Exercise-induced irisin–BDNF signaling in aging: implications for cognitive decline, sarcopenia, and neurodegeneration. A narrative review

Age-related cognitive decline is closely associated with diminished neuroplasticity and disrupted neurotrophic signaling. Exercise is a potent modulator of the irisin–BDNF axis, a molecular pathway with emerging relevance to healthy aging, neuroprotection, and the prevention of neurodegenerative diseases in older adults. Through this analysys the author aimed to review evidence on the effects of different exercise modalities — with emphasis on aging populations — on the PGC-1α–FNDC5–irisin–BDNF signaling pathway, and to examine implications for cognitive health and neuroplastic adaptations across the lifespan. A structured, reproducible search of PubMed, Scopus, Web of Science, and Google Scholar was conducted for studies published between January 1995 and September 2025, using Boolean combinations of 'irisin', 'BDNF', 'exercise', 'aging', 'neuroplasticity', and 'cognitive function'. Human and animal studies exploring the irisin–BDNF axis in the context of aging, physical activity, or immobilization were eligible. Data were extracted and synthesized qualitatively. Consistent with the narrative design, no formal risk-of-bias instrument or PRISMA systematic-review reporting framework was applied, and the review was not prospectively registered. Twenty-four studies met inclusion criteria. Resistance and High-Intensity Interval Training (HIIT) consistently increased circulating irisin and hippocampal BDNF levels. Aging-related declines in both biomarkers were attenuated by chronic resistance training, particularly in older adults. Immobilization suppressed the irisin–BDNF pathway. Epigenetic modifications at BDNF promoters represent a plausible mechanism for sustained neuroplastic adaptations. The PGC-1α–FNDC5–irisin–BDNF axis may constitute a key molecular link between skeletal muscle activity and brain health in aging populations. Resistance training and HIIT offer the most consistent evidence for attenuating age-related neurotrophic decline, although HIIT-specific data in older adults remain limited and warrant cautious interpretation. Causal conclusions remain premature given the predominantly associative and preclinical evidence base. Well-powered, longitudinal prospective trials in older adults with standardized biomarker protocols are needed.

1. Xu H, Tian X, Wang Y, et al. Exercise promotes hippocampal neurogenesis in T2DM mice via the irisin/TLR4/MyD88/NF-κB-mediated neuroinflammation pathway. Biol (Basel) 2024;13:100809. DOI: https://doi.org/10.3390/biology13100809

2. Halbach OV. BDNF effects on dendritic spine morphology and hippocampal function. Cell Tissue Res 2018;373:729–41. DOI: https://doi.org/10.1007/s00441-017-2782-x

3. Calabrese F, Molteni R, Racagni G, Riva MA. Neuronal plasticity: a link between stress and mood disorders. Psychoneuroendocrinology. 2009;34:S208–16. DOI: https://doi.org/10.1016/j.psyneuen.2009.05.014

4. Chen KW, Chen L. Epigenetic regulation of BDNF gene during development and diseases. Int J Mol Sci 2017;18:30571. DOI: https://doi.org/10.3390/ijms18030571

5. Leger C, Quirie A, Meloux A, et al. Impact of exercise intensity on cerebral BDNF levels: role of FNDC5/irisin. Int J Mol Sci 2024;25:2121. DOI: https://doi.org/10.3390/ijms25021213

6. Lindsay RM. Nerve growth factors (NGF, BDNF) enhance axonal regeneration but are not required for survival of adult sensory neurons. J Neurosci 1988;8:2394–405. DOI: https://doi.org/10.1523/JNEUROSCI.08-07-02394.1988

7. Jones KR, Farinas I, Backus C, Reichardt LF. Targeted disruption of the BDNF gene perturbs brain and sensory neuron development but not motor neuron development. Cell 1994;76:989–99. DOI: https://doi.org/10.1016/0092-8674(94)90377-8

8. Aid T, Kazantseva A, Piirsoo M, et al. Mouse and rat BDNF gene structure and expression revisited. J Neurosci Res 2007;85:525–35. DOI: https://doi.org/10.1002/jnr.21139

9. Pruunsild P, Kazantseva A, Aid T, et al. Dissecting the human BDNF locus: bidirectional transcription, complex splicing, and multiple promoters. Genomics 2007;90:397–406. DOI: https://doi.org/10.1016/j.ygeno.2007.05.004

10. Panja D, Bramham CR. BDNF mechanisms in late LTP formation: a synthesis and breakdown. Neuropharmacology 2014;76:664–76. DOI: https://doi.org/10.1016/j.neuropharm.2013.06.024

