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Age-related mechanisms in the context of rheumatic disease

Nature Reviews Rheumatology volume 18, pages 694–710 (2022)Cite this article

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Abstract

Ageing is characterized by a progressive loss of cellular function that leads to a decline in tissue homeostasis, increased vulnerability and adverse health outcomes. Important advances in ageing research have now identified a set of nine candidate hallmarks that are generally considered to contribute to the ageing process and that together determine the ageing phenotype, which is the clinical manifestation of age-related dysfunction in chronic diseases. Although most rheumatic diseases are not yet considered to be age related, available evidence increasingly emphasizes the prevalence of ageing hallmarks in these chronic diseases. On the basis of the current evidence relating to the molecular and cellular ageing pathways involved in rheumatic diseases, we propose that these diseases share a number of features that are observed in ageing, and that they can therefore be considered to be diseases of premature or accelerated ageing. Although more data are needed to clarify whether accelerated ageing drives the development of rheumatic diseases or whether it results from the chronic inflammatory environment, central components of age-related pathways are currently being targeted in clinical trials and may provide a new avenue of therapeutic intervention for patients with rheumatic diseases.

Key points

  • Rheumatic disease prevalence is increased as a consequence of population ageing.

  • Rheumatic diseases share common ageing characteristics and molecular pathways, which enables their classification as premature-ageing or accelerated-ageing diseases.

  • Ageing and inflammation form a self-perpetuating, vicious cycle to advance rheumatic disease in patients and accelerate ageing phenotypes.

  • Anti-ageing drugs may have therapeutic potential for the management and treatment of patients with rheumatic disease.

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Fig. 1: Classic hallmarks of ageing.
Fig. 2: Vicious cycle of premature ageing and inflammation in rheumatic diseases.

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References

  1. Partridge, L., Deelen, J. & Slagboom, P. E. Facing up to the global challenges of ageing. Nature 561, 45–56 (2018).

    Article  CAS  PubMed  Google Scholar 

  2. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. The hallmarks of aging. Cell 153, 1194–1217 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. GBD 2017 DALYs and HALE Collaborators. Global, regional, and national disability-adjusted life-years (DALYs) for 359 diseases and injuries and healthy life expectancy (HALE) for 195 countries and territories, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet 392, 1859–1922 (2018).

    Article  PubMed Central  Google Scholar 

  4. Shiels, P. G. et al. Manipulating the exposome to enable better ageing. Biochem. J. 478, 2889–2898 (2021).

    Article  CAS  PubMed  Google Scholar 

  5. Van Houtven, G., et al Costs of illness among older adults: an analysis of six major health conditions with significant environmental risk factors. RTI Press Publication No. RR-0002-0809. (RTI Press, 2008).

  6. Atella, V. et al. Trends in age-related disease burden and healthcare utilization. Aging Cell 18, e12861 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. Christensen, K., Doblhammer, G., Rau, R. & Vaupel, J. W. Ageing populations: the challenges ahead. Lancet 374, 1196–1208 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  8. Frenk, S. & Houseley, J. Can aging be beneficial? Aging 9, 2016–2017 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  9. Ferrucci, L., Levine, M. E., Kuo, P. L. & Simonsick, E. M. Time and the metrics of aging. Circ. Res. 123, 740–744 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Verstappen, S. M. M. & Carmona, L. Epidemiology of rheumatic and musculoskeletal diseases. Best. Pract. Res. Clin. Rheumatol. 32, 167–168 (2018).

    Article  PubMed  Google Scholar 

  11. Sangha, O. Epidemiology of rheumatic diseases. Rheumatology 39 (Suppl. 2), 3–12 (2000).

    Article  PubMed  Google Scholar 

  12. Branco, J. C. et al. Prevalence of rheumatic and musculoskeletal diseases and their impact on health-related quality of life, physical function and mental health in Portugal: results from EpiReumaPt — a national health survey. RMD Open 2, e000166 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  13. Gabriel, S. E. & Michaud, K. Epidemiological studies in incidence, prevalence, mortality, and comorbidity of the rheumatic diseases. Arthritis Res. Ther. 11, 229 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  14. Loeser, R. F., Collins, J. A. & Diekman, B. O. Ageing and the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 12, 412–420 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Boots, A. M. et al. The influence of ageing on the development and management of rheumatoid arthritis. Nat. Rev. Rheumatol. 9, 604–613 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Mahmoudi, S. & Brunet, A. Aging and reprogramming: a two-way street. Curr. Opin. Cell Biol. 24, 744–756 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Melzer, D., Pilling, L. C. & Ferrucci, L. The genetics of human ageing. Nat. Rev. Genet. 21, 88–101 (2020).

    Article  CAS  PubMed  Google Scholar 

  18. Sebastiani, P. & Perls, T. T. The genetics of extreme longevity: lessons from the New England centenarian study. Front. Genet. 3, 277 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Dorman, J. B., Albinder, B., Shroyer, T. & Kenyon, C. The age-1 and daf-2 genes function in a common pathway to control the lifespan of Caenorhabditis elegans. Genetics 141, 1399–1406 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Friedman, D. B. & Johnson, T. E. A mutation in the age-1 gene in Caenorhabditis elegans lengthens life and reduces hermaphrodite fertility. Genetics 118, 75–86 (1988).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Cagan, A. et al. Somatic mutation rates scale with lifespan across mammals. Nature 604, 517–524 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Amoretti, M. et al. Production and detection of cold antihydrogen atoms. Nature 419, 456–459 (2002).

    Article  CAS  PubMed  Google Scholar 

  23. Henis-Korenblit, S. et al. Insulin/IGF-1 signaling mutants reprogram ER stress response regulators to promote longevity. Proc. Natl Acad. Sci. USA 107, 9730–9735 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Martin, G. M. & Oshima, J. Lessons from human progeroid syndromes. Nature 408, 263–266 (2000).

    Article  CAS  PubMed  Google Scholar 

  25. Kazak, L., Reyes, A. & Holt, I. J. Minimizing the damage: repair pathways keep mitochondrial DNA intact. Nat. Rev. Mol. Cell Biol. 13, 659–671 (2012).

