conditions, the liver functions as a neuroprotective endocrine organ rather than merely a passive metabolic filter. This reframing has important implications for preventive neurology and geroscience. In the sections that follow, we will delineate the mechanisms by which exercise‑induced hepatic signalling influences the BBB and neural circuits, and we will translate these insights into pragmatic, evidence‑informed exercise prescriptions aimed at “brain‑first” prevention across the aging trajectory.

The Blood-Brain Barrier: Your Brain’s “Border Control”

The blood–brain barrier (BBB) is a highly specialized and tightly regulated interface composed of brain microvascular endothelial cells interconnected by complex tight junctions, supported structurally and functionally by pericytes and astrocytic end‑feet. It governs the selective exchange of ions, nutrients, and signaling molecules between the systemic circulation and the brain parenchyma, thereby maintaining cerebral homeostasis and shielding neural tissue from circulating toxins, pathogens, and inflammatory mediators. When this barrier becomes subtly compromised, even in the absence of overt disruption on conventional imaging, peripheral cytokines, immune cells, and xenobiotics can gain increased access to the central nervous system, triggering microglial activation, oxidative stress, and a cascade of neuroinflammatory processes that accelerate neurodegeneration [1,2,3,4].

Longitudinal and mechanistic studies increasingly indicate that BBB breakdown is not merely a downstream consequence of neurodegenerative pathology, but may represent an early and potentially initiating event in the trajectory of cognitive decline. In prodromal and early Alzheimer’s disease, BBB dysfunction has been detected before or in parallel with the appearance of classical hallmarks such as amyloid‑β plaques and tau neurofibrillary tangles, and has been associated with hippocampal atrophy and subtle cognitive impairment. This body of evidence shifts the focus of dementia prevention upstream: preserving BBB integrity in midlife and early late life may be as critical as, or even more critical than, targeting amyloid and tau once substantial pathology is established [5,6,7].

Against this backdrop, the emerging liver‑to‑brain narrative is particularly compelling because it connects peripheral metabolic fitness to BBB resilience, rather than conceptualizing the brain as an isolated target organ. Exercise‑induced hepatic factors, such as the hepatokine GPLD1, have been shown in preclinical models to modulate endothelial function, reduce maladaptive surface protein signaling, and enhance BBB integrity, leading to improved cognitive outcomes in aged and Alzheimer’s‑model animals. This integrative view supports a paradigm in which interventions that improve systemic and hepatic health, most notably structured physical activity are leveraged as indirect yet powerful strategies to maintain BBB function and, by extension, reduce the long‑term risk of neurodegenerative disease [8,9,10].

From “Exercise is Good for the Brain” to Specific Liver Signals

Classically, the cognitive benefits of physical exercise have been attributed to a set of partially overlapping mechanisms that act directly on the central nervous system. Aerobic and resistance training enhance cerebral blood flow, reduce systemic and neuroinflammation, improve insulin sensitivity, and upregulate neurotrophic factors such as brain‑derived neurotrophic factor (BDNF) and insulin‑like growth factor‑1 (IGF‑1), both of which support neuronal survival, synaptic plasticity, and neurogenesis. Over the last decade, however, this brain‑centric model has been expanded by the identification of “exerkines”, exercise‑induced signalling molecules secreted by skeletal muscle (myokines), liver (hepatokines), adipose tissue, and other organs which act in endocrine and paracrine fashions to link peripheral physical activity with central nervous system adaptation [11].

Among these exerkines, irisin, a cleavage product of the transmembrane protein FNDC5, is one of the best‑characterized myokines in the context of brain health. Experimental data demonstrate that irisin can increase BDNF expression in the hippocampus, promote neuronal proliferation, and enhance synaptic plasticity, effects mediated through intracellular cascades including MAPK/ERK, PI3K/Akt, and cAMP/PKA/CREB signalling pathways. Circulating irisin crosses the blood–brain barrier and engages integrin receptors on neurons and glia, thereby activating these pathways and contributing to neurogenesis, dendritogenesis, and improved cognitive performance in models of neurodegeneration and mood disorders. Notably, liver‑directed overexpression of FNDC5 increases circulating irisin and hippocampal BDNF levels in mice, indicating that the liver can participate in the exercise–brain axis even for factors initially described as muscle‑derived [12,13,14,15,16,17].

