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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]
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“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]
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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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“Similarly, p16-positive senescent T cells increase with age in mice (Yousefzadeh et al., 2021).”
BackgroundThe matricellular protein SPARC induces inflammatory interferon-response in macrophages during aging
Ryu, S., Sidorov, S., Ravussin, É., Artyomov, M. N., Iwasaki, A., Wang, A., & Dixit, V. D. (2022) · Immunity · doi:10.1016/j.immuni.2022.07.007 · Cited by 124
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“Other geroprotective compounds, such as SAM 229 , nicotinamide riboside 255 , NMN 208 , ascorbic acid 228 , rapamycin 204 , taurine 230 and urolithin A 220 , have also shown efficacy in mitigating genome instability and stimulating cell and tissue rejuvenation.”
Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging
Zhou, Z., Yao, J., Wu, D., Huang, X., Wang, Y., Li, X., Lu, Q., & Qiu, Y. (2024) · Immunity · doi:10.1016/j.immuni.2024.01.001 · Cited by 122
Self-citationp16-dependent increase of PD-L1 stability regulates immunosurveillance of senescent cells
Majewska, J., Agrawal, A., Mayo, A., Roitman, L., Chatterjee, R., Kralova, J. S., Landsberger, T., Katzenelenbogen, Y., Meir-Salame, T., Hagai, E., et al. (2024) · Nature Cell Biology · doi:10.1038/s41556-024-01465-0 · Cited by 126
“In each experiment, the number of animals was chosen to have sufficient statistical power on the basis of the literature and experience 6,7,15 .”
Gaikwad, S., Senapati, S., Haque, M. A., & Kayed, R. (2024) · Alzheimer's & Dementia · doi:10.1002/alz.13490 · Cited by 117
“60,61 Fundamentally, the SASP impairs tissue regenerative capacity through paracrine senescence in stem cells.”
BackgroundThe role of peripheral inflammatory insults in Alzheimer’s disease: a review and research roadmap
Walker, K. A., Page, L. M. L., Terrando, N., Duggan, M. R., Heneka, M. T., & Bettcher, B. M. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00627-2 · Cited by 121
Macrophage senescence in health and diseases
Wang, L., Hong, W., Zhu, H., He, Q., Yang, B., Wang, J., & Weng, Q. (2024) · Acta Pharmaceutica Sinica B · doi:10.1016/j.apsb.2024.01.008 · Cited by 117
“Rapamycin,theautophagyinducerimprovesimmune function by reducing senescent markers in immune cells in the Vav - iCre þ / (cid:2) ; Ercc1 e /flox mice (a model of immunosenescence) 182,185 .”
BackgroundImmune system and sarcopenia: Presented relationship and future perspective
Zhang, X., Li, H., He, M., Wang, J., Wu, Y., & Li, Y. (2022) · Experimental Gerontology · doi:10.1016/j.exger.2022.111823 · Cited by 119
The translational challenges of precision oncology
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Noncancerous disease-targeting AIEgens
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Cellular senescence, DNA damage, and neuroinflammation in the aging brain
Zhang, W., Sun, H., Wang, X., Dumont, A. S., & Liu, Q. (2024) · Trends in Neurosciences · doi:10.1016/j.tins.2024.04.003 · Cited by 121
Clonal hematopoiesis, somatic mosaicism, and age-associated disease
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NAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis
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Self-citationZhang, X., Pearsall, V. M., Carver, C. M., Atkinson, E. J., Clarkson, B. D. S., Grund, E. M., Baez-Faria, M., Pavelko, K. D., Kachergus, J. M., White, T. A., et al. (2022) · Nature Communications · doi:10.1038/s41467-022-33226-8 · Cited by 102
Self-citationCellular senescence and the skeleton: pathophysiology and therapeutic implications
Khosla, S., Farr, J. N., & Monroe, D. G. (2022) · Journal of Clinical Investigation · doi:10.1172/jci154888 · Cited by 106
“, vasculature, lung, liver) (38), although the skeleton was not evaluated in these studies and will be the subject of future work.”
BackgroundSex‐specific aging in animals: Perspective and future directions
Bronikowski, A. M., Meisel, R. P., Biga, P. R., Walters, J. R., Mank, J. E., Larschan, E., Wilkinson, G. S., Valenzuela, N., Conard, A. M., de Magalhães, J. P., et al. (2022) · Aging Cell · doi:10.1111/acel.13542 · Cited by 105
T Cell Fitness and Autologous CAR T Cell Therapy in Haematologic Malignancy
Mehta, P. H., Fiorenza, S., Koldej, R. M., Jaworowski, A., Ritchie, D. S., & Quinn, K. M. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.780442 · Cited by 99
“It is also becoming clear that chronic inflammation, driven by DNA, metabolic or other forms of cellular damage and an aged immune system, is a dominant driver of the ageing process (76).”
