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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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“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]
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“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]
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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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CXCR4-targeted dual softener for inducing senescence therapy in hepatic fibrosis
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González‐Gualda, E., Ou, H., Macías, D., & Muñoz‐Espín, D. (2021) · Elsevier eBooks · doi:10.1016/b978-0-12-822514-1.00016-x · Cited by 1
Ellison, G. M. (2022) · The Journal of Cardiovascular Aging · doi:10.20517/jca.2022.05 · Cited by 1
Pang, Y., Zhu, S., Xu, J., Su, C., Wu, B. Y., Zhang, C., & Gao, J. (2023) · Advanced Biology · doi:10.1002/adbi.202200321 · Cited by 1
Du, Y., Fang, J., Liang, M., Xia, Z., Long, J., Peng, T., & Lin, X. (2023) · CyTA - Journal of Food · doi:10.1080/19476337.2023.2213747 · Cited by 1
“Aging reduces the proliferative activity of splenic lymphocytes, which reflects the regenerative and rejuvenated function of immune cells (Yousefzadeh et al., 2021).”
BackgroundThe Therapeutic Values of IL-7/IL-7R and the Recombinant Derivatives in Glioma: A Narrative Review
Hesari, M., Attar, Z., Soltani-Shirazi, S., Keshavarzian, O., Taheri, R., Tabrizi, R., & Fouladseresht, H. (2023) · Journal of Interferon & Cytokine Research · doi:10.1089/jir.2023.0050 · Cited by 1
The accelerated organ senescence and proteotoxicity in thyrotoxicosis mice
Qin, F., Xia, W., Feng, Z., Tan, Y., Zhang, Y., Liu, D., & Zhang, G. (2023) · Journal of Cellular Physiology · doi:10.1002/jcp.31108 · Cited by 1
“Whereas lipotoxicity and immuno-senescence also led to senescence and age ‐ related degradation in solid organs (Kovilakath & Cowart, 2020; Vegiopoulos et al., 2017; Yousefzadeh et al., 2021).”
BackgroundApplication of proteomics in brain's aging research
Tan, Y., Luo, F., Wei, Y., & Liu, P. (2024) · Human Brain · doi:10.37819/hb.3.1778
Partial Cell Reprogramming as a Way to Revitalize Living Systems
Shorokhova, M. (2024) · Cell and Tissue Biology · doi:10.1134/s1990519x23700104 · Cited by 1
“Encouraging results have been achieved in the study of blood cell transplantation (Yousefzadeh et al., 2021).”
The immunoreactive signature of monocyte-derived dendritic cells from patients with Down syndrome
Nakashima, K., Imai, T., Shiraishi, A., Unose, R., Goto, H., Nagatomo, Y., Kojima‐Ishii, K., Mushimoto, Y., Nishiyama, K., Yamamura, K., et al. (2024) · Clinical & Experimental Immunology · doi:10.1093/cei/uxae048 · Cited by 1
Cherepanova, A. V., Bravy, Y. R., Karabelsky, A. V., Kotova, M. M., Shcherbakova, A. S., Apukhtin, K. V., Nikitin, V. S., Bobrov, М. Y., & Kalueff, A. V. (2024) · Journal of Evolutionary Biochemistry and Physiology · doi:10.1134/s0022093024040185 · Cited by 2
Allostatic load in rat model: An efficient tool for evaluating and understanding aging
Chen, D., Deng, X., Jia, Y., Sun, X., Duan, X., Yan, S., & Huang, J. (2024) · Geriatrics and gerontology international/Geriatrics & gerontology international · doi:10.1111/ggi.14950 · Cited by 1
“3 Mitochondrial function, 4 chronic in fl ammation, and the immune system 5 are also generally agreed to play an important role in aging.”
Oral administration of Lactobacillus kefiri Fanghua reduces immune senescence and aging phenotypes
Qiao, Z., Zhang, Y., Liu, H., Zou, H., Xie, Q., Liu, J., Zhang, H., Liu, T., Liu, Z., Qi, W., et al. (2024) · Food Science and Human Wellness · doi:10.26599/fshw.2024.9250286 · Cited by 1
Wilson, S., Mitin, N., Miller, V. L. A., Smitherman, A. B., & Carden, M. A. (2024) · Aging · doi:10.18632/aging.206152 · Cited by 1
Elucidating Sex-Specific Immune Profiles in a Breast Cancer Model
Hargrove-Wiley, E., Obodo, D., Bindeman, W. E., & Fingleton, B. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252313113 · Cited by 1
Mozas, P., Ammar, R., Chartier, L., Nastoupil, L. J., Bachy, E., Bezsera, S. M., Barnes, J. A., Bijou, F. D., Goy, A. H., Zerazhi, H., et al. (2025) · British Journal of Haematology · doi:10.1111/bjh.20038 · Cited by 1
“31 In this regard, we evaluated the prognostic association of the LMR with PFS according to age and found that it was significant in patients younger but not older than 60 years (Figure S9).”
