The Myokine Irisin Represents an Indirect Pathway Linking Exercise to Hippocampal Subfields Relevant to Alzheimer's Disease and Neurogenesis

Thomas Pace; Jacob M. Levenstein; Bonnie L. Quigley; Rhys Houston; Ana P. Bouças; Sophie C. Andrews

doi:10.1111/acel.70497

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The Myokine Irisin Represents an Indirect Pathway Linking Exercise to Hippocampal Subfields Relevant to Alzheimer's Disease and Neurogenesis

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The Myokine Irisin Represents an Indirect Pathway Linking Exercise to Hippocampal Subfields Relevant to Alzheimer's Disease and Neurogenesis

Thomas Pace, Jacob M. Levenstein, Bonnie L. Quigley, Rhys Houston, Ana P. Bouças and Sophie C. Andrews

Aging Cell, Vol.25(5), pp.1-14

2026

DOI: https://doi.org/10.1111/acel.70497

PMID: 42033046

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Abstract

ageing

Alzheimer's disease

exercise

hippocampus

irisin

myokines

neurodegeneration

While exercise is shown to reduce hippocampal atrophy, the underlying molecular mechanisms remain to be fully elucidated. Animal studies suggest the myokine irisin underlies exercise‐related hippocampal benefits, though human evidence is lacking. We cross‐sectionally examined 74 healthy older adults (age 65.47 ± 8.56 years). Participants completed Godin Leisure‐Time exercise questionnaires, provided fasting blood for irisin measurement and underwent structural MRI with hippocampal subfield segmentation. Hierarchical regression and mediation analyses tested irisin‐mediated exercise‐hippocampus relationships, controlling for age, sex and education. Exercise positively associated with circulating irisin (β = 0.365, p = 0.003). Irisin positively associated with bilateral hippocampal volumes (right: β = 0.353, p = 0.001; left: β = 0.275, p = 0.012), strongest in right‐CA3 (β = 0.530), right‐CA4/dentate gyrus (β = 0.471), and bilateral CA1 (β = 0.336–0.373) subfields. Mediation analysis revealed all exercise‐hippocampus relationships operated indirectly through irisin. This study provides first human evidence that irisin is a molecular mechanism linking exercise to hippocampal volume, particularly in subfields critical for memory, neurogenesis and Alzheimer's pathology. Trial Registration: Australian New Zealand Clinical Trials Registry: ACTRN12620000054910 We provide the first human evidence that the exercise‐induced myokine irisin mediates the relationship between physical activity and hippocampal volume in older adults, with strongest effects in CA1, CA3 and CA4 subfields. These regions are critical for memory and particularly vulnerable to Alzheimer's disease.

Details

Title: The Myokine Irisin Represents an Indirect Pathway Linking Exercise to Hippocampal Subfields Relevant to Alzheimer's Disease and Neurogenesis
Authors: Thomas Pace (Corresponding Author) - University of the Sunshine Coast
Jacob M. Levenstein - University of the Sunshine Coast
Bonnie L. Quigley - University of the Sunshine Coast
Rhys Houston - University of the Sunshine Coast
Ana P. Bouças - University of the Sunshine Coast
Sophie C. Andrews - University of the Sunshine Coast
Publication details: Aging Cell, Vol.25(5), pp.1-14
Publisher: Wiley-Blackwell Publishing Ltd.
Date published: 2026
DOI: 10.1111/acel.70497
ISSN: 1474-9726
PMID: 42033046
Copyright note: © 2026 The Author(s). Aging Cell published by Anatomical Society and John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Data Availability: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.
Grant note: This study was funded by the Wilson Foundation.
Organisation Unit: Healthy Ageing Research Cluster; Thompson Institute; Centre for Bioinnovation
Language: English
Record Identifier: 991225829402621
Output Type: Journal article

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