Building on this myokine‑centered framework, recent work has identified glycosylphosphatidylinositol‑specific phospholipase D1 (GPLD1) as a second major hepatokine mediating exercise‑induced neuroprotection. In preclinical studies, exercise and experimental elevation of liver‑derived GPLD1 increased circulating levels of this enzyme, improved dentate gyrus neurogenesis, enhanced cognitive performance, and strengthened blood–brain barrier integrity by modulating GPI‑anchored proteins on brain endothelial cells, including tissue‑nonspecific alkaline phosphatase (TNAP). These findings position GPLD1 as a key link between hepatic responses to physical activity, vascular and barrier function, and higher‑order cognitive outcomes, extending the exercise–brain paradigm from a primarily neurocentric view to an integrated muscle–liver–vasculature–brain network [11,18,19,20].

The New Data: Liver Exerkine GPLD1 and Memory

In a recent experimental series reported by Villeda and colleagues in Cell, investigators combined voluntary wheel running in aged mice with unbiased plasma proteomics to identify liver‑derived factors that are upregulated by exercise and potentially mediate its neuroprotective effects. Among the candidates, they focused on glycosylphosphatidylinositol‑specific phospholipase D1 (GPLD1), an enzyme produced predominantly in the liver that cleaves glycosylphosphatidylinositol (GPI)‑anchored proteins from cell surfaces. This approach positioned GPLD1 as a plausible “liver exerkine” linking peripheral physical activity to central nervous system outcomes [1,2].

A series of gain‑of‑function experiments provided mechanistic support for this hypothesis. Voluntary exercise increased circulating GPLD1 levels in aged mice, and viral overexpression of GPLD1 specifically in hepatocytes of sedentary aged and Alzheimer’s‑model mice recapitulated many of the cognitive benefits classically attributed to exercise, including improved performance on hippocampal‑dependent memory tasks. At the vascular interface, GPLD1 acted on GPI‑anchored proteins expressed by brain microvascular endothelial cells, notably tissue‑nonspecific alkaline phosphatase (TNAP), a molecule implicated in blood–brain barrier (BBB) dysfunction and cognitive decline. By trimming these GPI‑anchored substrates, GPLD1 reduced maladaptive endothelial signalling, improved BBB integrity, and promoted a more “youthful” cerebrovascular phenotype in aged animals [1].

Intervention studies targeting this axis further strengthened the causal link between hepatic GPLD1, vascular remodelling, and cognition. Experimental elevation of GPLD1 or pharmacologic inhibition of TNAP enhanced BBB tightness, reduced vascular leakage, and rejuvenated brain microvasculature, with parallel improvements in learning and memory outcomes in aged and neurodegenerative models [1–3]. Taken together, these data support a coherent mechanistic pathway in animals: endurance exercise induces hepatic GPLD1—> GPLD1 cleaves detrimental GPI-anchored proteins on rain endothelium (including TNAP) —> BBB integrity is restored —> neurovascular health and memory performance are improved []1,2.

Although human data remain preliminary and largely associative, they point in the same direction. Cross‑sectional analyses suggest that older adults with higher levels of habitual physical activity exhibit increased circulating GPLD1 concentrations and perform better on cognitive testing compared with less active peers. While these observations do not yet establish causality in humans, they provide translational plausibility that an exercise–liver–brain axis involving GPLD1 operates beyond rodent models and may represent a modifiable target for preserving BBB function and cognitive resilience in aging populations [1,2].

Integrating the Exercise-Liver-Brain Axis with Existing Muscle-Brain Science

The discovery of GPLD1 as a liver‑derived exerkine adds an important hepatic branch to, rather than replacing, the established paradigm of muscle–brain crosstalk. Exercise‑responsive myokines such as irisin and cathepsin B have been shown to mediate increases in hippocampal brain‑derived neurotrophic factor (BDNF), enhance adult neurogenesis, and improve performance on hippocampal‑dependent memory tasks in rodents, non‑human primates, and humans. Irisin, derived from FNDC5, and cathepsin B both cross the blood–brain barrier and activate intracellular signalling cascades that support synaptic plasticity, while also interacting with circadian regulatory structures such as the suprachiasmatic nucleus, thereby linking peripheral activity to central plasticity and temporal organization of brain function [21,22,23,24].

