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An aged immune system drives senescence and ageing of solid organs
Open accessAbstract
Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly 1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein 3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence 5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice 8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function 11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing.
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“Once senescent cell burden surpasses this threshold, continuing increases in proapoptotic/pro-inflammatory senescent cell burden may contribute to tissue destruction and hence development or progression of multiple diseases and age-related disorders (Table 2) as well as immune dysregulation, further amplifying senescent cell accumulation in a feed-forward loop36,38,62.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [38]
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“The senescent cell fate can be triggered by a number of stressors including DNA damage, cancerous mutations or oncogene activation, mitochondrial dysfunction, reactive metabolites, hyperoxia or hypoxia, proteotoxic stress, extracellular signals, infections, mechanical or shear stresses that deform cells, resistance exercise and factors secreted by other senescent cells18,38–47.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [38]
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In the citing paper
“Mouse models of rapid telomere shortening, dysfunctional mitosis or impaired DNA repair (Terc, BubR1, and Ercc1 mutant mice, respectively), display high levels of cellular senescence and accelerated aging86,99,100.”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [99]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“CD3+ T cells isolated from the blood of aged mice and of mice deficient in ERCC1, which is a crucial DNA repair protein, exhibit increased levels of multiple senescent markers, including Ccl2, Tnf, Il1b, Inhba, Spp1, Cdkn2a and Cdkn1a (refs. 85,86).”
From SenNet recommendations for detecting senescent cells in different tissues (2024) · cites this paper as [86]
Experimental — accuracy not yet measuredThe source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
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“As a result of the effects of cellular senescence, chronic inflammation, and immunosenescence, the pathological aging of organs increases the level of inflammation and makes repair difficult, ultimately leading to diseases.10”
From Inflammation and aging: signaling pathways and intervention therapies (2023) · cites this paper as [10]
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“In aging tissues, molecular and cellular changes disrupt spatial organization, resulting in uneven functional decline.”
From Spatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging (2024) · cites this paper as [5]
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“These and other models, for which it has been shown that accelerated aging depends, at least partly, on cellular senescence, are valuable for studying the impact of senescence on health and lifespan”
From Guidelines for minimal information on cellular senescence experimentation in vivo (2024) · cites this paper as [99]
The cited source says what the claim attributes to it.
In the citing paper
“Furthermore, the functionally weakened immune system in old age44 does not clear senescent cells, which may account for their persistence in damaged aged muscle; this exacerbates tissue regenerative impairment.”
From Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration (2023) · cites this paper as [44]
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“Premature aging of the immune system has been shown to drive aging of multiple other organ systems in mice 81.”
From Targeting the biology of aging with mTOR inhibitors (2023) · cites this paper as [81]
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In the citing paper
“Notably, clearing senescent cells in peripheral tissues may also positively impact the brain55.”
From Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial (2023) · cites this paper as [55]
Experimental — accuracy not yet measuredIn the citing paper
“suggesting that a senescent immune system contributes to aging phenotypic features in immune cells and in solid, nonlymphoid tissues.”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [26]
In the citing paper
“Deletion of ERCC1, a crucial DNA repair protein, in mouse hematopoietic cells leads to accelerated senescence of the immune system.”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [26]
In the citing paper
“Accordingly, mice lacking ERCC1 in hematopoietic cells, as well as aged mice, express elevated markers of senescence (p16, p21) in many immune cells with concomitant impairment of immune function.”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [26]
In the citing paper
“Strikingly, transfer of splenocytes from aged wild-type mice or mice lacking ERCC1 into young animals increased the senescence burden in nonlymphoid organs, suggesting that a senescent immune system contributes to aging phenotypic features in immune cells and in solid, nonlymphoid tissues.”
From Connecting aging biology and inflammation in the omics era (2022) · cites this paper as [26]
In the citing paper
“Notably, the selective induction of immune cell ageing increases the levels of the ageing markers p16 and p21 in multiple organs, including the brain,328 thereby highlighting the crucial roles played by the immune system in the process of ageing.”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [328]
In the citing paper
“Immunosenescence is characterized by dysfunctions in monocyte and neutrophil phagocytosis, decreased numbers of naive T cells, increased numbers of memory T cells,327 and increased SASP secretion by these cells,327,328 thereby weakening the immune response to foreign antigens.”
From Antiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances (2025) · cites this paper as [328]
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Additional file 1 of Accelerated immune ageing is associated with COVID-19 disease severity
Lord, J. M., Veenith, T., Sullivan, J., Sharma‐Oates, A., Richter, A. G., Greening, N. J., McAuley, H., Evans, R. A., Moss, P. A. H., Moore, S. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26666446
Additional file 1 of Decreased thymic output predicts progression of chronic kidney disease
Iio, K., Kabata, D., Iio, R., Shibamoto, S., Watanabe, Y., Morita, M., Imai, Y., Hatanaka, M., Omori, H., & Isaka, Y. (2024) · Figshare · doi:10.6084/m9.figshare.26568466
Additional file 2 of Accelerated immune ageing is associated with COVID-19 disease severity
Lord, J. M., Veenith, T., Sullivan, J., Sharma‐Oates, A., Richter, A. G., Greening, N. J., McAuley, H., Evans, R. A., Moss, P. A. H., Moore, S. C., et al. (2024) · Figshare · doi:10.6084/m9.figshare.26666449
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Wang, W., Peng, H., Zeng, M., Liu, J., Liang, G., & He, Z. (2024) · Figshare · doi:10.6084/m9.figshare.26650344
Xue, H., Lan, X., Xue, T., Tang, X., Yang, H., Hu, Z., Xu, N., & Xie, B. (2024) · Figshare · doi:10.6084/m9.figshare.25902278
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How and why does aging occur? Updating evolutionary theory to meet a new era of data
Metcalf, C. J. E., Anderson, R. M., Hochberg, M., Masel, J., Moorad, J. A., Promislow, D., Tuljapurkar, S. D., & Snyder‐Mackler, N. (2025) · Evolution Medicine and Public Health · doi:10.1093/emph/eoaf040
“Furthermore, while there is a rich body of work on specific measures, most focus on ‘hallmarks of aging’ [12], including the molecular age-associated heterogeneity in gene expression [1], epigenetic dysregulation [3], and immune function [13] (Box 1).”
Dobrokhotov, I. V., Владимировна, Я. Е., & Moskalev, A. A. (2025) · Pirogov Russian Journal of Surgery · doi:10.17116/hirurgia202511279
Systemic Amyloid-β Metabolism in Alzheimer’s Disease
Dong-yu, F., Wang, J., Gu, B. J., Masters, C. L., & Wang, Y. (2026) · Springer eBooks · doi:10.1007/978-981-95-5222-1_7
Self-citationCai, J., Zhang, J., Ning, Y., Zhang, J., Xu, T., Liu, M., Wang, K., & Chen, H. (2026) · Aging Cell · doi:10.1111/acel.70400
“Aging is characterized by chronic inflammation throughout the body, accompanied by cellular senescence, immune senescence, organ dysfunction and aging-related diseases (Arai et al. 2015; López-Otín et al. 2023; Sayed et al. 2021; Yousefzadeh et al. 2021).”
Olinger, B., Anerillas, C., Herman, A. B., Tsitsipatis, D., Banarjee, R., Tanaka, T., Candia, J., Maragkakis, M., Bandinelli, S., Walker, K. A., et al. (2026) · doi:10.64898/2026.02.06.26345739
How molecular mechanisms of aging drive Alzheimer's disease pathology
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“[55] In contrast, transplanting immune cells from young mice into Ercc1 -knockout mice delayed senescence.”
Transplanting ANXA1⁻ CD8⁺ Naïve T cells Delay Aging Through SenolysisPreprint
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Azhir, A., Cheng, J., Tian, J., Bassett, I. V., Patel, C. J., Klann, J. G., Murphy, S. N., & Estiri, H. (2026) · medRxiv · doi:10.64898/2026.02.24.26346989
Molecular evolution of animal aging
Nussey, D. H., di Fagagna, F. D., Bardin, A. J., Blau, H. M., Brunet, A., Bulavin, D. V., Guo, L., Hara, E., Junker, J. P., Gorbunova, V. A., et al. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00725-z · Cited by 1
“…adaptive immunity not only becomes less effective at controlling infections and tumors, but also fails to clear senescent cells (Carrasco et al, 2022), and may even become autoreactive, contributing to in fl ammaging (Desdin-Mico et al, 2020; Mogilenko et al, 2021; Yousefzadeh et al, 2021).”
Chickens and eggs? Aging-related immune dysfunction, epithelial senescence, and kidney fibrosis
Baird, D., & Ferenbach, D. A. (2026) · Kidney International · doi:10.1016/j.kint.2025.11.008
Dual roles of immunosenescence in cancer immunotherapy
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“And in murine models, mTOR inhibitors like rapamycin reduce p16 and p21 expression in CD3 + T cells, indicating their potential to mitigate T cell immunosenescence (9).”
The cellular and molecular pathophysiology of diabetes in aging
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Chronic exposure to interleukin-10 drives inflammaging and accelerated tissue senescencePreprint
Saraiva, M., Martins, A., Santos, R. F., Faria, I., Castro, J. P., Gonçalves, R., Sousa-Soares, C., Cardoso, M. S., Lima, T., Silva, E. D., et al. (2026) · Research Square · doi:10.21203/rs.3.rs-8603195/v1
Role of KLF4 in Neutrophil Aging in Periodontitis with Metabolic Syndrome
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“These senescent neutrophils are hyperreactive and exert proinflammatory effects, suggesting they may represent a major cellular driver of immunose-nescence phenotypes (Yousefzadeh et al 2021; Baragetti et al 2023).”