    Article  CAS  PubMed  Google Scholar 

  26. Blackburn, E. H., Greider, C. W. & Szostak, J. W. Telomeres and telomerase: the path from maize, Tetrahymena and yeast to human cancer and aging. Nat. Med. 12, 1133–1138 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Chalan, P., van den Berg, A., Kroesen, B. J., Brouwer, L. & Boots, A. Rheumatoid arthritis, immunosenescence and the hallmarks of aging. Curr. Aging Sci. 8, 131–146 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Souliotis, V. L. et al. DNA damage response and oxidative stress in systemic autoimmunity. Int. J. Mol. Sci. 21, 55 (2019).

    Article  PubMed Central  Google Scholar 

  29. Souliotis, V. L., Vlachogiannis, N. I., Pappa, M., Argyriou, A. & Sfikakis, P. P. DNA damage accumulation, defective chromatin organization and deficient DNA repair capacity in patients with rheumatoid arthritis. Clin. Immunol. 203, 28–36 (2019).

    Article  CAS  PubMed  Google Scholar 

  30. Shao, L. et al. Deficiency of the DNA repair enzyme ATM in rheumatoid arthritis. J. Exp. Med. 206, 1435–1449 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Micheli, C. et al. UCTD and SLE patients show increased levels of oxidative and DNA damage together with an altered kinetics of DSB repair. Mutagenesis 36, 429–436 (2021).

    Article  CAS  PubMed  Google Scholar 

  32. Mireles-Canales, M. P., Gonzalez-Chavez, S. A., Quinonez-Flores, C. M., Leon-Lopez, E. A. & Pacheco-Tena, C. DNA damage and deficiencies in the mechanisms of its repair: implications in the pathogenesis of systemic lupus erythematosus. J. Immunol. Res. 2018, 8214379 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  33. Noble, P. W. et al. DNA-damaging autoantibodies and cancer: the lupus butterfly theory. Nat. Rev. Rheumatol. 12, 429–434 (2016).

    Article  CAS  PubMed  Google Scholar 

  34. McConnell, J. R., Crockard, A. D., Cairns, A. P. & Bell, A. L. Neutrophils from systemic lupus erythematosus patients demonstrate increased nuclear DNA damage. Clin. Exp. Rheumatol. 20, 653–660 (2002).

    CAS  PubMed  Google Scholar 

  35. Vlachogiannis, N. I. et al. Association between DNA damage response, fibrosis and type I interferon signature in systemic sclerosis. Front. Immunol. 11, 582401 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Palomino, G. M. et al. Patients with systemic sclerosis present increased DNA damage differentially associated with DNA repair gene polymorphisms. J. Rheumatol. 41, 458–465 (2014).

    Article  CAS  PubMed  Google Scholar 

  37. Li, Y. et al. Deficient activity of the nuclease MRE11A induces T cell aging and promotes arthritogenic effector functions in patients with rheumatoid arthritis. Immunity 45, 903–916 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Rose, J. et al. DNA damage, discoordinated gene expression and cellular senescence in osteoarthritic chondrocytes. Osteoarthritis Cartilage 20, 1020–1028 (2012).

    Article  CAS  PubMed  Google Scholar 

  39. La Rubia, M., Rus, A., Molina, F. & Del Moral, M. L. Is fibromyalgia-related oxidative stress implicated in the decline of physical and mental health status? Clin. Exp. Rheumatol. 31, S121–S127 (2013).

    PubMed  Google Scholar 

  40. Talens, R. P. et al. Epigenetic variation during the adult lifespan: cross-sectional and longitudinal data on monozygotic twin pairs. Aging Cell 11, 694–703 (2012).

    Article  CAS  PubMed  Google Scholar 

  41. Fraga, M. F. & Esteller, M. Epigenetics and aging: the targets and the marks. Trends Genet. 23, 413–418 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Ballestar, E. & Li, T. New insights into the epigenetics of inflammatory rheumatic diseases. Nat. Rev. Rheumatol. 13, 593–605 (2017).

    Article  CAS  PubMed  Google Scholar 

  43. Nygaard, G. & Firestein, G. S. Restoring synovial homeostasis in rheumatoid arthritis by targeting fibroblast-like synoviocytes. Nat. Rev. Rheumatol. 16, 316–333 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Karouzakis, E. et al. DNA methylation regulates the expression of CXCL12 in rheumatoid arthritis synovial fibroblasts. Genes Immun. 12, 643–652 (2011).

    Article  CAS  PubMed  Google Scholar 

  45. Alsaleh, G. et al. Reduced DICER1 expression bestows rheumatoid arthritis synoviocytes proinflammatory properties and resistance to apoptotic stimuli. Arthritis Rheumatol. 68, 1839–1848 (2016).

    Article  CAS  PubMed  Google Scholar 

  46. Philippe, L. et al. MiR-20a regulates ASK1 expression and TLR4-dependent cytokine release in rheumatoid fibroblast-like synoviocytes. Ann. Rheum. Dis. 72, 1071–1079 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Grabiec, A. M. & Reedquist, K. A. Histone deacetylases in RA: epigenetics and epiphenomena. Arthritis Res. Ther. 12, 142 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Huber, L. C. et al. Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients. Arthritis Rheum. 56, 1087–1093 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Wang, Y. et al. Aberrant histone modification in peripheral blood B cells from patients with systemic sclerosis. Clin. Immunol. 149, 46–54 (2013).

    Article  CAS  PubMed  Google Scholar 

  50. Thabet, Y. et al. Epigenetic dysregulation in salivary glands from patients with primary Sjogren’s syndrome may be ascribed to infiltrating B cells. J. Autoimmun. 41, 175–181 (2013).

    Article  CAS  PubMed  Google Scholar 

  51. Yu, X. et al. DNA hypermethylation leads to lower FOXP3 expression in CD4+ T cells of patients with primary Sjogren’s syndrome. Clin. Immunol. 148, 254–257 (2013).

    Article  CAS  PubMed  Google Scholar 

  52. Huck, S. & Zouali, M. DNA methylation: a potential pathway to abnormal autoreactive lupus B cells. Clin. Immunol. Immunopathol. 80, 1–8 (1996).

