Moderate Exercise Inhibits Age-Related Inflammation, Liver Steatosis, Senescence, and Tumorigenesis
Open accessAbstract
Age-related chronic inflammation promotes cellular senescence, chronic disease, cancer, and reduced lifespan. In this study, we wanted to explore the effects of a moderate exercise regimen on inflammatory liver disease and tumorigenesis. We used an established model of spontaneous inflammaging, steatosis, and cancer (nfkb1−/− mouse) to demonstrate whether 3 mo of moderate aerobic exercise was sufficient to suppress liver disease and cancer development. Interventional exercise when applied at a relatively late disease stage was effective at reducing tissue inflammation (liver, lung, and stomach), oxidative damage, and cellular senescence, and it reversed hepatic steatosis and prevented tumor development. Underlying these benefits were transcriptional changes in enzymes driving the conversion of tryptophan to NAD+, this leading to increased hepatic NAD+ and elevated activity of the NAD+-dependent deacetylase sirtuin. Increased SIRT activity was correlated with enhanced deacetylation of key transcriptional regulators of inflammation and metabolism, NF-κB (p65), and PGC-1α. We propose that moderate exercise can effectively reprogram pre-established inflammatory and metabolic pathologies in aging with the benefit of prevention of disease.
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Interventions known to increase health span such as dietary restriction, exercise, rapamycin and 17β-oestradiol can reduce the frequency of cells with TAFs.
“First, interventions known to increase health span such as dietary restriction41, exercise42, rapamycin43,44 and 17β-oestradiol45 can reduce the frequency of cells with TAFs.”
From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [42]
In 16-month male Nfkb1−/− mice, treadmill exercise reduced liver inflammation.
“They found that exercise reduced liver inflammation, oxidative damage, and cellular senescence; improved hepatic steatosis; and prevented tumor development.”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [54]
In 16-month male Nfkb1−/− mice, treadmill exercise reduced oxidative damage.
“They found that exercise reduced liver inflammation, oxidative damage, and cellular senescence; improved hepatic steatosis; and prevented tumor development.”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [54]
In exercised Nfkb1−/− mice, immunohistochemistry on liver sections showed a significant reduction of P21-positive hepatocytes compared with sedentary mice.
“immunohistochemistry on liver sections showed a significant reduction of P21-positive hepatocytes in exercised mice compared with sedentary mice.”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [54]
In 16-month male Nfkb1−/− mice, treadmill exercise prevented tumor development.
“They found that exercise reduced liver inflammation, oxidative damage, and cellular senescence; improved hepatic steatosis; and prevented tumor development.”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [54]
In 16-month male Nfkb1−/− mice, treadmill exercise reduced cellular senescence.
“They found that exercise reduced liver inflammation, oxidative damage, and cellular senescence; improved hepatic steatosis; and prevented tumor development.”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [54]
In 16-month male Nfkb1−/− mice, treadmill exercise improved hepatic steatosis.
“They found that exercise reduced liver inflammation, oxidative damage, and cellular senescence; improved hepatic steatosis; and prevented tumor development.”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [54]
Reduced P21 was associated with a reduction in TAF-positive hepatocytes and lower levels of 4HNE staining in the liver.
“Reduced P21 was associated with a reduction in TAF-positive hepatocytes and lower levels of 4HNE staining, which is a lipid peroxidation marker (54).”
From Exercise Counters the Age-Related Accumulation of Senescent Cells (2022) · cites this paper as [54]
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- [32]Rothgiesser KM Erener S Waibel S Luscher B Hottiger MO SIRT2 regulates NF-kappaB dependent gene expression through deacetylation of p65 Lys310 J Cell Sci 2010 123 4251 8 21081649
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Sorted by citations
Cellular senescence: the good, the bad and the unknown
Huang, W., Hickson, L. J., Eirin, A., Kirkland, J. L., & Lerman, L. O. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00601-z · Cited by 1,150 · see citing works
Telomere dysfunction in ageing and age-related diseases
Rossiello, F., Jurk, D., Passos, J. F., & d’Adda di Fagagna, F. (2022) · Nature Cell Biology · doi:10.1038/s41556-022-00842-x · Cited by 754 · see citing works
Self-citationTargeting cellular senescence in metabolic disease
Palmer, A. K., Tchkonia, T., & Kirkland, J. L. (2022) · Molecular Metabolism · doi:10.1016/j.molmet.2022.101601 · Cited by 75 · see citing works
“Exercise also reduced liver senescent cells in a mouse model of spontaneous liver inflammation and steatosis [71].”