BackgroundExtremely Differentiated T Cell Subsets Contribute to Tissue Deterioration During Aging
Soto‐Heredero, G., Heras, M. M. G. D. L., Escrig-Larena, J. I., & Mittelbrunn, M. (2023) · Annual Review of Immunology · doi:10.1146/annurev-immunol-101721-064501 · Cited by 96
Telomeres, aging, and cancer: the big picture
Lansdorp, P. M. (2022) · Blood · doi:10.1182/blood.2021014299 · Cited by 96
“The progressive loss of telomere repeats in lymphocytes with age (Figures 2 and 3) is likely to compromise innate and adaptive immune responses in the elderly.(88) Leukocyte telomere length has been reported to be a heritable biomarker of genomic aging,(89) and short telomeres in leukocytes are associated with adverse…”
BackgroundThe 3 I’s of immunity and aging: immunosenescence, inflammaging, and immune resilience
Wrona, M. V., Ghosh, R. B., Coll, K., Chun, C., & Yousefzadeh, M. J. (2024) · Frontiers in Aging · doi:10.3389/fragi.2024.1490302 · Cited by 107
Self-citationFisetin as a senotherapeutic agent: Evidence and perspectives for age-related diseases
Tavenier, J., Nehlin, J. O., Houlind, M. B., Rasmussen, L. J., Tchkonia, T., Kirkland, J. L., Andersen, O., & Rasmussen, L. J. H. (2024) · Mechanisms of Ageing and Development · doi:10.1016/j.mad.2024.111995 · Cited by 103
“A gradual accumulation of senescent cells is observed with age in the skin, bone marrow, and bones of older individuals possibly due, in part, to reduced immune clearance (Farr et al., 2016; Gnani et al., 2019; Waaijer et al., 2012; Yousefzadeh et al., 2021).”
Biological ageing with HIV infection: evaluating the geroscience hypothesis
Montano, M. A., Oursler, K. K., Xu, K., Sun, Y. V., & Marconi, V. C. (2022) · The Lancet Healthy Longevity · doi:10.1016/s2666-7568(21)00278-6 · Cited by 94
Progress on mechanisms of age-related hearing loss
Yang, W., Zhao, X., Chai, R., & Fan, J. (2023) · Frontiers in Neuroscience · doi:10.3389/fnins.2023.1253574 · Cited by 89
IL-33 causes thermogenic failure in aging by expanding dysfunctional adipose ILC2
Goldberg, E. L., Shchukina, I., Youm, Y., Ryu, S., Tsusaka, T., Young, K. C., Camell, C. D., Dlugos, T., Artyomov, M. N., & Dixit, V. D. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.08.004 · Cited by 89
“The potential importance of acquisition of a senescent/SASP phenotype in aging immune cells was recently demonstrated to drive detrimental aging processes in multiple tissues (Yousefzadeh et al., 2021).”
BackgroundVitamin D as a Shield against Aging
Fantini, C., Corinaldesi, C., Lenzi, A., Migliaccio, S., & Crescioli, C. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24054546 · Cited by 100
“In this scenario, age-related biomolecular changes in the immune response and immune cells are acknowledged to play a causal role in driving whole-body aging [16].”
BackgroundSmall circular RNAs as vaccines for cancer immunotherapy
Zhang, Y., Liu, X., Shen, T., Wang, Q., Zhou, S., Yang, S., Liao, S., Su, T., Mei, L., Zhang, B., et al. (2025) · Nature Biomedical Engineering · doi:10.1038/s41551-025-01344-5 · Cited by 94
Klopack, E. T., Crimmins, E. M., Cole, S. W., Seeman, T. E., & Carroll, J. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2202780119 · Cited by 87
“, cancer (15) and cardiovascular disease (16)], weakened response to acute infections, increased risk of pneumonia, reduced efficacy of vaccines (17), and organ system aging (10).”
BackgroundWang, Y., Che, L., Chen, X., He, Z., Song, D., Yuan, Y., & Liu, C. (2023) · Bioactive Materials · doi:10.1016/j.bioactmat.2023.01.009 · Cited by 86
Self-citationKumar, P., Osahon, O. W., & Sekhar, R. V. (2022) · Nutrients · doi:10.3390/nu14051114 · Cited by 83
“Immune health and immunosenescence are reported to contribute to the morbidity and mortality of the elderly [54], and although the effect of GlyNAC on immune health was not evaluated in our study, this should be addressed in future studies.”