    Article  CAS  PubMed  Google Scholar 

  53. Hu, N. et al. Abnormal histone modification patterns in lupus CD4+ T cells. J. Rheumatol. 35, 804–810 (2008).

    CAS  PubMed  Google Scholar 

  54. Javierre, B. M. et al. Changes in the pattern of DNA methylation associate with twin discordance in systemic lupus erythematosus. Genome Res. 20, 170–179 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Deng, C. et al. Decreased Ras-mitogen-activated protein kinase signaling may cause DNA hypomethylation in T lymphocytes from lupus patients. Arthritis Rheum. 44, 397–407 (2001).

    Article  CAS  PubMed  Google Scholar 

  56. Li, Y., Gorelik, G., Strickland, F. M. & Richardson, B. C. Oxidative stress, T cell DNA methylation, and lupus. Arthritis Rheumatol. 66, 1574–1582 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Ugalde, A. P., Espanol, Y. & Lopez-Otin, C. Micromanaging aging with miRNAs: new messages from the nuclear envelope. Nucleus 2, 549–555 (2011).

    Article  PubMed  Google Scholar 

  58. Maurer, B. et al. MicroRNA-29, a key regulator of collagen expression in systemic sclerosis. Arthritis Rheum. 62, 1733–1743 (2010).

    Article  CAS  PubMed  Google Scholar 

  59. Alsaleh, G. et al. MiR-30a-3p negatively regulates BAFF synthesis in systemic sclerosis and rheumatoid arthritis fibroblasts. PLoS One 9, e111266 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  60. Pauley, K. M. et al. Altered miR-146a expression in Sjogren’s syndrome and its functional role in innate immunity. Eur. J. Immunol. 41, 2029–2039 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Shi, H., Zheng, L. Y., Zhang, P. & Yu, C. Q. miR-146a and miR-155 expression in PBMCs from patients with Sjogren’s syndrome. J. Oral. Pathol. Med. 43, 792–797 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Wang, X. et al. MicroRNA-146a-5p enhances T helper 17 cell differentiation via decreasing a disintegrin and metalloprotease 17 level in primary Sjogren’s syndrome. Bioengineered 12, 310–324 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Qin, H. et al. MicroRNA-29b contributes to DNA hypomethylation of CD4+ T cells in systemic lupus erythematosus by indirectly targeting DNA methyltransferase 1. J. Dermatol. Sci. 69, 61–67 (2013).

    Article  CAS  PubMed  Google Scholar 

  64. Pan, W. et al. MicroRNA-21 and microRNA-148a contribute to DNA hypomethylation in lupus CD4+ T cells by directly and indirectly targeting DNA methyltransferase 1. J. Immunol. 184, 6773–6781 (2010).

    Article  CAS  PubMed  Google Scholar 

  65. Zhu, J. et al. Stem cell-homing hydrogel-based miR-29b-5p delivery promotes cartilage regeneration by suppressing senescence in an osteoarthritis rat model. Sci. Adv. 8, eabk0011 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. De Cecco, M. et al. L1 drives IFN in senescent cells and promotes age-associated inflammation. Nature 566, 73–78 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  67. Mavragani, C. P. et al. Expression of Long Interspersed Nuclear Element 1 retroelements and induction of type I interferon in patients with systemic autoimmune disease. Arthritis Rheumatol. 68, 2686–2696 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Simon, M. et al. LINE1 derepression in aged wild-type and SIRT6-deficient mice drives inflammation. Cell Metab. 29, 871–885 e875 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Gorbunova, V. et al. The role of retrotransposable elements in ageing and age-associated diseases. Nature 596, 43–53 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Blasco, M. A. Telomere length, stem cells and aging. Nat. Chem. Biol. 3, 640–649 (2007).

    Article  CAS  PubMed  Google Scholar 

  71. Armanios, M. et al. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am. J. Hum. Genet. 85, 823–832 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Blasco, M. A. et al. Telomere shortening and tumor formation by mouse cells lacking telomerase RNA. Cell 91, 25–34 (1997).

    Article  CAS  PubMed  Google Scholar 

  73. Herrera, E. et al. Disease states associated with telomerase deficiency appear earlier in mice with short telomeres. EMBO J. 18, 2950–2960 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Steer, S. E. et al. Reduced telomere length in rheumatoid arthritis is independent of disease activity and duration. Ann. Rheum. Dis. 66, 476–480 (2007).

    Article  CAS  PubMed  Google Scholar 

  75. Koetz, K. et al. T cell homeostasis in patients with rheumatoid arthritis. Proc. Natl Acad. Sci. USA 97, 9203–9208 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Zeng, Z. et al. Association of telomere length with risk of rheumatoid arthritis: a meta-analysis and Mendelian randomization. Rheumatology 59, 940–947 (2020).

    Article  CAS  PubMed  Google Scholar 

  77. Tamayo, M. et al. Differing patterns of peripheral blood leukocyte telomere length in rheumatologic diseases. Mutat. Res. 683, 68–73 (2010).

    Article  CAS  PubMed  Google Scholar 

  78. Yudoh, K., Matsuno, H., Nezuka, T. & Kimura, T. Different mechanisms of synovial hyperplasia in rheumatoid arthritis and pigmented villonodular synovitis: the role of telomerase activity in synovial proliferation. Arthritis Rheum. 42, 669–677 (1999).

    Article  CAS  PubMed  Google Scholar 

  79. Haque, S. et al. Shortened telomere length in patients with systemic lupus erythematosus. Arthritis Rheum. 65, 1319–1323 (2013).

    Article  PubMed  Google Scholar 

  80. Lee, Y. H. et al. Association between shortened telomere length and systemic lupus erythematosus: a meta-analysis. Lupus 26, 282–288 (2017).

    Article  CAS  PubMed  Google Scholar 

  81. MacIntyre, A. et al. Association of increased telomere lengths in limited scleroderma, with a lack of age-related telomere erosion. Ann. Rheum. Dis. 67, 1780–1782 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Lakota, K. et al. Short lymphocyte, but not granulocyte, telomere length in a subset of patients with systemic sclerosis. Ann. Rheum. Dis. 78, 1142–1144 (2019).