11. Poduslo JF, Curran GL. Permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: NGF, CNTF, NT-3, BDNF. Brain Res Mol Brain Res 1996;36:280–6. DOI: https://doi.org/10.1016/0169-328X(95)00250-V

12. Okamoto M, Mizuuchi D, Omura K, et al. High-intensity intermittent training enhances spatial memory and hippocampal neurogenesis associated with BDNF signaling in rats. Cereb Cortex 2021;31:4386–97. DOI: https://doi.org/10.1093/cercor/bhab093

13. Tsai CL, Pan CY, Tseng YT, et al. Acute effects of high-intensity interval training and moderate-intensity continuous exercise on BDNF and irisin levels and neurocognitive performance in late middle-aged and older adults. Behav Brain Res 2021;413:113472. DOI: https://doi.org/10.1016/j.bbr.2021.113472

14. Martinowich K, Hattori D, Wu H, et al. DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 2003;302:890–3. DOI: https://doi.org/10.1126/science.1090842

15. Vaynman S, Ying Z, Gomez-Pinilla F. Hippocampal BDNF mediates the efficacy of exercise on synaptic plasticity and cognition. Eur J Neurosci 2004;20:2580–90. DOI: https://doi.org/10.1111/j.1460-9568.2004.03720.x

16. Patterson SL, Abel T, Deuel TA, et al. Recombinant BDNF rescues deficits in basal synaptic transmission and hippocampal LTP in BDNF knockout mice. Neuron 1996;16:1137–45. DOI: https://doi.org/10.1016/S0896-6273(00)80140-3

17. Moreno-Navarrete JM, Ortega F, Serrano M, et al. Irisin is expressed and produced by human muscle and adipose tissue in association with obesity and insulin resistance. J Clin Endocrinol Metab 2013;98:E769–75. DOI: https://doi.org/10.1210/jc.2012-2749

18. Cosio PL, Crespo-Posadas M. Effect of chronic resistance training on circulating irisin: systematic review and meta-analysis of randomized controlled trials. Int J Environ Res Public Health 2021;18:2476. DOI: https://doi.org/10.3390/ijerph18052476

19. Belviranli M, Okudan N. Exercise training protects against aging-induced cognitive dysfunction via activation of the hippocampal PGC-1alpha/FNDC5/BDNF pathway. Neuromolecular Med 2018;20:386–400. DOI: https://doi.org/10.1007/s12017-018-8500-3

20. Kim HJ, So B, Choi M, et al. Resistance exercise training increases the expression of irisin concomitant with improvement of muscle function in aging mice and humans. Exp Gerontol 2015;70:11–17. DOI: https://doi.org/10.1016/j.exger.2015.07.006

21. Farshbaf MJ. Multiple roles in neuroprotection for the exercise-derived myokine irisin. Front Aging Neurosci 2021;13:649929. DOI: https://doi.org/10.3389/fnagi.2021.649929

22. Pignataro M, Dicarlo M, Zerlotin R, et al. FNDC5/Irisin system in neuroinflammation and neurodegenerative diseases: update and novel perspective. Int J Mol Sci 2021;22:1605. DOI: https://doi.org/10.3390/ijms22041605

23. Lourenco MV, Frozza RL, de Freitas GB, et al. Exercise-linked FNDC5/irisin rescues synaptic plasticity and memory defects in Alzheimer's models. Nat Med 2019;25:165–75. DOI: https://doi.org/10.1038/s41591-018-0275-4

24. Eidukaite S, Masiulis N, Kvedaras M. Exploring the preliminary effects of resistance training on total BDNF levels in elderly individuals: a pilot study. Balt J Sport Health Sci 2023;2:4–10. DOI: https://doi.org/10.33607/bjshs.v2i129.1377

25. Afshar R, Rahmati M, Mirnasouri R. The effect of 12 weeks of strength training on muscular strength, body fat percentage, irisin and BDNF in active middle-aged women. J Arak Univ Med Sci 2025;28:1–8. DOI: https://doi.org/10.61186/jams.28.1.1

26. Wrann CD. FNDC5/irisin – their role in the nervous system and as a mediator for beneficial effects of exercise on the brain. Brain Plast 2015;1:55–61. DOI: https://doi.org/10.3233/BPL-150019

27. Schmolesky MT, Webb DL, Hansen RA. The effects of aerobic exercise intensity and duration on levels of brain-derived neurotrophic factor in healthy men. J Sports Sci Med 2013;12:502–11.