In humans, long‑term exercise training has been associated with improved memory performance alongside altered peripheral profiles of BDNF, cathepsin B, and oxidative stress markers, suggesting a durable systemic remodelling rather than a transient “post‑workout” effect. These data support the concept of a multi‑organ “exercise connectome,” in which skeletal muscle communicates with the brain via myokines and trophic factors, while the liver contributes complementary signals such as GPLD1 that act on the cerebral vasculature and blood–brain barrier. Clinically, this integrated view reframes exercise prescriptions for cognitive health: beyond increasing cerebral perfusion or “boosting BDNF,” structured physical activity is understood as conditioning both muscle and liver to secrete factors that stabilize the blood–brain barrier, modulate neuroinflammation, and maintain neurovascular integrity over time [11,18,19,20,24,26,28,29].

Practical: How to “Train” Your Liver to Heal Your Brain

Given the current state of the field, pharmacologic strategies that directly target exerkines such as GPLD1 or irisin remain experimental, and no agonists are yet approved for clinical use in humans. Consequently, structured physical activity continues to represent the safest and most effective way to harness the exercise–liver–brain axis, with international guidelines recommending 150–300 minutes per week of moderate‑intensity aerobic activity or 75–150 minutes per week of vigorous‑intensity exercise, ideally distributed across most days of the week. Aerobic modalities such as brisk walking, jogging, and cycling have been consistently associated with improved cognitive performance, enhanced vascular function, and favourable modulation of circulating neurotrophic and inflammatory markers, supporting their role as a foundational intervention for brain health [11,17,18,26,27].

Within this framework, incorporating brief bouts of higher‑intensity effort appears to confer additional benefit when it is safe and feasible. Short intervals of 30–90 seconds of more strenuous activity interspersed with recovery can amplify cardiovascular adaptations, improve insulin sensitivity, and may augment the release of exerkines and myokines compared with strictly continuous moderate exercise. In older adults or individuals with cardiometabolic comorbidities, such “intensity pulses” can be operationalized as alternating fast–slow walking rather than formal high‑intensity interval training, allowing clinicians to individualize prescriptions while preserving the underlying physiological rationale [11,27].

Complementary resistance training two to three times per week, focusing on large muscle groups with progressive overload using bodyweight or external resistance, is equally important for engaging the muscle–liver–brain network. Skeletal muscle is a major source of myokines, including irisin, that interact with hepatic and central targets to enhance BDNF signalling, improve metabolic flexibility, and support neuroplasticity, providing a mechanistic basis for combining aerobic and strength‑based modalities in cognitive prevention programs. Over time, such multimodal training promotes favourable changes in body composition and glycemic control, which further reduce systemic inflammatory burden [11,17,24,30].

Beyond intensity and modality, the temporal patterning of exercise relative to the circadian cycle is an emerging, clinically relevant dimension. Experimental work indicates that irisin/BDNF signalling interfaces with circadian regulation in the suprachiasmatic nucleus, and that stable circadian rhythms support both metabolic and cognitive health. Encouraging patients to schedule most exercise during the daytime and to maintain consistent timing across the week may therefore reinforce circadian alignment, whereas very late‑night vigorous activity could be counterproductive for sleep and rhythm stability in many individuals [15,24].

Finally, the benefits of exercise‑induced GPLD1 and myokines are likely to be maximized when other major insults to the blood–brain barrier and neurovascular unit are simultaneously minimized. Comprehensive risk‑factor management, including tight control of blood pressure and glycemia, smoking cessation, prioritization of adequate and regular sleep, and active treatment of chronic inflammatory drivers such as visceral adiposity, periodontal disease, and uncontrolled autoimmune activity creates a systemic milieu in which hepatic and muscular exerkines can more effectively stabilize the BBB and dampen neuroinflammation. Framing this integrated approach for patients as “training your liver and blood vessels to become part of your brain’s protection team” can make the concept more tangible than abstract discussions of amyloid or tau, and may improve adherence to long‑term lifestyle prescriptions [17].

Future Therapies: From Exerkines to “Exercise in a Pill”?

The identification of GPLD1 and irisin as mediators of exercise–brain communication naturally raises the possibility of pharmacologically mimicking the neuroprotective effects of physical activity. In murine models, systemic delivery or liver‑targeted overexpression of the liver exerkine GPLD1 reverses aging‑ and Alzheimer’s‑related memory loss, restores youthful hippocampal transcriptional signatures, and ameliorates amyloid pathology, in part by targeting tissue‑nonspecific alkaline phosphatase (TNAP) on the brain vasculature and tightening the blood–brain barrier (BBB). Similarly, experimental delivery or forced expression of irisin increases hippocampal BDNF, activates ERK and related signalling pathways, reduces amyloid‑β–induced oxidative stress, and improves behavioural outcomes in preclinical models of neurodegeneration. These findings have prompted speculation about “exercise mimetics” or “cognitomimetics” that could capture at least part of the brain benefits of exercise in drug form [30,31].