Riera‐Arnau, J., Luxi, N., Riefolo, F., Solórzano, M., Pazos, I., Ballarín, E., Svingel, L. S., Chiusaroli, L., Martín‐Merino, E., Barbieri, E., et al. (2026) · Pharmacoepidemiology and Drug Safety · doi:10.1002/pds.70362
How Somatic Mutations cause Aging without Causing AgingPreprint
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Wang, Y.-R., Tan, L., Zhang, F., Zhang, C.-T., & Liang, W. (2026) · BMC Public Health · doi:10.1186/s12889-026-27266-8
“Aging is accompanied by a decline in bodily functions [34], and the immune system’s ability to effectively resist and repair the body’s weakened state diminishes with age [35].”
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High altitude–mediated immune remodeling accelerates aging
Yu, X., Li, Y., Mao, Y., Jin, Z., Sun, M., Wang, X., Gan, Z., Song, Y., Li, J., Zhang, Z., et al. (2026) · Science Advances · doi:10.1126/sciadv.aeb5599
“One of the characteristics of B cell aging is the accumulation of B m cells as well as the reduction of B n cells, promoting an inflammatory phenotype ( 40 ).”
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“Senescence is a state characterized by impaired T cell function 30 and is prevalent in HIV infection.”
Codonopsis pilosula Polysaccharide (CPP) Alleviates D-Gal-Induced Aging and Gut Microbiota Dysbiosis
Zhang, B., Zhang, C., Yu, M., Zhang, Y., Wang, X., Chen, R. Y., & Sun, X. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27093933
“Senescent cells secrete cytokines, chemokines, and proteases, known as the senescence-associated secretory phenotype (SASP), which sustains immune activation and results in persistent low-grade inflammation [5,6].”
Xie, F., Shen, Y., Zhao, J., Geng, X., Zeng, N., Han, R., Wang, Y., Wang, Y., Xu, W., & Fan, J. (2026) · Nutrition & Metabolism · doi:10.1186/s12986-026-01131-2
“At the molecular level, cells secrete pro-inflammatory factors after aging, which promote the occurrence of chronic inflammation and promote the aging process of normal cells [22].”
Self-citation
Metadata
- Authors
- Yousefzadeh, M. J., Flores, R. R., Zhu, Y., Schmiechen, Z. C., Brooks, R. W., Trussoni, C. E., Cui, Y., Angelini, L., Lee, K.-A., McGowan, S. J., Burrack, A. L., Wang, D., Dong, Q., Lu, A., Sano, T., O’Kelly, R. D., McGuckian, C. A., Kato, J. I., Bank, M. P., Wade, E. A., Pillai, S. P. S., Klug, J., Ladiges, W. C., Burd, C. E., Lewis, S. E., LaRusso, N. F., Vo, N. V., Wang, Y., Kelley, E. E., Huard, J., Stromnes, I. M., Robbins, P. D., & Niedernhofer, L. J.
- Affiliations
- University of Minnesota (US)
- Mayo Clinic (US)
- Scripps Research Institute (US)
- University of California, Riverside (US)
- University of Pittsburgh (US)
- The University of Texas Health Science Center at Houston (US)
- Fred Hutch Cancer Center (US)
- University of Washington (US)
- The Ohio State University (US)
- West Virginia University (US)
- Corresponding author
- Robbins, Paul D.
- Niedernhofer, Laura J.
- ORCID
- Yousefzadeh, Matthew J.
- Flores, Rafael R.
- Zhu, Yi
- Schmiechen, Zoe C.
- Trussoni, Christy E.
- Cui, Yuxiang
- Lee, Kyoo-A
- McGowan, Sara J.
- Burrack, Adam L.
- Wang, Dong
- Dong, Qing
- Lu, Aiping
- Sano, Tokio
- Pillai, Smitha P. S.
- Ladiges, Warren C.
- Burd, Christin E.
- Lewis, Sara E.
- LaRusso, Nicholas F.
- Vo, Nam V.
- Wang, Yinsheng
- Huard, Johnny
- Stromnes, Ingunn M.
- Robbins, Paul D.
- Niedernhofer, Laura J.
- Venue
- Nature
- Published
- 2021-05-12
- Volume
- 594
- Issue
- 7861
- Pages
- 100-105
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC8684299
- OpenAlex
- W3161778279
- Cited by
- 972
- References
- 43
- Citations by year
- 2026: 176 · 2025: 219 · 2024: 219 · 2023: 186 · 2022: 131 · 2021: 41
- FWCI
- 91.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- National Institute on Aging (P01AG043376, R01AG059711, R01AG067193, R01AG044376, R56AG059676, R56AG058543, T32AG029796, U19AG056278, P01AG062413, R01AG063543)
- National Cancer Institute (R01CA249393, R01CA255039)
- National Institute of Diabetes and Digestive and Kidney Diseases (P30DK084567)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and B-cell Immunology
- Keywords
- immunosenescence, cellular senescence, ERCC1, DNA repair, endogenous DNA damage, hematopoietic cells, rapamycin, senolytics, healthy aging
- MeSH terms
- Immunosenescence, Healthy Aging, Aging, Animals, DNA Damage, DNA Repair, DNA-Binding Proteins, Endonucleases, Female, Homeostasis, Immune System, Male, Organ Specificity, Rejuvenation, Spleen, Sirolimus, Mice
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