    Article  PubMed  Google Scholar 

  83. Artlett, C. M., Black, C. M., Briggs, D. C., Stevens, C. O. & Welsh, K. I. Telomere reduction in scleroderma patients: a possible cause for chromosomal instability. Br. J. Rheumatol. 35, 732–737 (1996).

    Article  CAS  PubMed  Google Scholar 

  84. Tarhan, F. et al. Telomerase activity in connective tissue diseases: elevated in rheumatoid arthritis, but markedly decreased in systemic sclerosis. Rheumatol. Int. 28, 579–583 (2008).

    Article  CAS  PubMed  Google Scholar 

  85. Hassett, A. L. et al. Pain is associated with short leukocyte telomere length in women with fibromyalgia. J. Pain. 13, 959–969 (2012).

    Article  CAS  PubMed  Google Scholar 

  86. Mensa, E. et al. The telomere world and aging: analytical challenges and future perspectives. Ageing Res. Rev. 50, 27–42 (2019).

    Article  CAS  PubMed  Google Scholar 

  87. Heba, A. C. et al. Telomeres: new players in immune-mediated inflammatory diseases? J. Autoimmun. 123, 102699 (2021).

    Article  CAS  PubMed  Google Scholar 

  88. Hipp, M. S., Kasturi, P. & Hartl, F. U. The proteostasis network and its decline in ageing. Nat. Rev. Mol. Cell Biol. 20, 421–435 (2019).

    Article  CAS  PubMed  Google Scholar 

  89. Sasaki, H. et al. Autophagy modulates osteoarthritis-related gene expression in human chondrocytes. Arthritis Rheum. 64, 1920–1928 (2012).

    Article  CAS  PubMed  Google Scholar 

  90. Hui, W. et al. Oxidative changes and signalling pathways are pivotal in initiating age-related changes in articular cartilage. Ann. Rheum. Dis. 75, 449–458 (2016).

    Article  CAS  PubMed  Google Scholar 

  91. Dumit, V. I. et al. Altered MCM protein levels and autophagic flux in aged and systemic sclerosis dermal fibroblasts. J. Invest. Dermatol. 134, 2321–2330 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Zhang, Y. et al. Cartilage-specific deletion of mTOR upregulates autophagy and protects mice from osteoarthritis. Ann. Rheum. Dis. 74, 1432–1440 (2015).

    Article  CAS  PubMed  Google Scholar 

  93. Clarke, A. J. et al. Autophagy is activated in systemic lupus erythematosus and required for plasmablast development. Ann. Rheum. Dis. 74, 912–920 (2015).

    Article  PubMed  Google Scholar 

  94. Sorice, M. et al. Autophagy generates citrullinated peptides in human synoviocytes: a possible trigger for anti-citrullinated peptide antibodies. Rheumatology 55, 1374–1385 (2016).

    Article  CAS  PubMed  Google Scholar 

  95. Serrano, R. L., Chen, L. Y., Lotz, M. K., Liu-Bryan, R. & Terkeltaub, R. Impaired proteasomal function in human osteoarthritic chondrocytes can contribute to decreased levels of SOX9 and aggrecan. Arthritis Rheumatol. 70, 1030–1041 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Radwan, M. et al. Protection against murine osteoarthritis by inhibition of the 26 S proteasome and lysine-48 linked ubiquitination. Ann. Rheum. Dis. 74, 1580–1587 (2015).

    Article  CAS  PubMed  Google Scholar 

  97. Tan, L., Register, T. C. & Yammani, R. R. Age-related decline in expression of molecular chaperones induces endoplasmic reticulum stress and chondrocyte apoptosis in articular cartilage. Aging Dis. 11, 1091–1102 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  98. Ariosa-Morejon, Y. et al. Age-dependent changes in protein incorporation into collagen-rich tissues of mice by in vivo pulsed SILAC labelling. Elife 10, e66635 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Edgar, D. et al. Random point mutations with major effects on protein-coding genes are the driving force behind premature aging in mtDNA mutator mice. Cell Metab. 10, 131–138 (2009).

    Article  CAS  PubMed  Google Scholar 

  100. Green, D. R., Galluzzi, L. & Kroemer, G. Mitochondria and the autophagy-inflammation-cell death axis in organismal aging. Science 333, 1109–1112 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Kujoth, G. C. et al. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science 309, 481–484 (2005).

    Article  CAS  PubMed  Google Scholar 

  102. Trifunovic, A. et al. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature 429, 417–423 (2004).

    Article  CAS  PubMed  Google Scholar 

  103. Blanco, F. J., Valdes, A. M. & Rego-Perez, I. Mitochondrial DNA variation and the pathogenesis of osteoarthritis phenotypes. Nat. Rev. Rheumatol. 14, 327–340 (2018).

    Article  CAS  PubMed  Google Scholar 

  104. Fearon, U., Canavan, M., Biniecka, M. & Veale, D. J. Hypoxia, mitochondrial dysfunction and synovial invasiveness in rheumatoid arthritis. Nat. Rev. Rheumatol. 12, 385–397 (2016).

    Article  CAS  PubMed  Google Scholar 

  105. Mancini, O. K. et al. Oxidative stress-induced senescence mediates inflammatory and fibrotic phenotypes in fibroblasts from systemic sclerosis patients. Rheumatology 61, 1265–1275 (2021).

    Article  Google Scholar 

  106. Barrera, M. J. et al. Dysfunctional mitochondria as critical players in the inflammation of autoimmune diseases: potential role in Sjogren’s syndrome. Autoimmun. Rev. 20, 102867 (2021).

    Article  CAS  PubMed  Google Scholar 

  107. Vaamonde-Garcia, C. & Lopez-Armada, M. J. Role of mitochondrial dysfunction on rheumatic diseases. Biochem. Pharmacol. 165, 181–195 (2019).

    Article  CAS  PubMed  Google Scholar 

  108. Leishangthem, B. D., Sharma, A. & Bhatnagar, A. Role of altered mitochondria functions in the pathogenesis of systemic lupus erythematosus. Lupus 25, 272–281 (2016).

