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 the senescent cell burden passes a threshold, further increases in proapoptotic/pro-inflammatory senescent cells may cause tissue destruction, disease progression, immune dysregulation, and a feed-forward loop of accumulation.
“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]
The Abstract describes senescent cells as pro-inflammatory and tissue damaging and links them to age-related diseases. The “Rapamycin rejuvenates immune cells” section reports that immune-cell senescence impairs immunity and drives senescence in solid organs. Neither passage establishes a burden threshold, describes these cells as proapoptotic, or identifies the claimed feed-forward loop of accumulation; page numbers are not available in our copy. (LLM, conf=0.87)
Experimental — accuracy not yet measuredSenescent cell fate can be triggered by many stressors, including DNA damage, oncogene activation, mitochondrial dysfunction, reactive metabolites, oxygen extremes, proteotoxic stress, extracellular signals, infections, mechanical or shear stress, resistance exercise, and factors secreted by other senescent cells.
“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]
The Abstract (page unavailable) says stress can activate senescence, and the Rapamycin rejuvenates immune cells section specifically links unrepaired endogenous DNA damage to immune-cell senescence. The Cell autonomous mechanism section also suggests aged splenocytes can drive senescence in other tissues. The paper does not establish the rest of the listed triggers, including oxygen extremes, mechanical stress and resistance exercise. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMouse 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 aging.
“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]
The Abstract (page not provided) says that reduced ERCC1–XPF impairs DNA repair, increases senescent cells in mouse tissues, and accelerates ageing. The paper’s passages do not address Terc or BubR1 mutant mice, so it supports only the Ercc1 portion of the claim. (LLM, conf=0.88)
Experimental — accuracy not yet measuredCD3+ T cells from aged mice and ERCC1-deficient mice show increased levels of Ccl2, Tnf, Il1b, Inhba, Spp1, Cdkn2a, and Cdkn1a.
“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]
The Immune cell senescence section reports increased senescence and SASP markers in peripheral CD3+ cells from aged ERCC1-deficient mice, analogous to aged wild-type mice. It identifies p16 (Cdkn2a), p21 (Cdkn1a), Ccl2, Tnf and Il1b among the markers studied, but does not establish that every listed gene increased in blood CD3+ cells in both groups. Searches for Inhba and Spp1 found no supporting passage. (LLM, conf=0.86)
Experimental — accuracy not yet measuredPathological aging of organs increases the level of inflammation and makes repair difficult, ultimately leading to diseases.
“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]
The Tissue damage section (page unavailable) reports increased inflammatory factors and impaired muscle regeneration in mice with an aged immune system. The paper links senescent immune cells to damage and age-related changes in solid organs, but it does not establish the claim’s sequence that pathological organ ageing itself increases inflammation, impedes repair generally, and ultimately causes disease. (LLM, conf=0.86)
Experimental — accuracy not yet measured
In aging tissues, molecular and cellular changes disrupt spatial organization, resulting in uneven functional decline.
“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]
The paper’s conclusions (section “Rapamycin rejuvenates immune cells”; page unavailable) say that senescent immune cells drive age-related changes in solid organs and that parenchymal damage involves cell-autonomous and non-cell-autonomous mechanisms. Our copy does not establish that these changes disrupt spatial organization or result in uneven functional decline. (LLM, conf=0.83)
Experimental — accuracy not yet measuredIn these models, accelerated aging depends, at least partly, on cellular senescence.
“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 functionally weakened immune system in old age does not clear senescent cells, which may account for their persistence in damaged aged muscle; this exacerbates tissue regenerative impairment.
“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]
Clearing senescent cells in peripheral tissues may also positively impact the brain.
“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]
The Abstract discusses senolytics as a way to remove senescent cells, and the ‘Rapamycin rejuvenates immune cells’ section links immune-cell senescence to ageing in solid organs. Neither passage addresses whether clearing senescent cells in peripheral tissues benefits the brain; searches for brain outcomes and peripheral clearance found no such passage. (LLM, conf=0.73)
Experimental — accuracy not yet measuredA senescent immune system contributes to aging phenotypic features in immune cells and in solid, nonlymphoid tissues.
“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]
Deletion of ERCC1 in mouse hematopoietic cells leads to accelerated senescence of the immune system.
“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]
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.