28. Jaberi S, Fahnestock M. Mechanisms of the beneficial effects of exercise on brain-derived neurotrophic factor expression in Alzheimer's disease. Biomolecules 2023;13:11577. DOI: https://doi.org/10.20944/preprints202309.0210.v1

29. El Hayek L, Khalifeh M, Zibara V, et al. Lactate mediates the effects of exercise on learning and memory through SIRT1-dependent activation of hippocampal BDNF. J Neurosci 2019;39:2369–82. DOI: https://doi.org/10.1523/JNEUROSCI.1661-18.2019

30. Dicarlo M, Zerlotin R, Zecca C, et al. Short-term irisin treatment enhanced neurotrophin expression differently in the hippocampus and the prefrontal cortex of young mice. Int J Mol Sci 2023;24:6715. DOI: https://doi.org/10.3390/ijms24119111

31. Kazeminasab F, Sadeghi E, Afshari-Safavi A. Comparative impact of various exercises on circulating irisin in healthy subjects: a systematic review and network meta-analysis. Oxid Med Cell Longev 2022;2022:8235809. DOI: https://doi.org/10.1155/2022/8235809

32. Liu Y. The neuroprotective effect of irisin in ischemic stroke. Front Aging Neurosci 2020;12:588958. DOI: https://doi.org/10.3389/fnagi.2020.588958

33. Ceylan HI, Silva AF, Ramirez-Campillo R, Murawska-Cialowicz E. Exploring the effect of acute and regular physical exercise on circulating BDNF levels in individuals with obesity: a comprehensive systematic review and meta-analysis. Biol (Basel) 2024;13:323. DOI: https://doi.org/10.3390/biology13050323

34. Nibuya M, Morinobu S, Duman RS. Regulation of BDNF and TrkB mRNA in rat brain by chronic electroconvulsive seizure and antidepressant drug treatments. J Neurosci 1995;15:7539–47. DOI: https://doi.org/10.1523/JNEUROSCI.15-11-07539.1995

35. Trombeta JC, Cavaglieri CR, Bonfante ILP, et al. Combined physical training increases plasma BDNF levels, but not irisin, in people living with HIV/AIDS. Int J Exerc Sci 2021;14:1004–17. DOI: https://doi.org/10.70252/HOMO5275

36. Radikova Z, Mosna L, Eckerstorfer C, et al. Plasma irisin and BDNF levels in sedentary subjects: effect of 8-week lifestyle intervention. Endocr Regul 2024;58:115–28. DOI: https://doi.org/10.2478/enr-2024-0013

37. Afzalpour ME, Chadorneshin HT, Foadoddini M, Eivari HA. Comparing interval and continuous exercise training regimens on neurotrophic factors in rat brain. Physiol Behav 2015;147:78–83. DOI: https://doi.org/10.1016/j.physbeh.2015.04.012

38. Shirvani H, Arabzadeh E. Metabolic cross-talk between skeletal muscle and adipose tissue in high-intensity interval training vs moderate-intensity continuous training by regulation of PGC-1alpha. Eat Weight Disord 2020;25:17–24. DOI: https://doi.org/10.1007/s40519-018-0491-4

39. Arabzadeh E, Shirvani H, Ebadi Zahmatkesh M, et al. Irisin/FNDC5 influences myogenic markers on skeletal muscle following high- and moderate-intensity exercise training in STZ-diabetic rats. 3 Biotech 2022;12:193. DOI: https://doi.org/10.1007/s13205-022-03253-9

40. Peng J, Wu J. Effects of the FNDC5/Irisin on elderly dementia and cognitive impairment. Front Aging Neurosci 2022;14:863901. DOI: https://doi.org/10.3389/fnagi.2022.863901

41. Guo A, Li K, Xiao Q. Irisin ameliorates age-associated sarcopenia and metabolic dysfunction. J Cachexia Sarcopenia Muscle 2023;14:391–405. DOI: https://doi.org/10.1002/jcsm.13141

42. Zhang L, Peng Y, Qie Y, et al. Relationship of irisin and apelin levels with sarcopenia and body composition in community-dwelling older adults: a paired case-control study. Appl Physiol Nutr Metab 2025;50:1–11. DOI: https://doi.org/10.1139/apnm-2024-0473

43. Cheng Y, Liu Y, Ma J, et al. Effects of three aerobic exercise modalities (walking, running, and cycling) on circulating brain-derived neurotrophic factor in older adults: a systematic review and meta-analysis. Front Aging Neurosci 2025;17:1673786. DOI: https://doi.org/10.3389/fnagi.2025.1673786

44. Carraro U. Invitations to participate in the new 2024 section of the EJTM and in PDM3 2025, March 25-29, Terme Euganee, Padua, Italy. Eur J Transl Myol 2024;34:12970.