    Article  CAS  PubMed  Google Scholar 

  109. Da Sylva, T. R., Connor, A., Mburu, Y., Keystone, E. & Wu, G. E. Somatic mutations in the mitochondria of rheumatoid arthritis synoviocytes. Arthritis Res. Ther. 7, R844–R851 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  110. Cordero, M. D. et al. Mutation in cytochrome b gene of mitochondrial DNA in a family with fibromyalgia is associated with NLRP3-inflammasome activation. J. Med. Genet. 53, 113–122 (2016).

    Article  CAS  PubMed  Google Scholar 

  111. Gazdhar, A. et al. Time-dependent and somatically acquired mitochondrial DNA mutagenesis and respiratory chain dysfunction in a scleroderma model of lung fibrosis. Sci. Rep. 4, 5336 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Fernandez-Moreno, M. et al. Mitochondrial DNA haplogroups influence the risk of incident knee osteoarthritis in OAI and CHECK cohorts. A meta-analysis and functional study. Ann. Rheum. Dis. 76, 1114–1122 (2017).

    Article  CAS  PubMed  Google Scholar 

  113. Chang, M. C. et al. Accumulation of mitochondrial DNA with 4977-bp deletion in knee cartilage — an association with idiopathic osteoarthritis. Osteoarthritis Cartilage 13, 1004–1011 (2005).

    Article  PubMed  Google Scholar 

  114. Onishi, M., Yamano, K., Sato, M., Matsuda, N. & Okamoto, K. Molecular mechanisms and physiological functions of mitophagy. EMBO J. 40, e104705 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Akamata, K. et al. SIRT3 is attenuated in systemic sclerosis skin and lungs, and its pharmacologic activation mitigates organ fibrosis. Oncotarget 7, 69321–69336 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  116. Patel, A. S. et al. Epithelial cell mitochondrial dysfunction and PINK1 are induced by transforming growth factor-beta1 in pulmonary fibrosis. PLoS One 10, e0121246 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  117. Cordero, M. D. et al. Mitochondrial dysfunction and mitophagy activation in blood mononuclear cells of fibromyalgia patients: implications in the pathogenesis of the disease. Arthritis Res. Ther. 12, R17 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  118. Green, C. L., Lamming, D. W. & Fontana, L. Molecular mechanisms of dietary restriction promoting health and longevity. Nat. Rev. Mol. Cell Biol. 23, 56–73 (2022).

    Article  CAS  PubMed  Google Scholar 

  119. Harrison, D. E. et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature 460, 392–395 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Selman, C. et al. Ribosomal protein S6 kinase 1 signaling regulates mammalian life span. Science 326, 140–144 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Laragione, T. & Gulko, P. S. mTOR regulates the invasive properties of synovial fibroblasts in rheumatoid arthritis. Mol. Med. 16, 352–358 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  122. Saxena, A., Raychaudhuri, S. K. & Raychaudhuri, S. P. Interleukin-17-induced proliferation of fibroblast-like synovial cells is mTOR dependent. Arthritis Rheum. 63, 1465–1466 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Javier, A. F. et al. Rapamycin (sirolimus) inhibits proliferating cell nuclear antigen expression and blocks cell cycle in the G1 phase in human keratinocyte stem cells. J. Clin. Invest. 99, 2094–2099 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Chen, S. et al. mTOR Blockade by rapamycin in spondyloarthritis: impact on inflammation and new bone formation in vitro and in vivo. Front. Immunol. 10, 2344 (2019).

    Article  CAS  PubMed  Google Scholar 

  125. Buerger, C., Malisiewicz, B., Eiser, A., Hardt, K. & Boehncke, W. H. Mammalian target of rapamycin and its downstream signalling components are activated in psoriatic skin. Br. J. Dermatol. 169, 156–159 (2013).

    Article  CAS  PubMed  Google Scholar 

  126. Yoshizaki, A. et al. Treatment with rapamycin prevents fibrosis in tight-skin and bleomycin-induced mouse models of systemic sclerosis. Arthritis Rheum. 62, 2476–2487 (2010).

    Article  CAS  PubMed  Google Scholar 

  127. Tamaki, Z. et al. Effects of the immunosuppressant rapamycin on the expression of human alpha2(I) collagen and matrix metalloproteinase 1 genes in scleroderma dermal fibroblasts. J. Dermatol. Sci. 74, 251–259 (2014).

    Article  CAS  PubMed  Google Scholar 

  128. Zhang, M. et al. mTOR activation in CD8+ cells contributes to disease activity of rheumatoid arthritis and increases therapeutic response to TNF inhibitors. Rheumatology 61, 3010–3022 (2021).

    Article  Google Scholar 

  129. Guan, Y., Yang, X., Yang, W., Charbonneau, C. & Chen, Q. Mechanical activation of mammalian target of rapamycin pathway is required for cartilage development. FASEB J. 28, 4470–4481 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Lopez de Figueroa, P., Lotz, M. K., Blanco, F. J. & Carames, B. Autophagy activation and protection from mitochondrial dysfunction in human chondrocytes. Arthritis Rheumatol. 67, 966–976 (2015).

    Article  CAS  PubMed  Google Scholar 

  131. Cejka, D. et al. Mammalian target of rapamycin signaling is crucial for joint destruction in experimental arthritis and is activated in osteoclasts from patients with rheumatoid arthritis. Arthritis Rheum. 62, 2294–2302 (2010).

    Article  CAS  PubMed  Google Scholar 

  132. Deng, Z. et al. The role of sirtuin 1 and its activator, resveratrol in osteoarthritis. Biosci. Rep. 39, BSR20190189 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Matsuzaki, T. et al. Disruption of Sirt1 in chondrocytes causes accelerated progression of osteoarthritis under mechanical stress and during ageing in mice. Ann. Rheum. Dis. 73, 1397–1404 (2014).