“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]
Transfer of splenocytes from aged wild-type mice or mice lacking ERCC1 into young animals increased the senescence burden in nonlymphoid organs.
“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]
Selective induction of immune cell ageing increases the levels of the ageing markers p16 and p21 in multiple organs, including the brain, highlighting the crucial roles played by the immune system in the process of ageing.
“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]
Immunosenescence is characterized by dysfunctions in monocyte and neutrophil phagocytosis, decreased numbers of naive T cells, increased numbers of memory T cells, and increased SASP secretion by these cells, thereby weakening the immune response to foreign antigens.
“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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Biological aging processes underlying cognitive decline and neurodegenerative disease
Gonzales, M. M., Garbarino, V. R., Pollet, E., Palavicini, J. P., Kellogg, D. L., Kraig, E., & Orr, M. E. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158453 · Cited by 394 · see citing works
“With advancing age, senescent cells increase in tissues throughout the body, including the brain (95, 96).”
BackgroundGuidelines for minimal information on cellular senescence experimentation in vivo
Ogrodnik, M., Carlos Acosta, J., Adams, P. D., d’Adda di Fagagna, F., Baker, D. J., Bishop, C. L., Chandra, T., Collado, M., Gil, J., Gorgoulis, V., et al. (2024) · Cell · doi:10.1016/j.cell.2024.05.059 · Cited by 376 · see citing works
Self-citationRedox regulation: mechanisms, biology and therapeutic targets in diseases
Li, B., Ming, H., Qin, S., Nice, E. C., Dong, J., Du, Z., & Huang, C. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-02095-6 · Cited by 364 · see citing works
“410,411 414 In cases where the immune system fails to eliminate senescent cells, chronic in fl ammation can contribute to a range of age-related diseases, including but not limited to cancer, 415,416 through the persistent presence of senescence-associated secretory phenotype (SASP).”
Senolytic therapy in mild Alzheimer's disease: a phase 1 feasibility trial
Gonzales, M. M., Garbarino, V. R., Kautz, T. F., Palavicini, J. P., Lopez-Cruzan, M., Dehkordi, S. K., Mathews, J. J., Zare, H., Xu, P., Zhang, B., et al. (2023) · Nature Medicine · doi:10.1038/s41591-023-02543-w · Cited by 310 · see citing works
Interconnections between Inflammageing and Immunosenescence during Ageing
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“This has been most clearly demonstrated in a mouse model bearing immune-specific mutation of the DNA repair factor ercc1, wherein the damage-driven accelerated ageing of immune cells led both to the premature accumulation of senescent cells in multiple organs and reduced lifespan [39].”
BackgroundImmune Senescence, Immunosenescence and Aging
Lee, K.-A., Flores, R. R., Jang, I. H., Saathoff, A., & Robbins, P. D. (2022) · Frontiers in Aging · doi:10.3389/fragi.2022.900028 · Cited by 283 · see citing works
Self-citationHallmarks of cardiovascular ageing
Abdellatif, M., Rainer, P. P., Sedej, S., & Kroemer, G. (2023) · Nature Reviews Cardiology · doi:10.1038/s41569-023-00881-3 · Cited by 285 · see citing works
Human trials exploring anti-aging medicines
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Cellular senescence at the crossroads of inflammation and Alzheimer's disease
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Targeting immune dysfunction in aging
Borgoni, S., Kudryashova, K. S., Burka, K., & de Magalhães, J. P. (2021) · Ageing Research Reviews · doi:10.1016/j.arr.2021.101410 · Cited by 227 · see citing works
“This resulted not only in impaired immune function but also in systemic premature aging, which could be attenuated by young immune cells transplantation (Yousefzadeh et al., 2021).”
