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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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In the citing paper
“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]
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
“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]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
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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]
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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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“This leads to the reduction in the T cell repertoire and diminished responsiveness to new antigens [11,57,58] During the process, a chronic low-grade inflammatory state which is called inflammaging[7] is linked to immune dysfunction occurs [57,59] As a result of the occurrence of immunosenescence,…”
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CD8+ T cell aging, senescence, and related disease
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Aging Reshapes γ/δ T‐Cell Immunity Through a Type I Interferon–Foxo1 Axis
Durand, A., Porte, S., Xing, E., Wu, C., Bon, A. L., Auffray, C., Lucas, B., & Martin, B. (2026) · Aging Cell · doi:10.1111/acel.70389 · Cited by 2
“…as “inflammaging,” is thought to contribute to the pathogenesis of numerous age-related diseases, including cardiovascular disease, neurodegeneration (Yousefzadeh et al. 2021; Carrasco et al. 2022), impaired immune responses to infections (Stout-Delgado et al. 2009), and reduced efficacy of cancer…”
Li, X., Zhang, M., Chi, A., Mo, J., Tan, X., Chen, H., Deng, C., Sun, X., Feng, X., & Chen, Z. (2026) · GeroScience · doi:10.1007/s11357-026-02109-x · Cited by 2
“Aging disrupts immune homeostasis, impairing tissue function and increasing susceptibility to various diseases [23–26].”
Chen, W., Liu, S., Xu, G., Liu, X., Shi, Y., Wang, G., Ning, Y., Yuan, C., Lu, Z., Cao, Y., et al. (2026) · Immunity & Ageing · doi:10.1186/s12979-026-00560-0 · Cited by 2
“This approach aligns with established models of immunose-nescence [3, 22].”
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Battaglia, M. C., Bhalla, M., Marzullo, B. J., Betadpur, A., Lenhard, A. P., Mohamed, R. H., Kalem, M. C., Heinzinger, L. R., Leus, P. A., Labarron, S., et al. (2026) · Aging Cell · doi:10.1111/acel.70435 · Cited by 2
“These therapies have been shown to improve immune responses following treat-ment of senescent T cells, B cells, macrophages, and hematopoietic cells in malignancies (Cai et al. 2020; Chang et al. 2016; Cobanoglu et al. 2023; Yousefzadeh et al. 2021).”
Kang, H.-X., Fu, Y.-F., Wu, H., Yan, X.-L., Wu, J.-J., Jiang, L.-Z., Wang, L.-S., Xiao, Y.-R., Zhang, Z.-Z., Yuan, F., et al. (2026) · Frontiers in Immunology · doi:10.3389/fimmu.2026.1770516 · Cited by 2
“In parallel, DCs in fi brotic lungs exhibit functional reprogramming, with diminished antigen-presenting capacity but preserved or enhanced ability to shape local in fl ammatory and repair-associated signaling networks (95, 96).”
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Skiles, C. M., Fennel, Z. J., Bourrant, P., Yee, E. M., Castro, R. J., Zabriskie, H. A., Itinose, M., Supiano, M. A., O’Connell, R. M., & Drummond, M. J. (2026) · The Journal of Physiology · doi:10.1113/jp290346 · Cited by 2
“Given that immunosenescence is prevalent with ageing (Yousefzadeh et al., 2021; Moiseeva et al., 2023), the robust cell infiltration may have triggered an expansion of senescent macrophages in aged skeletal muscle tissue.”
SenSet defines cell-type specific senescence signatures in the aged human lung
Hasanaj, E., Beaulieu, D., Wang, C., Hu, Q., Rosas, L., Bueno, M., Sembrat, J., Pineda, R., Melo-Narváez, M. C., Cárdenes, N., et al. (2026) · The EMBO Journal · doi:10.1038/s44318-026-00762-8 · Cited by 11
“It is well-established that senescence increases in multiple organs with age (Yousefzadeh et al, 2021; Mebratu et al, 2023; Calhoun et al, 2016).”