    Article  CAS  PubMed  Google Scholar 

  134. Sacitharan, P. K., Bou-Gharios, G. & Edwards, J. R. SIRT1 directly activates autophagy in human chondrocytes. Cell Death Discov. 6, 41 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Wendling, D. et al. Dysregulated serum IL-23 and SIRT1 activity in peripheral blood mononuclear cells of patients with rheumatoid arthritis. PLoS One 10, e0119981 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  136. Hah, Y. S. et al. Myeloid deletion of SIRT1 aggravates serum transfer arthritis in mice via nuclear factor-κB activation. PLoS One 9, e87733 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  137. Woo, S. J. et al. Myeloid deletion of SIRT1 suppresses collagen-induced arthritis in mice by modulating dendritic cell maturation. Exp. Mol. Med. 48, e221 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Niederer, F. et al. SIRT1 overexpression in the rheumatoid arthritis synovium contributes to proinflammatory cytokine production and apoptosis resistance. Ann. Rheum. Dis. 70, 1866–1873 (2011).

    Article  CAS  PubMed  Google Scholar 

  139. Li, G. et al. SIRT1 inhibits rheumatoid arthritis fibroblast-like synoviocyte aggressiveness and inflammatory response via suppressing NF-κB pathway. Biosci. Rep. 38, BSR20180541 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. Wang, Z. L. et al. Resveratrol possesses protective effects in a pristane-induced lupus mouse model. PLoS One 9, e114792 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  141. Zhang, J. et al. The type III histone deacetylase Sirt1 is essential for maintenance of T cell tolerance in mice. J. Clin. Invest. 119, 3048–3058 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Schett, G. et al. Diabetes is an independent predictor for severe osteoarthritis: results from a longitudinal cohort study. Diabetes Care 36, 403–409 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  143. Quevedo-Abeledo, J. C. et al. Higher prevalence and degree of insulin resistance in patients with rheumatoid arthritis than in patients with systemic lupus erythematosus. J. Rheumatol. 48, 339–347 (2021).

    Article  PubMed  Google Scholar 

  144. Giles, J. T. et al. Insulin resistance in rheumatoid arthritis: disease-related indicators and associations with the presence and progression of subclinical atherosclerosis. Arthritis Rheumatol. 67, 626–636 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. Sanchez-Perez, H. et al. Insulin resistance in systemic lupus erythematosus patients: contributing factors and relationship with subclinical atherosclerosis. Clin. Exp. Rheumatol. 35, 885–892 (2017).

    PubMed  Google Scholar 

  146. Chen, H. H. et al. Ankylosing spondylitis and other inflammatory spondyloarthritis increase the risk of developing type 2 diabetes in an Asian population. Rheumatol. Int. 34, 265–270 (2014).

    Article  CAS  PubMed  Google Scholar 

  147. Ribeiro, M. et al. Diabetes-accelerated experimental osteoarthritis is prevented by autophagy activation. Osteoarthritis Cartilage 24, 2116–2125 (2016).

    Article  CAS  PubMed  Google Scholar 

  148. Richter, F. C., Obba, S. & Simon, A. K. Local exchange of metabolites shapes immunity. Immunology 155, 309–319 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Davan-Wetton, C. S. A., Pessolano, E., Perretti, M. & Montero-Melendez, T. Senescence under appraisal: hopes and challenges revisited. Cell. Mol. Life Sci. 78, 3333–3354 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  150. Pawlik, A. et al. The expansion of CD4+CD28− T cells in patients with rheumatoid arthritis. Arthritis Res. Ther. 5, R210–R213 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Petersen, L. E. et al. Premature immunosenescence is associated with memory dysfunction in rheumatoid arthritis. Neuroimmunomodulation 22, 130–137 (2015).

    Article  CAS  PubMed  Google Scholar 

  152. Zabinska, M., Krajewska, M., Koscielska-Kasprzak, K. & Klinger, M. CD3+CD8+CD28− T lymphocytes in patients with lupus nephritis. J. Immunol. Res. 2016, 1058165 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  153. Schirmer, M. et al. Circulating cytotoxic CD8+ CD28− T cells in ankylosing spondylitis. Arthritis Res. 4, 71–76 (2002).

    Article  PubMed  Google Scholar 

  154. Fessler, J. et al. Senescent T-cells promote bone loss in rheumatoid arthritis. Front. Immunol. 9, 95 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  155. Sawai, H. et al. T cell costimulation by fractalkine-expressing synoviocytes in rheumatoid arthritis. Arthritis Rheum. 52, 1392–1401 (2005).

    Article  CAS  PubMed  Google Scholar 

  156. Fessler, J. et al. Novel senescent regulatory T-cell subset with impaired suppressive function in rheumatoid arthritis. Front. Immunol. 8, 300 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Stranks, A. J. et al. Autophagy controls acquisition of aging features in macrophages. J. Innate Immun. 7, 375–391 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Ong, S. M. et al. The pro-inflammatory phenotype of the human non-classical monocyte subset is attributed to senescence. Cell Death Dis. 9, 266 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Pai, S. & Thomas, R. Immune deficiency or hyperactivity-Nf-κb illuminates autoimmunity. J. Autoimmun. 31, 245–251 (2008).

    Article  CAS  PubMed  Google Scholar 

  160. Xu, M. et al. Transplanted senescent cells induce an osteoarthritis-like condition in mice. J. Gerontol. A Biol. Sci. Med. Sci. 72, 780–785 (2017).

    CAS  PubMed  Google Scholar 

  161. Jeon, O. H. et al. Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment. Nat. Med. 23, 775–781 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Del Rey, M. J. et al. Senescent synovial fibroblasts accumulate prematurely in rheumatoid arthritis tissues and display an enhanced inflammatory phenotype. Immun. Ageing 16, 29 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  163. Taniguchi, K. et al. Induction of the p16INK4a senescence gene as a new therapeutic strategy for the treatment of rheumatoid arthritis. Nat. Med. 5, 760–767 (1999).

    Article  CAS  PubMed  Google Scholar 

  164. Nasu, K. et al. Adenoviral transfer of cyclin-dependent kinase inhibitor genes suppresses collagen-induced arthritis in mice. J. Immunol. 165, 7246–7252 (2000).

    Article  CAS  PubMed  Google Scholar 

  165. Murakami, Y., Mizoguchi, F., Saito, T., Miyasaka, N. & Kohsaka, H. p16INK4a exerts an anti-inflammatory effect through accelerated IRAK1 degradation in macrophages. J. Immunol. 189, 5066–5072 (2012).