Inflammaging: Implications in Sarcopenia
Antuña, E., Cachán-Vega, C., Bermejo-Millo, J. C., Potes, Y., Caballero, B., Vega‐Naredo, I., Coto‐Montes, A. M., & García-González, C. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms232315039 · Cited by 223 · see citing works
Inflammation and DNA damage: cause, effect or both
Pezone, A., Olivieri, F., Napoli, M. V., Procopio, A., Avvedimento, E. V., & Gabrielli, A. (2023) · Nature Reviews Rheumatology · doi:10.1038/s41584-022-00905-1 · Cited by 212 · see citing works
Immunosenescence, aging and successful aging
Wang, Y., Chen, D., Han, Y., Gu, Z., & Sun, C. C. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.942796 · Cited by 215 · see citing works
Self-citationAge-associated remodeling of T cell immunity and metabolism
Han, S., Georgiev, P., Ringel, A. E., Sharpe, A. H., & Haigis, M. C. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.11.005 · Cited by 193 · see citing works
Connecting aging biology and inflammation in the omics era
Walker, K. A., Basisty, N., Wilson, D. M., & Ferrucci, L. (2022) · Journal of Clinical Investigation · doi:10.1172/jci158448 · Cited by 189 · see citing works
“Yousefzadeh and colleagues recently suggested a causative link between a senescent immune system and nonlymphoid tissue aging (26).”
BackgroundAging and InflammationPreprint
Singh, A., Schurman, S. H., Bektas, A., Kaileh, M., Roy, R., Wilson, D. M., Sen, R., & Ferrucci, L. (2023) · Cold Spring Harbor Perspectives in Medicine · doi:10.1101/cshperspect.a041197 · Cited by 194 · see citing works
Apolipoprotein E induces pathogenic senescent-like myeloid cells in prostate cancer
Bancaro, N., Calì, B., Troiani, M., Elia, A. R., Arzola, R. A., Attanasio, G., Lai, P., Crespo, M., Gürel, B., Pereira, R., et al. (2023) · Cancer Cell · doi:10.1016/j.ccell.2023.02.004 · Cited by 185 · see citing works
Stress-induced biological aging: A review and guide for research priorities
Polsky, L. R., Rentscher, K. E., & Carroll, J. (2022) · Brain Behavior and Immunity · doi:10.1016/j.bbi.2022.05.016 · Cited by 181 · see citing works
Mitochondrial dysfunction in the regulation of aging and aging-related diseases
Zhang, X., Gao, Y., Zhang, S., Wang, Y., Pei, X., Chen, Y., Zhang, J., Zhang, Y., Du, Y., Hao, S., et al. (2025) · Cell Communication and Signaling · doi:10.1186/s12964-025-02308-7 · Cited by 175 · see citing works
“Organismal aging is accompanied by a series of age-related changes, including the loss of bone and muscle strength, alterations in hormone levels due to endocrine dysfunction, changes in blood pressure and lipids associated with the circulatory system, and reduced immune resistance [3–6].”
Self-citationAntiageing strategy for neurodegenerative diseases: from mechanisms to clinical advances
Jiang, Q., Liu, J., Huang, S., Wang, X.-Y., Chen, X., Liu, G.-H., Ye, K., Song, W., Masters, C. L., Wang, J., et al. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02145-7 · Cited by 165 · see citing works
“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.”
Self-citationSpatial transcriptomic landscape unveils immunoglobin-associated senescence as a hallmark of aging
Ma, S., Ji, Z., Zhang, B., Geng, L., Cai, Y., Nie, C., Li, J., Zuo, Y., Sun, Y., Xu, G., et al. (2024) · Cell · doi:10.1016/j.cell.2024.10.019 · Cited by 162 · see citing works
Metabolic programs tailor T cell immunity in viral infection, cancer, and aging
Møller, S. H., Hsueh, P., Yu, Y.-R., Zhang, L., & Ho, P. (2022) · Cell Metabolism · doi:10.1016/j.cmet.2022.02.003 · Cited by 148 · see citing works
Aging and chronic inflammation: highlights from a multidisciplinary workshop
Saavedra, D., Añé-Kourí, A. L., Barzilai, N., Caruso, C., Cho, K., Fontana, L., Franceschi, C., Frasca, D., Ledón, N., Niedernhofer, L. J., et al. (2023) · Immunity & Ageing · doi:10.1186/s12979-023-00352-w · Cited by 151 · see citing works
“One intriguing model even stated that aged immune cells are actually responsible for organismal aging [9].”
BackgroundSelf-citationImmunosenescence: signaling pathways, diseases and therapeutic targets
Fu, Y., Wang, B., Alu, A., Hong, W., Hong, L., He, X., Shi, H., Cheng, P., & Yang, X. (2025) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-025-02371-z · Cited by 157 · see citing works
“443 Furthermore, systemic AAV vector-mediated LAV-BPIFB4 gene transfer has been shown to redirect circulating SnCs to the spleen and increase the activity of immune cells within the spleen, thereby effectively eliminating senescent immune cells.”