BackgroundEmerging insights in senescence: pathways from preclinical models to therapeutic innovations
Mansfield, L., Ramponi, V., Gupta, K., Stevenson, T., Mathew, A. B., Barinda, A. J., Herbstein, F., & Morsli, S. (2024) · npj Aging · doi:10.1038/s41514-024-00181-1 · Cited by 88
Cellular senescence and the host immune system in aging and age-related disorders
Giannoula, Y., Kroemer, G., & Pietrocola, F. (2023) · Biomedical Journal · doi:10.1016/j.bj.2023.02.001 · Cited by 81
“[84] Yousefzadeh MJ, Flores RR, Zhu Y, Schmiechen ZC, Brooks RW, Trussoni CE, et al.”
BackgroundZhang, Q., An, Z.-Y., Jiang, W. G., Jin, W., & He, X. (2023) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2023.115390 · Cited by 79
Age-related bone diseases: Role of inflammaging
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“This gradual deterioration compromises the ability to mount effective immune responses, with aged CD8 + T cells, memory B cells, and senescence-associated macrophages particularly affected (Liu et al., 2023; Ovadya et al., 2018; Yousefzadeh et al., 2021 ).”
BackgroundSharma, R. (2022) · Probiotics and Antimicrobial Proteins · doi:10.1007/s12602-021-09903-3 · Cited by 81
Understanding Immune‐Driven Brain Aging by Human Brain Organoid Microphysiological Analysis Platform
Ao, Z., Song, S., Tian, C., Cai, H., Li, X., Miao, Y., Wu, Z., Krzesniak, J., Ning, B., Gu, M., et al. (2022) · Advanced Science · doi:10.1002/advs.202200475 · Cited by 77
Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging
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RetractedInflammation and gut dysbiosis as drivers of CKD–MBD
Evenepoel, P., Stenvinkel, P., Shanahan, C. M., & Pacifici, R. (2023) · Nature Reviews Nephrology · doi:10.1038/s41581-023-00736-7 · Cited by 82
Inflammation: a matter of immune cell life and death
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Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems
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The stromal microenvironment and ovarian aging: mechanisms and therapeutic opportunities
Shen, L., Liu, J., Luo, A., & Wang, S. (2023) · Journal of Ovarian Research · doi:10.1186/s13048-023-01300-4 · Cited by 79
“Matthew et al. recently demonstrated the key role of the immune system and senescent immune cells in organic damage and organism aging [80].”
BackgroundRosenberg, N., Van Haele, M., Lanton, T., Brashi, N., Bromberg, Z., Adler, H., Giladi, H., Peled, A., Goldenberg, D. S., Axelrod, J. H., et al. (2022) · Journal of Hepatology · doi:10.1016/j.jhep.2022.07.029 · Cited by 72
Hallmarks and Biomarkers of Skin Senescence: An Updated Review of Skin Senotherapeutics
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Replication stress as a driver of cellular senescence and aging
Herr, L. M., Schaffer, E. D., Fuchs, K. F., Datta, A., & Brosh, R. M. (2024) · Communications Biology · doi:10.1038/s42003-024-06263-w · Cited by 72
“Deletion of ERCC1 in hematopoietic cells induces immune cell senescence and premature age-related immune dysfunction in mice 126 .”
BackgroundTherapeutic targeting of senescent cells in the CNS
Riessland, M., Ximerakis, M., Jarjour, A. A., Zhang, B., & Orr, M. E. (2024) · Nature Reviews Drug Discovery · doi:10.1038/s41573-024-01033-z · Cited by 77
“that the benefits were an indirect result of clearance of senescent peripheral cells, which have been shown to impact senescent cell accumulation in the brain 205 .”
Impact of aging on treatment considerations for multiple sclerosis patients
Macaron, G., Larochelle, C., Arbour, N., Galmard, M., Girard, M., Prat, A., & Duquette, P. (2023) · Frontiers in Neurology · doi:10.3389/fneur.2023.1197212 · Cited by 71
Zhao, B., Wu, B. C., Feng, N., Zhang, X., Zhang, X., Wei, Y., & Zhang, W. (2023) · Journal of Hematology & Oncology · doi:10.1186/s13045-023-01426-4 · Cited by 68
“However, senescent cancer cells potentially remain dormant for a long time, evading therapy and posing a risk for tumor relapse [15, 89, 90].”
Background
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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