BackgroundAntifibrotic therapy in nonalcoholic steatohepatitis: time for a human-centric approach
Brennan, P. N., Elsharkawy, A. M., Kendall, T. J., Loomba, R., Mann, D. A., & Fallowfield, J. A. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00796-x · Cited by 68 · see citing works
Self-citationExercise Counters the Age-Related Accumulation of Senescent Cells
Zhang, X., Englund, D. A., Aversa, Z., Jachim, S. K., White, T. A., & LeBrasseur, N. K. (2022) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000302 · Cited by 63 · see citing works
“Reduced P21was associatedwith a reduction in TAF-positive hepatocytes and lower levels of 4HNE staining, which is a lipid peroxidation marker (54).”
BackgroundNAFLD-Associated HCC: Progress and Opportunities
Geh, D., Anstee, Q. M., & Reeves, H. L. (2021) · Journal of Hepatocellular Carcinoma · doi:10.2147/jhc.s272213 · Cited by 61 · see citing works
“112 The exercise intervention reversed steatosis within the liver and reduced inflammation, oxidative damage and cellular senescence.”
InfluentialMetabolic dysfunction and cancer in HCV: Shared pathways and mutual interactions
Leslie, J., Geh, D., Elsharkawy, A. M., Mann, D. A., & Vacca, M. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.01.029 · Cited by 61 · see citing works
Self-citationNeto, I. V. D. S., Pinto, A. P., Muñoz, V. R., Marqueti, R. D. C., Pauli, J. R., Ropelle, E. R., & da Silva, A. S. R. (2023) · Ageing Research Reviews · doi:10.1016/j.arr.2023.101935 · Cited by 56 · see citing works
Emery, A., Moore, S. E., Turner, J. E., & Campbell, J. P. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.788113 · Cited by 44 · see citing works
“This study suggests that regular exercise may in fact avert early neoplasia, in a process that may be independent of immune involvement (73).”
BackgroundInfluentialCellular senescence in liver diseases: From molecular drivers to therapeutic targeting
Du, K., Umbaugh, D. S., Ren, N., & Diehl, A. M. (2025) · Journal of Hepatology · doi:10.1016/j.jhep.2025.08.021 · Cited by 42 · see citing works
Walzik, D., Jonas, W., Joisten, N., Belen, S., Wüst, R. C. I., Guillemin, G. J., & Zimmer, P. (2023) · Acta Physiologica · doi:10.1111/apha.13921 · Cited by 32 · see citing works
Cao, X., & Thyfault, J. P. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112178 · Cited by 25 · see citing works
Kidney Disease as a Driver of Immunosenescence
Song, Z., Tsou, S., Martin, F., Kayumov, M., Xiao, Y., Zhou, H., Abdi, R., & Tullius, S. G. (2025) · Journal of the American Society of Nephrology · doi:10.1681/asn.0000000896 · Cited by 20 · see citing works
Gao, Y., Lu, J., Liu, X., Liu, J., Ma, Q., Shi, Y., & Su, H. (2021) · Frontiers in Physiology · doi:10.3389/fphys.2021.748517 · Cited by 18 · see citing works
“This could be considered the ability of long-term exercise to improve the inflammatory state of the liver by increasing SIRT activity and enhancing the deacetylation of key transcription factors of inflammation and metabolism, such as NF-κB and PGC-1α (Bianchi et al., 2021), which in turn improves the state of the liv…”
BackgroundAbuse of Anabolic-Androgenic Steroids and Adverse Effects on Human Organ Health: A Review
(2022) · Biointerface Research in Applied Chemistry · doi:10.33263/briac133.281 · Cited by 16 · see citing works
Cai, Y., Wang, S., Wang, S., Gu, Q., Huang, Y., Li, J., Wang, R., & Liu, X. (2023) · Experimental Gerontology · doi:10.1016/j.exger.2023.112250 · Cited by 16 · see citing works
Exercise as a Therapy to Maintain Telomere Function and Prevent Cellular Senescence