SGLT2 inhibition eliminates senescent cells and alleviates pathological aging
Katsuumi, G., Shimizu, I., Suda, M., Yoshida, Y., Furihata, T., Joki, Y., Hsiao, C.-L., Liang, J., Fujiki, S., Abe, M., et al. (2024) · Nature Aging · doi:10.1038/s43587-024-00642-y · Cited by 145 · see citing works
“…aging and pathological conditions, this removal mechanism becomes dysfunctional (anergy) and senescent cells continue to accumulate in tissues; the increased secretion of SASP factors triggers chronic inflammation, which is thought to be involved in the development of aging-related diseases 23,24 .”
Hematopoietic aging promotes cancer by fueling IL-1⍺–driven emergency myelopoiesis
Park, M. D., Bérichel, J. L., Hamon, P., Wilk, C. M., Belabed, M., Yatim, N., Saffon, A., Boumelha, J., Falcomatà, C., Tepper, A., et al. (2024) · Science · doi:10.1126/science.adn0327 · Cited by 145 · see citing works
“Furthermore, we find that our findings are consistent with recent observations that hematopoietic aging drives systemic increases in immunosenescence, which promotes lung cancer (126–128).”
ResultMi, B.-B., Xiong, Y., Knoedler, S. A., Alfertshofer, M. G., Panayi, A. C., Wang, H., Lin, S.-E., Li, G., & Liu, G. (2024) · Bone Research · doi:10.1038/s41413-024-00346-4 · Cited by 138 · see citing works
NAD metabolism: Role in senescence regulation and aging
Chini, C. C. S., Cordeiro, H. S., Tran, N. L. K., & Chini, E. N. (2023) · Aging Cell · doi:10.1111/acel.13920 · Cited by 138 · see citing works
“Interestingly, a senescent immune system was shown to drive systemic aging and senescence in solid organs (Yousefzadeh et al., 2021).”
BackgroundSenNet Consortium, Writing Group, Lee, P. J., Benz, C. C., Blood, P., Börner, K., Campisi, J., Chen, F., Daldrup-Link, H., De Jager, P., et al. (2022) · Nature Aging · doi:10.1038/s43587-022-00326-5 · Cited by 122 · see citing works
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“Studies have shown that senescence and aging are systematically propagated 64,65 .”
Game changers in science and technology - now and beyond
Betz, U. A. K., Arora, L., Assal, R. A., de Azevedo, H. F. Z., Baldwin, J., Becker, M. S., Bostock, S., Cheng, V. W. T., Egle, T., Ferrari, N., et al. (2023) · Technological Forecasting and Social Change · doi:10.1016/j.techfore.2023.122588 · Cited by 146 · see citing works
Role of Cellular Senescence in Type II Diabetes
Narasimhan, A., Flores, R. R., Robbins, P. D., & Niedernhofer, L. J. (2021) · Endocrinology · doi:10.1210/endocr/bqab136 · Cited by 133 · see citing works
Self-citationUpregulation of PD-L1 in Senescence and Aging
Onorati, A., Havas, A. P., Lin, B., Rajagopal, J., Sen, P., Adams, P. D., & Dou, Z. (2022) · Molecular and Cellular Biology · doi:10.1128/mcb.00171-22 · Cited by 131 · see citing works
Role of hypoxia in cellular senescence
Gao, H., Nepovimová, E., Heger, Z., Valko, M., Wu, Q., Kuča, K., & Adam, V. (2023) · Pharmacological Research · doi:10.1016/j.phrs.2023.106841 · Cited by 130 · see citing works
Lipids as Regulators of Cellular Senescence
Hamsanathan, S., & Gurkar, A. U. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.796850 · Cited by 120 · see citing works
“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 121 · see citing works
Hematopoietic stem cells through the ages: A lifetime of adaptation to organismal demands
Kasbekar, M., Mitchell, C. A., Proven, M. A., & Passegue, E. A. (2023) · Cell stem cell · doi:10.1016/j.stem.2023.09.013 · Cited by 122 · see citing works
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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 120 · see citing works
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 · see citing works
“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 · see citing works
“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 118 · see citing works
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 115 · see citing works
“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 112 · see citing works
The translational challenges of precision oncology
Pich, O., Bailey, C., Watkins, T. B. K., Zaccaria, S., Jamal‐Hanjani, M., & Swanton, C. (2022) · Cancer Cell · doi:10.1016/j.ccell.2022.04.002 · Cited by 111 · see citing works
Noncancerous disease-targeting AIEgens
Duo, Y., Luo, G., Zhang, W., Wang, R., Xiao, G. G., Li, Z., Li, X., Chen, M., Yoon, J., & Tang, B. Z. (2023) · Chemical Society Reviews · doi:10.1039/d2cs00610c · Cited by 106 · see citing works
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 112 · see citing works