Several important caveats temper this enthusiasm, particularly for a clinician audience. First, the majority of data on GPLD1, irisin, and related exerkines remain preclinical; human intervention trials directly targeting these pathways are limited or absent, and safety, dosing, and long‑term effects are unknown. Second, exerkines operate within a broad, coordinated adaptive network that includes multiple myokines, hepatokines, cytokines, and metabolic changes; isolating a single molecule may not recapitulate the full benefit of exercise and could have unanticipated off‑target effects given their pleiotropic signalling roles and capacity to act on many cell types. Third, physical exercise exerts system‑wide effects on the heart, vasculature, immune system, endocrine axis, and microbiome, many of which feedback on brain health and are unlikely to be duplicated by any single pharmacologic agent [32,33,34,35].

In the near term, the most realistic translational opportunities lie not in “exercise in a pill,” but in refining exercise prescriptions and developing more precise biomarkers of response. This includes using circulating exerkines such as GPLD1, irisin, and related vascular or inflammatory markers as potential indicators of whether a given exercise program is engaging the desired organ–brain axes, as well as stratifying patients by baseline exerkine profiles or BBB‑related markers to individualize interventions. From a clinical standpoint, these advances support a model in which targeted pharmacology, if and when it becomes available, is seen as an adjunct rather than a replacement for structured physical activity, with exercise remaining the primary, pleiotropic “drug” for engaging the liver–brain and muscle–brain networks that underlie cognitive resilience [19,31,33,34,35].

Prescribing Exercise as Liver-Mediated Brain Medicine

The emerging concept of an exercise–liver–brain axis invites a fundamental reappraisal of how physical activity is deployed in the prevention of cognitive decline. Rather than being viewed primarily as a means to increase energy expenditure or maintain cardiorespiratory fitness, structured exercise can be understood as a targeted stimulus that pharmacologically “activates” the liver to secrete neuroprotective factors. Within this framework, hepatokines such as GPLD1, acting on the cerebral microvasculature and blood–brain barrier, and exercise‑responsive mediators like irisin, modulating BDNF signalling and synaptic plasticity, become key components of a multi‑organ communication network that underpins cognitive resilience across the lifespan.

For clinicians operating at the intersection of wellness, aging, and biohacking, this mechanistic perspective provides both a compelling narrative and a strong biological rationale for prioritizing exercise as a first‑line, brain‑directed intervention. Prescribing physical activity is no longer simply “advising patients to move more,” but can be framed as activating a coordinated liver–vascular–brain program designed to preserve barrier integrity, dampen neuroinflammation, and sustain neurotrophic support. In practical terms, this means elevating individualized, structured exercise prescriptions to the same level of importance as pharmacologic and nutraceutical strategies in cognitive prevention protocols. Ultimately, the therapeutic journey begins in the periphery, with the conditioning of the liver and systemic milieu, but its most meaningful endpoint is central: the maintenance of memory, function, and reduced dementia risk in aging individuals.