Kim, J., Ahn, A., Ying, J. Y., Hickman, E., & Ludlow, A. T. (2023) · Exercise and Sport Sciences Reviews · doi:10.1249/jes.0000000000000324 · Cited by 17 · see citing works
(2022) · Biointerface Research in Applied Chemistry · doi:10.33263/briac132.146 · Cited by 15 · see citing works
Translating cellular senescence research into clinical practice for metabolic disease
Chaib, S., Palmer, A. K., Wyles, S. P., Musi, N., Kirkland, J. L., & Tchkonia, T. (2025) · Nature Reviews Endocrinology · doi:10.1038/s41574-025-01187-9 · Cited by 14 · see citing works
“…becomes a primary site for accumulation of senescent cells, which is associated with ectopic lipid accumulation that contributes to conditions such as hepatic steatosis, non-alcoholic fatty liver disease (also known as metabolic dysfunction-associated steatotic liver disease) and cancers 60,61 .”
Cellular senescence in acute kidney injury: Target and opportunity
Li, T., Yang, K., Gao, W., Peng, F., & Zou, X. (2024) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2024.149744 · Cited by 12 · see citing works
Fico, B. G., Maharaj, A., Pena, G. S., & Huang, C. (2023) · Biology · doi:10.3390/biology12060865 · Cited by 14 · see citing works
“Studies utilizing animal models provide organ-specific mechanistic insight (e.g., liver, lung, stomach) for improvements in inflammation, oxidative damage, cellular senescence, and hepatic function after 3 months of aerobic exercise training via changes in sirtuin activity, nuclear factor kappa B (NF-κB), and peroxiso…”
BackgroundHuang, M., Yang, J., Wang, Y., & Wu, J. (2024) · Frontiers in Physiology · doi:10.3389/fphys.2024.1428723 · Cited by 10 · see citing works
The effect of physical activity on anti-infection immunity: a review
Wang, J., Zhao, W. L., Ding, J., & Li, Y. (2025) · Health Information Science and Systems · doi:10.1007/s13755-025-00360-8 · Cited by 8 · see citing works
“This is especially important because IgA is the first line of defense against pathogens breathed in or eaten [46].”
Autophagy modulation in cancer
Guilbaud, E., Ryan, K. M., Green, D. R., & Galluzzi, L. (2026) · Nature Reviews Drug Discovery · doi:10.1038/s41573-026-01449-9 · Cited by 10 · see citing works
“A similar oncosuppressive effect of exercise has been documented in mice subjected to ultraviolet B-induced skin carcinogenesis 348 and in Nfkb1 −/− mice, which spontaneously develop hepatic neoplasms 349 .”
Chen, J., Wang, S., Xin, X., & Xie, J. (2025) · BMC Gastroenterology · doi:10.1186/s12876-025-04517-3 · Cited by 7 · see citing works
“Regarding the underlying mechanisms, aerobic exercise may lower ALT primarily by promoting lipolysis, reducing intrahepatic lipid accumulation, and thereby alleviating insulin resistance as well as attenuating hepatocellular inflammation and oxidative stress [50].”
Cao, L., Zhang, X., Ji, B., Ding, S., & Qi, Z. (2021) · Clinical and Experimental Pharmacology and Physiology · doi:10.1111/1440-1681.13536 · Cited by 6 · see citing works
Casso-Chapa, B., González, N. A. V., Le, N., Palaskas, N. L., Nead, K. T., Eutsey, L. P., Samanthapudi, V. S. K., Osborn, A. M., Lee, J., Mejia, G. F., et al. (2025) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/atvbaha.124.319870 · Cited by 5 · see citing works
“Bianchi et al 28 Anti-inflammatory: after exercising, anti-inflammatory changes were seen in neutrophils, B cells, NK cells, and CD4 + , CD8 + , and FOXP3 + T cells, as well as significant decreases in levels of the proinflammatory cytokines IL-6 and TNF-α .”