Foffa, I., Esposito, A., Simonini, L., Berti, S. L., & Vecoli, C. (2025) · Journal of Cardiovascular Development and Disease · doi:10.3390/jcdd12040135 · Cited by 1
“This accumulation contributes to chronic inflammation, organ dysfunction, and disease progression [56–58].”
Wu, H., Cai, Z., Liu, W., Wang, Z., Qiu, B., Liu, W., & Zhuang, W.-H. (2025) · Cancer Medicine · doi:10.1002/cam4.70999 · Cited by 1
“First, with age, the function of the human immune system gradually declines, and immune surveillance capacity is weakened, making the elderly more susceptible to malignant tumours, including MM [50].”
Old, but gold? Not the case for the immune system when promoting systemic ageing
Bollini, S., & Guzik, T. J. (2021) · Cardiovascular Research · doi:10.1093/cvr/cvab366 · Cited by 1
Introduction: Trends, Puzzles, and Hopes for the Future of Healthcare
Ehsani, S., Glauner, P., Plugmann, P., & Thieringer, F. M. (2022) · Future of business and finance · doi:10.1007/978-3-030-99838-7_1 · Cited by 1
Zhang, X., Tyrrell, D. J., Alliston, T. N., Schilling, B., Yousefzadeh, M. J., & Schafer, M. J. (2023) · The Journals of Gerontology Series A · doi:10.1093/gerona/glad120 · Cited by 1
Self-citationNIH SenNet Consortium: Mapping Senescent Cells in the Human Body to Understand Health and DiseasePreprint
Lee, P., Blood, P. D., Börner, K., Campisi, J., Chen, F., Daldrup-Link, H. E., Jager, P. L. D., Ding, L., Duncan, F. E., Eickelberg, O., et al. (2022) · Preprints.org · doi:10.20944/preprints202207.0160.v1 · Cited by 2
Self-citationExcessive apoptosis of naïve T cells resulting hyperactivation as a cause of mammalian agingPreprint
Wang, L., Zhang, X., Zhang, H., Lu, K., Li, M., Li, X., Ou, Y., Zhao, X., Wu, X., Wu, X., et al. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.02.24.529806 · Cited by 1
Mitin, N., Entwistle, A., Knecht, A. K., Strum, S. L., Ross, A., Nyrop, K. A., Muss, H. B., Tsygankov, D., & Raffaele, J. M. (2023) · medRxiv · doi:10.1101/2023.08.25.23294589 · Cited by 1
Wang, L., Deng, Z., Li, Y., Wu, Y., Yao, R.-Q., Cao, Y., Wang, M., Zhou, F., Zhu, H., & Kang, H. (2023) · Research Square · doi:10.21203/rs.3.rs-3318999/v1 · Cited by 1
The Immune Landscape of Murine Skeletal Muscle Regeneration and AgingPreprint
Sousa, N. S., Bica, M., Brás, M. F., Antunes, I. B., Encarnação, I. A., Costa, T., Martins, I. B., Barbosa‐Morais, N. L., Sousa‐Victor, P., & Neves, J. (2023) · SSRN Electronic Journal · doi:10.2139/ssrn.4663954 · Cited by 1
Haem toxicity in the aged spleen impairs T-cell immunity through iron deprivationPreprint
Ezuz, D., Ombashe, H., watted, L., Atar, O., & Ron‐Harel, N. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.05.05.592551 · Cited by 1
Niu, Y., Wu, D., Zhang, S., Zheng, H., Wu, X., Chen, J., Zhang, Y., Zhang, T., He, W., & Chen, L. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.10.28.620557 · Cited by 1
“Meanwhile, genes associated with immune stress responses are involved in managing cellular damage and inflammation 37 .”
BackgroundBMAL1 and YAP cooperate to hijack enhancers and promote inflammation in the aged epidermisPreprint
Bonjoch, J., Solá, P., Reina, Ó., Mortimer, T., Miroshnikova, Y. A., Wickström, S. A., Attolini, C. S., Álvarez, L., Benitah, S. A., & Solanas, G. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.04.22.649967 · Cited by 1
Wang, Y., Wang, X., Pan, Q., Kou, H., Zhang, C., She, S., Yin, J., Liao, X., Wang, W., Zhang, L., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.08.11.669448 · Cited by 1
Self-citationMulti-tissue spatial transcriptomics reveals biological age hotspots in mouse and human agingPreprint
Vicente-Alvarez, V., de Magalhaes, C. G., Glubokov, D., Molière, A., Tyshkovskiy, A., & Gladyshev, V. N. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.11.23.689860 · Cited by 1
“These regions were enriched in innate immune signatures, including neutrophil activation and antimicrobial responses, consistent with chronic inflammation as a pattern of aging 30,31 .”