Reference

  1. Norwitz N. Stress Makes Sugar (Literally!): How to Hack The Brain–Liver Axis [Internet]. Substack.com. StayCurious Metabolism; 2025 [cited 2026 Apr 1]. Available from: https://staycuriousmetabolism.substack.com/p/stress-makes-sugar-literally-this
  2. Norwitz N. Metabolism Highlight Reel: Fan Favorites from StayCurious Metabolism in 2025 [Internet]. LinkedIn. 2026 [cited 2026 Apr 1]. Available from: https://www.linkedin.com/posts/nicknorwitz_staycurious-metabolism-2025-in-review-activity-7412463634922123264-yJ9r
  3. Norwitz N. StayCurious Metabolism [Internet]. Substack.com. StayCurious Metabolism; 2026 [cited 2026 Apr 1]. Available from: https://staycuriousmetabolism.substack.com/
  4. Norwitz N. How to Make Your Liver Heal Your Brain with Exercise [Internet]. Substack.com. StayCurious Metabolism; 2026 [cited 2026 Apr 1]. Available from: https://staycuriousmetabolism.substack.com/p/the-exerciseliverbrain-axis-new-science
  5. Montagne A, Nation DA, Pa J, et al. Brain imaging of neurovascular dysfunction in Alzheimer’s disease. Acta Neuropathol. 2016;131(5):687–70
  6. Montagne A, Barnes SR, Sweeney MD, et al. Blood–brain barrier breakdown in the aging human hippocampus. Neuron. 2015;85(2):296–302
  7. Nation DA, Sweeney MD, Montagne A, et al. Blood–brain barrier breakdown is an early biomarker of human cognitive dysfunction. Nat Med. 2019;25(2):270–6
  8. Sweeney MD, Sagare AP, Zlokovic BV. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14(3):133–50
  9. Villeda SA, et al. Liver‑derived exerkine GPLD1 mediates exercise‑induced improvements in brain vascular integrity and cognition. Cell. 2026
  10. Deak F, et al. Systemic mediators of exercise‑induced neuroprotection: roles of myokines and hepatokines. Front Physiol. 2021;12:
  11. Liu W, Zhang H, Zeng Q, Cai W, Rui Y, Sun J. Break free from cognitive impairment: The magic of exercise-induced molecules. Brain, Behavior, & Immunity – Health [Internet]. 2025 Sep 29;49:101117. Available from: https://www.sciencedirect.com/science/article/pii/S2666354625001759
  12. Inyushkin AN, Poletaev VS, Inyushkina EM, Kalberdin IS, Inyushkin AA. Irisin/BDNF signaling in the muscle-brain axis and circadian system: a review. Journal of Biomedical Research [Internet]. 2024 Jan 1;38(1):1–1. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10818175/
  13. Gupta AK, Gupta S, Mehan S, Khan Z, Das Gupta G, Narula AS. Exploring the Connection Between BDNF/TrkB and AC/cAMP/PKA/CREB Signaling Pathways: Potential for Neuroprotection and Therapeutic Targets for Neurological Disorders. Molecular Neurobiology. 2025 May 9;
  14. Sandoval EYH, Gómez ZJD. Irisin and neuroinflammation: Challenges and opportunities. Experimental and Molecular Pathology. 2024 Dec;140:104941.
  15. Inyushkin AN, Poletaev VS, Inyushkina EM, Kalberdin IS, Inyushkin AA. Irisin/BDNF signaling in the muscle-brain axis and circadian system: a review. Journal of Biomedical Research [Internet]. 2024 Jan 1;38(1):1–1. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10818175/
  16. Liu Y, Fu X, Zhao X, Cui R, Yang W. The role of exercise-related FNDC5/irisin in depression. Frontiers in Pharmacology. 2024 Oct 17;15.
  17. Ma M, Jing G, Tian Y, Yin R, Zhang M. Irisin: Emerging Therapeutic Targets for Cognitive Impairment-Related Diseases. Expert Reviews in Molecular Medicine [Internet]. 2025 [cited 2026 Mar 19];27. Available from: https://www.cambridge.org/core/journals/expert-reviews-in-molecular-medicine/article/irisin-emerging-therapeutic-targets-for-cognitive-impairmentrelated-diseases/A2577ABD13B4D09BE4D9EEFEA9F744E3
  18. Brent L. New research links exercise, the liver, and brain health – Parsemus Foundation [Internet]. Parsemus Foundation. 2026 [cited 2026 Apr 3]. Available from: https://www.parsemus.org/2026/03/new-research-links-exercise-the-liver-and-brain-health/
  19. Dai Y, Dou X, Nie B, Sun Y, Chen P, Fu C, et al. Exercise and the Organ-Brain Axis: Regulation of Neurological Disorders by Emerging Exerkines. PubMed. 2025 Aug 14;107913–3.
  20. Wei C, Li X, Jin Y, Zhang Y, Yuan Q. Does the liver facilitate aging‐related cognitive impairment: Conversation between liver and brain during exercise? Journal of Cellular Physiology. 2024 May 5;239(8).
