The effects of long-term lactate and high-intensity interval training (HIIT) on brain neuroplasticity of aged mice
Open accessAbstract
Extensive research has confirmed numerous advantages of exercise for promoting brain health. More recent studies have proposed the potential benefits of lactate, the by-product of exercise, in various aspects of brain function and disorders. However, there remains a gap in understanding the effects of lactate dosage and its impact on aged rodents. The present study first examined the long-term effects of three different doses of lactate intervention (2000 mg/kg, 1000 mg/kg, and 500 mg/kg) and high-intensity interval training (HIIT) on aging mice (20-22 months) as the 1st experiment. Subsequently, in the 2nd experiment, we investigated the long-term effects of 500 mg/kg lactate intervention and HIIT on brain neuroplasticity in aged mice (25-27 months). The results of the 1st experiment demonstrated that both HIIT and different doses of lactate intervention (500 mg/kg and 2000 mg/kg) positively impacted the neuroplasticity biomarker VEGF in the hippocampus of aging mice. Subsequently, the 2nd experiment revealed that long-term HIIT significantly improved the performance of mice in open-field, novel object recognition, and passive avoidance tests. However, lactate intervention did not significantly affect these behavioral tests. Moreover, compared to the control group, both HIIT and lactate intervention positively influenced the angiogenesis signaling pathway (p/t-AKT/ENOS/VEGF), mitochondrial biomarker (SDHA), and metabolic protein (p/t-CREB, p/t-HSL, and LDH) in the hippocampus of aged mice. Notably, only lactate intervention significantly elevated the BDNF (PGC-1α, SIRT1, and BDNF) signaling pathway and metabolic content (lactate and pyruvate). In the end, long-term HIIT and lactate intervention failed to change the protein expression of p/t-MTOR, iNOS, nNOS, HIF-1α, SYNAPSIN, SIRT3, NAMPT, CS, FNDC5 and Pan Lactic aid-Lysine in the hippocampus of aged mice. In summary, the present study proved that long-term HIIT and lactate treatment have positive effects on the brain functions of aged mice, suggesting the potential usage of lactate as a therapeutic strategy in neurodegenerative diseases in the elderly population.
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Physical activity elevates systemic lactate levels and may influence neuronal gene expression partially through histone lactylation.
“Physical activity, which elevates systemic lactate levels, may therefore influence neuronal gene expression partially through histone lactylation (Lei et al., 2024).”
From Histone modifications and depression: epigenetic mechanisms, therapeutic targets, and translational outlook (2026) · cites this paper as Lei et al., 2024
The Introduction describes lactate as a by-product of exercise, and the Results section on Pan Lactic acid-Lysine protein expression reports a proposed link between histone lactylation and gene transcription (page numbers unavailable). But the paper measures elevated blood lactate after lactate injection, not physical activity, and finds no change in the hippocampal lactylation marker after HIIT or lactate intervention in aged mice. It therefore supports the proposed mechanism, not evidence that exercise influences neuronal gene expression through it. (LLM, conf=0.86)
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- Authors
- Lei, Z., Mozaffaritabar, S., Kawamura, T., Koike, A., Kolonics, A., Kéringer, J., Pinho, R. A., Sun, J., Shangguan, R., & Radák, Z.
- Affiliations
- Hungarian University of Sports Science (HU)
- Waseda University (JP)
- The University of Tokyo (JP)
- Pontifícia Universidade Católica do Paraná (BR)
- Sichuan University (CN)
- Chengdu University (CN)
- ORCID
- Venue
- Heliyon
- Publisher
- Elsevier BV
- Published
- 2024-01
- Volume
- 10
- Issue
- 2
- Pages
- e24421
- ISSN
- 2405-8440 (ISSN-L)
- PMC
- PMC10826720
- OpenAlex
- W4390775410
- Cited by
- 36
- References
- 33
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 4
- FWCI
- 5.81
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Heliyon (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Topics
- Life Sciences › Neuroscience › Developmental Neuroscience › Neurogenesis and neuroplasticity mechanisms
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Neurology › Neurological Disease Mechanisms and Treatments
- Keywords
- lactate, high-intensity interval training, aging, hippocampus, vascular endothelial growth factor, angiogenesis, BDNF signaling, mitochondrial metabolism, physical activity, neurodegenerative diseases, aged mice
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