    Article  CAS  PubMed  Google Scholar 

  166. Gu, Z. et al. Upregulation of p16INK4A promotes cellular senescence of bone marrow-derived mesenchymal stem cells from systemic lupus erythematosus patients. Cell. Signal. 24, 2307–2314 (2012).

    Article  CAS  PubMed  Google Scholar 

  167. Valencia, X., Yarboro, C., Illei, G. & Lipsky, P. E. Deficient CD4+CD25high T regulatory cell function in patients with active systemic lupus erythematosus. J. Immunol. 178, 2579–2588 (2007).

    Article  CAS  PubMed  Google Scholar 

  168. Camernik, K. et al. Increased exhaustion of the subchondral bone-derived mesenchymal stem/stromal cells in primary versus dysplastic osteoarthritis. Stem Cell Rev. Rep. 16, 742–754 (2020).

    Article  CAS  PubMed  Google Scholar 

  169. Murphy, J. M. et al. Reduced chondrogenic and adipogenic activity of mesenchymal stem cells from patients with advanced osteoarthritis. Arthritis Rheum. 46, 704–713 (2002).

    Article  PubMed  Google Scholar 

  170. Chia, S. L. et al. Fibroblast growth factor 2 is an intrinsic chondroprotective agent that suppresses ADAMTS-5 and delays cartilage degradation in murine osteoarthritis. Arthritis Rheum. 60, 2019–2027 (2009).

    Article  CAS  PubMed  Google Scholar 

  171. Lee, H. J. et al. Chronic inflammation-induced senescence impairs immunomodulatory properties of synovial fluid mesenchymal stem cells in rheumatoid arthritis. Stem Cell Res. Ther. 12, 502 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Cheng, R. J. et al. Mesenchymal stem cells: allogeneic MSC may be immunosuppressive but autologous MSC are dysfunctional in lupus patients. Front. Cell Dev. Biol. 7, 285 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  173. Pang, W. W. et al. Human bone marrow hematopoietic stem cells are increased in frequency and myeloid-biased with age. Proc. Natl Acad. Sci. USA 108, 20012–20017 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Caiado, F., Pietras, E. M. & Manz, M. G. Inflammation as a regulator of hematopoietic stem cell function in disease, aging, and clonal selection. J. Exp. Med. 218, e20201541 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Challen, G. A. et al. Dnmt3a is essential for hematopoietic stem cell differentiation. Nat. Genet. 44, 23–31 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  176. Solimando, A. G., Melaccio, A. & Ria, R. The bone marrow niche landscape: a journey through aging, extrinsic and intrinsic stressors in the haemopoietic milieu. J. Cancer Metastasis Treat. 8, 9 (2022).

    Google Scholar 

  177. Sikora, K. A., Wells, K., Bolek, E. C., Jones, A. I. & Grayson, P. C. Somatic mutations in rheumatologic diseases: VEXAS syndrome and beyond. Rheumatology 61, 3149–3160 (2022).

    Article  PubMed  Google Scholar 

  178. Abplanalp, W. T. et al. Clonal hematopoiesis-driver DNMT3A mutations alter immune cells in heart failure. Circ. Res. 128, 216–228 (2021).

    Article  CAS  PubMed  Google Scholar 

  179. Fuster, J. J. et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science 355, 842–847 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Savola, P. et al. Author correction: clonal hematopoiesis in patients with rheumatoid arthritis. Blood Cancer J. 11, 36 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  181. Papadaki, H. A. et al. Bone marrow progenitor cell reserve and function and stromal cell function are defective in rheumatoid arthritis: evidence for a tumor necrosis factor alpha-mediated effect. Blood 99, 1610–1619 (2002).

    Article  CAS  PubMed  Google Scholar 

  182. Colmegna, I. et al. Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis. Arthritis Rheum. 58, 990–1000 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Colmegna, I., Pryshchep, S., Oishi, H., Goronzy, J. J. & Weyand, C. M. Dampened ERK signaling in hematopoietic progenitor cells in rheumatoid arthritis. Clin. Immunol. 143, 73–82 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Alvarado-de la Barrera, C., Alcocer-Varela, J., Richaud-Patin, Y., Alarcon-Segovia, D. & Llorente, L. Differential oncogene and TNF-α mRNA expression in bone marrow cells from systemic lupus erythematosus patients. Scand. J. Immunol. 48, 551–556 (1998).

    Article  CAS  PubMed  Google Scholar 

  185. Tiefenthaler, M. et al. Apoptosis of CD34 cells after incubation with sera of leukopenic patients with systemic lupus erythematosus. Lupus 12, 471–478 (2003).

    Article  CAS  PubMed  Google Scholar 

  186. Hernandez, G. et al. Pro-inflammatory cytokine blockade attenuates myeloid expansion in a murine model of rheumatoid arthritis. Haematologica 105, 585–597 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Papadaki, H. A., Kritikos, H. D., Valatas, V., Boumpas, D. T. & Eliopoulos, G. D. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood 100, 474–482 (2002).

    Article  CAS  PubMed  Google Scholar 

  188. Corrado, A., Di Bello, V., d’Onofrio, F., Maruotti, N. & Cantatore, F. P. Anti-TNF-α effects on anemia in rheumatoid and psoriatic arthritis. Int. J. Immunopathol. Pharmacol. 30, 302–307 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Chen, Y. et al. Serum levels of hepcidin in rheumatoid arthritis and its correlation with disease activity and anemia: a meta-analysis. Immunol. Invest. 50, 243–258 (2021).

    Article  CAS  PubMed  Google Scholar 

  190. Beck, D. B. et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N. Engl. J. Med. 383, 2628–2638 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Acosta, J. C. et al. A complex secretory program orchestrated by the inflammasome controls paracrine senescence. Nat. Cell Biol. 15, 978–990 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  192. Munoz-Espin, D. & Serrano, M. Cellular senescence: from physiology to pathology. Nat. Rev. Mol. Cell Biol. 15, 482–496 (2014).