Tilekli, M. M., Yılmaz, A. K., Yasul, Y., Çon, N., Mercan, S., & Tek, N. A. (2024) · Experimental and Molecular Pathology · doi:10.1016/j.yexmp.2024.104947 · Cited by 5 · see citing works
Role of Exercise and Natural Protective Substances on Sirtuin Activation
Ricordi, C., Zanuso, S., & Menichelli, M. (2021) · doi:10.33696/rehabilitation.3.019 · Cited by 5 · see citing works
Role of L-carnitine in exercise training: Anti-inflammatory, antioxidant, and metabolic interactions
Aminizadeh, S., Zarezadehmehrizi, A., Deh-Ahmadi, M. A., & Shahouzehi, B. (2025) · Advances in Redox Research · doi:10.1016/j.arres.2025.100149 · Cited by 4 · see citing works
Chronic Kidney Disease and Cellular Senescence
Morevati, M., Tavenier, J., Scheibye‐Knudsen, M., Houlind, M. B., Hedayati, A., & Hornum, M. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27073205 · Cited by 4 · see citing works
“These benefits are attributed to the modulation of mitochondrial function, inflammation, the SASP, and the process of lipolysis [197,198,246].”
Katsarou, A., Papadopoulos, G., Moustakas, I. I., Papadopetraki, Α., Moustogiannis, A., Legaki, A., Giannousi, E., Agrogiannis, G. D., Pantelis, P., Veroutis, D., et al. (2025) · Metabolism · doi:10.1016/j.metabol.2025.156325 · Cited by 4 · see citing works
Saez-Berlanga, Á., Gené‐Morales, J., Juesas, Á., Jiménez‐Martínez, P., Alix‐Fages, C., Garrido, J. F., Caballero, O., Janicijevic, D. N., Gallo, V., & Colado, J. C. (2025) · Applied Sciences · doi:10.3390/app152412862 · Cited by 2 · see citing works
From Diagnosis to Recovery: The Life-Changing Benefits of Exercise for Cancer Patients
Koper, M., Bochenek, O., Nowak, A., Kałuża, J. A., Konaszczuk, A., Ratyna, K., Kozyra, O., Szypuła, Z., Paluch, K., & Skarbek, M. (2024) · Quality in Sport · doi:10.12775/qs.2024.20.54212 · Cited by 2 · see citing works
“Additionally, exercise has been found to inhibit age-related inflammation, liver steatosis, senescence, and tumorigenesis, underscoring its role in mitigating various aspects of cancer development and progression [39].”
BackgroundSoares, J., Cardoso, R., Almeida, V., Pereira, A., Silva, A. M., & Mota, M. P. (2024) · Healthcare · doi:10.3390/healthcare12030350 · Cited by 2 · see citing works
“Moreover, several works have demonstrated the positive anti-inflammatory effect of regular physical exercise [38,39].”
BackgroundThe Influence of an Acute Endurance Intervention on Breast Cancer Cell Growth—A Pilot Study
Gunasekara, N., Clauss, D., Voss, A., Schurz, K., Fleck, K., Neu-Gil, P., & Bloch, W. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26093976 · Cited by 1 · see citing works
“Additionally, since the analysis captures only a fraction of cellular states, identifying dynamic changes remains challenging despite the controlled serum conditions.”
Determinants of abnormal liver-related biomarkers in adult COVID-19 patients
ZHANG, S., Hu, Y., Liu, L., Ning, X., Li, Q., & Xiao, G. (2026) · Frontiers in Cellular and Infection Microbiology · doi:10.3389/fcimb.2025.1662585 · Cited by 1 · see citing works
“Other studies have demonstrated that age-related chronic in fl ammation can promote hepatocyte senescence and chronic liver disease (Go ́ mez-Santos et al., 2020; Bianchi et al., 2021).”