Inflammaging in aged tissues drives remodeling of the CD8+ T cell compartment
Shchukina, I., Rodríguez-Hernández, C. J., Ruiz, H. S., Kleverov, M., Mintz, R. L., Mineura, K., Gunawardana, S. C., Hsiung, S., Bhattarai, B., Vachova, V., et al. (2026) · Cell Reports · doi:10.1016/j.celrep.2026.117303 · Cited by 2
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Cellular senescence: from pathogenic mechanisms to precision anti-aging interventions
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“The current challenge lies in achieving molecular granularity — precisely targeting the “senescent state” without compromising the pathogen surveillance and homeostatic endocytic functions of the healthy macrophage repertoire [95, 147].”
The immunology behind inflammaging—causes, sources, and mechanisms
Sturmlechner, I., LeBrasseur, N. K., Weyand, C. M., & Goronzy, J. J. (2026) · Journal of Allergy and Clinical Immunology · doi:10.1016/j.jaci.2026.05.031 · Cited by 3
Immune aging biomarkers for clinical trials
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Aging and cancer: current understandings and future perspectives
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“74 In terms of the improvement in immune functions in old age by mTOR inhibition, short-term (6 weeks) administration of rapamycin to 26-month-old aged mice has been demonstrated to extend lifespan by rejuvenating hematopoietic stem cell function, boosting the generation of naïve lymphocytes, and…”
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Immune surveillance and immune evasion of senescent cells
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Spent hen: Insights into pharmaceutical and commercial prospects
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“…the augmentation of the protective immune system, known as immunosenescence, which makes older people more susceptible to pathogenic, carcinogenic, and many degenerative diseases and contributes to severe morbidity and mortality of them (Weyand and Goronzy 2016; Yousefzadeh et al. 2021).”
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Sex difference and immunosenescence affect transplantation outcomes
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Endothelial cellular senescence and tau accumulation: An interplay full of opportunities?
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“Clearing senescent cells in peripheral tissues may also positively impact the brain, 28 but developing delivering strategies promoting both BBB crossing and specific targeting is desirable.”
BackgroundVitamin D-dependent microbiota-enhancing tumor immunotherapy
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“More intriguingly, there is evidence to suggest that immune system aging may drive the aging of other organs/tissues [9] and that inhibiting the immune system may slow organ/tissue aging and even rejuvenate organs/tissues [10].”
Role of immunosenescence in impaired wound healing with age
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“17 23 However, many aspects of the critical progression of COVID-19 in the elderly population remain unclear, severely limiting the development of effective clinical therapies and the implementation of efficient countermeasures.”
BackgroundIntegrating cuproptosis and immunosenescence: A novel therapeutic strategy in cancer treatment
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“Diseases are caused by the degenerative aging of organs, which raises inflammation levels and makes healing challenging due to the impacts of cellular senescence, immunosenescence, and chronic inflammation [152].”
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Welch, C., Acharjee, A., Birch, R. J., de Magalhães, J. P., Duggal, N. A., Hainsworth, A. J., Hombrebueno, J. R., Jones, S. W., Lewis, J., Mazaheri, A., et al. (2025) · BMC Geriatrics · doi:10.1186/s12877-025-06109-y · Cited by 2
“Immune-senescence has been shown in mice to be a key driver of frailty [28] and in humans to predict impaired resilience in patients following traumatic injury [29].”
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“By accelerating solid organ senescence, they contribute to systemic aging [4].”
Bioinformatics driven in gene targeting platform for gold anticancer strategy delivery
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“The immune system, therefore, functions as both a target of senescence and a regulator of the senescence process [64].”
T cell senescence: A novel therapeutic target for aging
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Potential role of mesenchymal stem cells in T cell aging
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“…soluble molecules) signaling, SnCs could interfere with the function of other non-SnCs in the TME, including non-senescent cancer cells (non-SnCCs), normal cells, immune cells, cancer stem cells (CSCs), endothelial cells, CAFs, and stromal cells (Figure 1A and 1B) (Yousefzadeh et al., 2021).”
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Understanding immune-driven brain aging by human brain organoid microphysiological analysis platformPreprint
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Murine Progeria Model Exhibits Delayed Fracture Healing with Dysregulated Local Immune ResponsePreprint
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Bhushan, A., & Thompson, P. J. (2024) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041605 · Cited by 4
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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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