Clonal hematopoiesis, somatic mosaicism, and age-associated disease
Evans, M. A., & Walsh, K. (2022) · Physiological Reviews · doi:10.1152/physrev.00004.2022 · Cited by 105 · see citing works
NAD+ rescues aging-induced blood-brain barrier damage via the CX43-PARP1 axis
Zhan, R., Meng, X., Tian, D., Xu, J., Cui, H., Yang, J., Xu, Y., Shi, M., Xue, J., Yu, W., et al. (2023) · Neuron · doi:10.1016/j.neuron.2023.08.010 · Cited by 109 · see citing works
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 · see citing works
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 102 · see citing works
“, 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., Meisel, R., Biga, P. R., Walters, J., Mank, J., Larschan, E. N., Wilkinson, G., Valenzuela, N., Conard, A., de Magalhães, J. D., et al. (2022) · Aging Cell · doi:10.1111/acel.13542 · Cited by 78 · see citing works
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 98 · see citing works
“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 95 · see citing works
Telomeres, aging, and cancer: the big picture
Lansdorp, P. M. (2022) · Blood · doi:10.1182/blood.2021014299 · Cited by 95 · see citing works
“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 102 · see citing works
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 97 · see citing works
“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 89 · see citing works
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 · see citing works
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 87 · see citing works
“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 96 · see citing works
“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 90 · see citing works
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 85 · see citing works
“, 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 · see citing works
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“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 91 · see citing works
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 · see citing works
“[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 · see citing works
Age-related bone diseases: Role of inflammaging
Bi, J., Zhang, C., Lu, C., Mo, C., Zeng, J., Yao, M., Jia, B., Liu, Z., Yuan, P., & Xu, S. (2024) · Journal of Autoimmunity · doi:10.1016/j.jaut.2024.103169 · Cited by 83 · see citing works
Jang, D. S., Shin, J., Shim, E., Ohtani, N., & Jeon, O. H. (2024) · Aging Cell · doi:10.1111/acel.14315 · Cited by 84 · see citing works
“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 80 · see citing works
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 · see citing works
Senescent immune cells accumulation promotes brown adipose tissue dysfunction during aging
Xu, F., Wang, L., Zhou, R., Zhou, R., Chen, L., Peng, H., Huang, Y., Guo, Q., Luo, X., & Zhou, H. (2023) · Nature Communications · doi:10.1038/s41467-023-38842-6 · Cited by 76 · see citing works
Inflammation 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 78 · see citing works
Inflammation: a matter of immune cell life and death
Bender, E. C., Tareq, H. S., & Suggs, L. J. (2025) · npj Biomedical Innovations. · doi:10.1038/s44385-025-00010-4 · Cited by 80 · see citing works
Understanding Long COVID; Mitochondrial Health and Adaptation—Old Pathways, New Problems
Nunn, A. V. W., Guy, G. W., Brysch, W., & Bell, J. D. (2022) · Biomedicines · doi:10.3390/biomedicines10123113 · Cited by 73 · see citing works
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 74 · see citing works
“Matthew et al. recently demonstrated the key role of the immune system and senescent immune cells in organic damage and organism aging [80].”
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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 68 · see citing works
“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 74 · see citing works
“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 67 · see citing works
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 65 · see citing works
“However, senescent cancer cells potentially remain dormant for a long time, evading therapy and posing a risk for tumor relapse [15, 89, 90].”
BackgroundImmunosenescence in atherosclerosis: A role for chronic viral infections
Talepoor, A. G., & Doroudchi, M. (2022) · Frontiers in Immunology · doi:10.3389/fimmu.2022.945016 · Cited by 64 · see citing works
- 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
- Health Sciences › Medicine › Physiology › 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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