Impact of exercise intervention on immune function during aging
Bai, J., & Zhang, J. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1817225 · Cited by 1 · see citing works
Exercise: Preventive and Therapeutic Benefits in Cancer
Agarwal, S. K. (2021) · Journal of cancer research updates · doi:10.30683/1929-2279.2021.10.02 · Cited by 1 · see citing works
“However, the beneficial effects of exercise on retarding liver cancer were recently documented in mice [82].”
BackgroundPalmer, A. K., & Kirkland, J. L. (2024) · Elsevier eBooks · doi:10.1016/b978-0-443-15500-0.00012-8 · Cited by 1 · see citing works
Huyen, V. T., Echizen, K., Yamagishi, R., Kumagai, M., Nonaka, Y., Kodama, T., Ando, T., Yano, M., Takada, N., Takasugi, M., et al. (2024) · Genes to Cells · doi:10.1111/gtc.13161 · Cited by 1 · see citing works
Katsarou, A., Papadopoulos, G., Moustakas, I. I., Papadopetraki, Α., Moustogiannis, A., Legaki, A., Giannousi, E., Veroutis, D., Kotsinas, A., Gorgoulis, V. G., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.12.03.626591
Karaushi, T., Ogawa, T., Fusagawa, H., Kudo, T., Inoue, Y., Yamada, T., Ichise, N., Sato, T., & Tohse, N. (2025) · Physiological Reports · doi:10.14814/phy2.70468
“While exercise is an established strategy for ameliorating inflammation (Bianchi et al., 2021; Scheffer & Latini, 2020), care must be taken with the intensity and type of exercise.”
Hei, Y., & Xie, Y. (2025) · Nutrition Reviews · doi:10.1093/nutrit/nuaf217
Shahouzehi, B., Jafari, H., & Rostamzadeh, F. (2026) · European Journal of Applied Physiology · doi:10.1007/s00421-026-06484-3
- Authors
- Bianchi, A., Marchetti, L., Hall, Z., Lemos, H., Vacca, M., Paish, H., Green, K., Elliott, B., Tiniakos, D., Passos, J. F., Jurk, D., Mann, D. A., & Wilson, C. L.
- Affiliations
- Newcastle University (GB)
- Imperial College London (GB)
- Department of Biochemistry, University of Cambridge , Cambridge CB2 1QW ,
- University of Sheffield (GB)
- Mayo Clinic (US)
- Corresponding author
- Wilson, Caroline L
- ORCID
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2021-02
- Volume
- 206
- Issue
- 4
- Pages
- 904-916
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- PMC
- PMC7851741
- OpenAlex
- W3119588296
- Cited by
- 45
- References
- 72
- Citations by year
- 2026: 5 · 2025: 12 · 2024: 8 · 2023: 7 · 2022: 8 · 2021: 5
- FWCI
- 3.67
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Locations
- The Journal of Immunology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- CINECA IRIS Institutional Research Information System (University of Bari Aldo Moro) (submittedVersion, cc-by)
- Spiral (Imperial College London) (submittedVersion, cc-by)
- Newcastle University ePrints (Newcastle Univesity) (cc-by)
- Funders
- Cancer Research UK (23390)
- Medical Research Council (MR/R023026/1)
- Biotechnology and Biological Sciences Research Council (BB/K017314/1)
- National Institute on Aging (P01AG062413)
- Topics
- Health Sciences › Medicine › Rehabilitation › Exercise and Physiological Responses
- Health Sciences › Medicine › Geriatrics and Gerontology › Sirtuins and Resveratrol in Medicine
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Keywords
- moderate-intensity exercise, inflammaging, hepatic steatosis, cellular senescence, carcinogenesis, NAD+ salvage pathway, tryptophan metabolism, sirtuins, NF-κB, PGC-1α, oxidative damage, aging, aerobic exercise, inflammation, metabolic reprogramming
- MeSH terms
- Aging, Animals, Fatty Liver, Inflammation, Liver Neoplasms, Physical Conditioning, Animal, Cellular Senescence, Mice, Knockout, Mice, NF-kappa B p50 Subunit, Carcinogenesis
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