  21. Moon H, Becke A, Berron D, Becker B, Sah N, Benoni G, et al. Running-Induced Systemic Cathepsin B Secretion Is Associated with Memory Function. Cell Metabolism. 2016 Aug;24(2):332–40.
  22. Gao L, Sun W, Shi H, Zhu W, Wang H, Wang J, et al. Irisin Research Landscape (2012–2024): A Bibliometric and Visual Analysis of Evolving Hotspots and Future Trends. Biologics [Internet]. 2025 Oct 1;Volume 19:595–611. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC12554271/
  23. Welcome To Zscaler Directory Authentication [Internet]. Fightaging.org. 2026 [cited 2026 Apr 3]. Available from: https://www.fightaging.org/archives/2016/06/exercise-promotes-cathepsin-b-expression-neurogenesis-and-memory-function/
  24. Kostka M, Morys J, Andrzej Małecki, Nowacka-Chmielewska M. Muscle–brain crosstalk mediated by exercise-induced myokines – insights from experimental studies. Frontiers in Physiology. 2024 Dec 2;15.
  25. Beneficial Effects From the Liver to the Brain. Scienceorg [Internet]. 2026 [cited 2026 Apr 3]; Available from: https://www.science.org/content/blog-post/beneficial-effects-liver-brain
  26. De la Rosa A, Solana E, Corpas R, Bartrés-Faz D, Pallàs M, Vina J, et al. Long-term exercise training improves memory in middle-aged men and modulates peripheral levels of BDNF and Cathepsin B. Scientific Reports. 2019 Mar 4;9(1).
  27. Dadkhah M, Saadat M, Ghorbanpour AM, Moradikor N. Experimental and clinical evidence of physical exercise on BDNF and cognitive function: A comprehensive review from molecular basis to therapy. Brain Behavior and Immunity Integrative [Internet]. 2023 Jul 1;3:100017. Available from: https://www.sciencedirect.com/science/article/pii/S2949834123000168
  28. Yu Q, Zhang Z, Herold F, Ludyga S, Kuang J, Chen Y, et al. Physical activity, cathepsin B, and cognitive health. Trends in molecular medicine [Internet]. 2025 Summer;S1471-4914(24)003435. Available from: https://pubmed.ncbi.nlm.nih.gov/39848868/
  29. Pena GS, Paez HG, Johnson TK, Halle JL, Carzoli JP, Visavadiya NP, et al. Hippocampal Growth Factor and Myokine Cathepsin B Expression following Aerobic and Resistance Training in 3xTg-AD Mice. International Journal of Chronic Diseases. 2020 Jan 30;2020:1–11.
  30. Inyushkin AN, Poletaev VS, Inyushkina EM, Kalberdin IS, Inyushkin AA. Irisin/BDNF signaling in the muscle-brain axis and circadian system: a review. Journal of Biomedical Research [Internet]. 2024 Jan 1;38(1):1–1. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10818175/
  31. Bieri G, Pratt KJB, Fuseya Y, Aghayev T, Sucharov J, Horowitz AM, et al. Liver exerkine reverses aging- and Alzheimer’s-related memory loss via vasculature. Cell [Internet]. 2026 Feb [cited 2026 Feb 22]; Available from: https://www.cell.com/cell/fulltext/S0092-8674(26)00111-X?_returnURL=https%3A%2F%2Flinkinghub.elsevier.com%2Fretrieve%2Fpii%2FS009286742600111X%3Fshowall%3Dtrue
  32. Chen K, Wang K, Wang T. Protective effect of irisin against Alzheimer’s disease. Frontiers in Psychiatry [Internet]. 2022 Sep 20;13:967683. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9530446/#B38
  33. Walzik D, Wences TY, Zimmer P, Niklas Joisten. Molecular insights of exercise therapy in disease prevention and treatment. Signal transduction and targeted therapy. 2024 May 29;9(1).
  34. Hannan AJ. Enviromimetics: From exercise mimetics to cognitomimetics in the quest for enhanced brain health and cognition. The Journal of Physiology [Internet]. 2025 Sep 29 [cited 2026 Apr 3];604(6):2458–72. Available from: https://pmc.ncbi.nlm.nih.gov/articles/PMC12997027/
  35. Lourenco MV, de Freitas GB, Raony Í, Ferreira ST, De Felice FG. Irisin stimulates protective signaling pathways in rat hippocampal neurons. Frontiers in Cellular Neuroscience. 2022 Sep 9;16.
  36. Role of the Circulating Exerkine GPLD1 in Ameliorating Alzheimer’s Disease Pathology – Cure Alzheimer’s Fund [Internet]. Cure Alzheimer’s Fund. 2024 [cited 2026 Apr 3]. Available from: https://curealz.org/research/translational/studies-of-alternative-neurodegenerative-pathways/role-of-the-circulating-exerkine-gpld1-in-ameliorating-alzheimers-disease-pathology/

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