Multiple thymi and no thymic involution in naked mole rats?
Pawelec, G. (2021) · Immunity & Ageing · doi:10.1186/s12979-021-00253-w
“Nonetheless, it provides an intriguing model for interactions of immune ageing with organismal ageing, which is likely to be of great importance, at least in mice [1].”
Lewik, G., & Issa, F. (2021) · Transplantation · doi:10.1097/tp.0000000000003979
Wang, Y., Che, L., Chen, X., He, Z., Song, D., Yuan, Y., & Liu, C. (2022) · Research Square · doi:10.21203/rs.3.rs-1444778/v1
Self-citationGenetic and epigenetic processes linked to cancer
Anisman, H., & Kusnecov, A. W. (2022) · Elsevier eBooks · doi:10.1016/b978-0-323-91904-3.00013-6
Wu, Y., Zhu, B., Zhang, R., Goplen, N. P., Gao, X., Narasimhan, H., Shi, A., Chen, Y. M., Li, Y., Dong, H., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.06.04.494822
Tong, R., Li, R., Zhao, Y., Luo, L., Zhong, J., Li, Z., Lin, W., Chen, Y., Shi, J., Gao, Y., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.11.498621 · Cited by 1
NIH SenNet Consortium: Mapping Senescent Cells in the Human Body to Understand Health and DiseasePreprint
Lee, P. J., Blood, P. D., Börner, K., Campisi, J., Chen, F., Daldrup-Link, H. E., Jager, P. L. D., Ding, L., Duncan, F. E., Eickelberg, O., et al. (2022) · Preprints.org · doi:10.20944/preprints202207.0160.v2
Self-citationResearch progress and prospect of aging mechanism and anti-aging
Tian, H. (2022) · International Conference on Biomedical and Intelligent Systems (IC-BIS) · doi:10.1117/12.2660284
“Various factors such as biological metabolic disorders, ingested food and drugs, and ultraviolet rays may cause large amounts of free radicals in the body [3].”
BackgroundVACCINATION EFFECTIVENESS IN THE POPULATION OF THE ELDERLY PEOPLE AND THE AGING OF THE IMMUNE SYSTEM
Zuziak, P., Przeorski, K., Dereziński, M. M., Mendowski, M., & Kliniec, K. (2022) · Postepy Biologii Komorki · doi:10.59674/pbk3
Age-Related Skin Inflammation in A 2,4-Dintrochlorobenzene-Induced Atopic Dermatitis Mouse Model.
Cho, K., Kwon, J. Y., Kim, H. J., & Woo, S. (2023) · PubMed Central · doi:10.22074/cellj.2023.2001403.1301
Wu, Y., Liu, X., Wang, X., Yu, L., Yan, H., Xie, Y., Pu, Q., Cai, X., Kong, Y., & Yang, Z. (2023) · OncoTargets and Therapy · doi:10.2147/ott.s426195
“35,39 According to statistics, the median age of HCC patients was 55 years in China, 40 which was consistent with the age of our enrolled patients.”
ResultInteraktionen Inaktivität, Krankheitsentwicklungen und Alterungsprozess
Laube, W. (2023) · Springer eBooks · doi:10.1007/978-3-662-67753-7_4
Liu, C., Lin, L., Wang, X., Qin, S., Wan, Q., Chen, H., Wang, Q., Jiang, H., Wang, Y., Wang, T., et al. (2023) · Sleep Epidemiology · doi:10.1016/j.sleepe.2023.100069
Self-citationChanges in Immune Cell Subtypes During Ageingchanges in Immune Cell Subtypes During AgeingPreprint
Thin, K. A., Cross, A. L., Angsuwatcharakon, P., Mutirangura, A., Puttipanyalears, C., & Edwards, S. (2023) · SSRN Electronic Journal · doi:10.2139/ssrn.4628537
Reversing the Aged Immune System with Stem Cells
Sherman, L. S., Petryna, A., Munoz, S. M., Gubenko, E. E., & Rameshwar, P. (2023) · Springer eBooks · doi:10.1007/978-981-99-0846-2_27-1
Immune Cell Senescence and body Aging
Yoshimura, A. (2023) · Personalized Medicine Universe · doi:10.46459/pmu.2023006
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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