    Article  CAS  PubMed  Google Scholar 

  193. Philipot, D. et al. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis Res. Ther. 16, R58 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  194. Gu, Z. et al. Rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from MRL/lpr mice and systemic lupus erythematosus patients through inhibition of the mTOR signaling pathway. Aging 8, 1102–1114 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Yoshida, M. et al. Extracellular vesicle-contained eNAMPT delays aging and extends lifespan in mice. Cell Metab. 30, 329–342 e325 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  196. Nederveen, J. P., Warnier, G., Di Carlo, A., Nilsson, M. I. & Tarnopolsky, M. A. Extracellular vesicles and exosomes: insights from exercise science. Front. Physiol. 11, 604274 (2020).

    Article  PubMed  Google Scholar 

  197. Basisty, N. et al. A proteomic atlas of senescence-associated secretomes for aging biomarker development. PLoS Biol. 18, e3000599 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Borghesan, M. et al. Small extracellular vesicles are key regulators of non-cell autonomous intercellular communication in senescence via the interferon protein IFITM3. Cell Rep. 27, 3956–3971 e3956 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Mensa, E. et al. Small extracellular vesicles deliver miR-21 and miR-217 as pro-senescence effectors to endothelial cells. J. Extracell. Vesicles 9, 1725285 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  200. Khayrullin, A. et al. Very long-chain C24:1 ceramide is increased in serum extracellular vesicles with aging and can induce senescence in bone-derived mesenchymal stem cells. Cells 8, 37 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  201. Ahmadi, M. & Rezaie, J. Ageing and mesenchymal stem cells derived exosomes: molecular insight and challenges. Cell Biochem. Funct. 39, 60–66 (2021).

    Article  CAS  PubMed  Google Scholar 

  202. Dong, C. et al. Circulating exosomes derived-miR-146a from systemic lupus erythematosus patients regulates senescence of mesenchymal stem cells. Biomed. Res. Int. 2019, 6071308 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Kolhe, R. et al. Gender-specific differential expression of exosomal miRNA in synovial fluid of patients with osteoarthritis. Sci. Rep. 7, 2029 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  204. Kato, T. et al. Exosomes from IL-1β stimulated synovial fibroblasts induce osteoarthritic changes in articular chondrocytes. Arthritis Res. Ther. 16, R163 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  205. Skriner, K., Adolph, K., Jungblut, P. R. & Burmester, G. R. Association of citrullinated proteins with synovial exosomes. Arthritis Rheum. 54, 3809–3814 (2006).

    Article  CAS  PubMed  Google Scholar 

  206. Cloutier, N. et al. The exposure of autoantigens by microparticles underlies the formation of potent inflammatory components: the microparticle-associated immune complexes. EMBO Mol. Med. 5, 235–249 (2013).

    Article  CAS  PubMed  Google Scholar 

  207. Sokolove, J., Zhao, X., Chandra, P. E. & Robinson, W. H. Immune complexes containing citrullinated fibrinogen costimulate macrophages via Toll-like receptor 4 and Fcγ receptor. Arthritis Rheum. 63, 53–62 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Zhang, H. G. et al. A membrane form of TNF-α presented by exosomes delays T cell activation-induced cell death. J. Immunol. 176, 7385–7393 (2006).

    Article  CAS  PubMed  Google Scholar 

  209. Cosenza, S., Ruiz, M., Toupet, K., Jorgensen, C. & Noel, D. Mesenchymal stem cells derived exosomes and microparticles protect cartilage and bone from degradation in osteoarthritis. Sci. Rep. 7, 16214 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  210. Wang, Y. et al. Exosomes from embryonic mesenchymal stem cells alleviate osteoarthritis through balancing synthesis and degradation of cartilage extracellular matrix. Stem Cell Res. Ther. 8, 189 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. You, D. G. et al. Metabolically engineered stem cell-derived exosomes to regulate macrophage heterogeneity in rheumatoid arthritis. Sci. Adv. 7, eabe0083 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Jin, J. et al. BMSC-derived extracellular vesicles intervened the pathogenic changes of scleroderma in mice through miRNAs. Stem Cell Res. Ther. 12, 327 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  213. Clark, R. I. et al. Distinct shifts in microbiota composition during drosophila aging impair intestinal function and drive mortality. Cell Rep. 12, 1656–1667 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Barcena, C. et al. Healthspan and lifespan extension by fecal microbiota transplantation into progeroid mice. Nat. Med. 25, 1234–1242 (2019).

    Article  CAS  PubMed  Google Scholar 

  215. Parker, A. et al. Fecal microbiota transfer between young and aged mice reverses hallmarks of the aging gut, eye, and brain. Microbiome 10, 68 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Chan, M. M. et al. The microbial metabolite trimethylamine N-oxide links vascular dysfunctions and the autoimmune disease rheumatoid arthritis. Nutrients 11, 1821 (2019).

    Article  CAS  PubMed Central  Google Scholar 

  217. Boini, K. M., Hussain, T., Li, P. L. & Koka, S. Trimethylamine-N-oxide instigates NLRP3 inflammasome activation and endothelial dysfunction. Cell. Physiol. Biochem. 44, 152–162 (2017).

    Article  PubMed  Google Scholar 

  218. Seldin, M. M. et al. Trimethylamine N-oxide promotes vascular inflammation through signaling of mitogen-activated protein kinase and nuclear factor-κB. J. Am. Heart Assoc. 5, e002767 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  219. Ctoi, A. F. et al. Gut microbiota and aging-a focus on centenarians. Biochim. Biophys. Acta Mol. Basis Dis. 1866, 165765 (2020).

    Article  PubMed  Google Scholar 

  220. DeJong, E. N., Surette, M. G. & Bowdish, D. M. E. The gut microbiota and unhealthy aging: disentangling cause from consequence. Cell Host Microbe 28, 180–189 (2020).

    Article  CAS  PubMed  Google Scholar 

  221. Evers, A. W., Zautra, A. & Thieme, K. Stress and resilience in rheumatic diseases: a review and glimpse into the future. Nat. Rev. Rheumatol. 7, 409–415 (2011).

    Article  PubMed  Google Scholar 

  222. Clegg, A., Young, J., Iliffe, S., Rikkert, M. O. & Rockwood, K. Frailty in elderly people. Lancet 381, 752–762 (2013).

    Article  PubMed  Google Scholar 

  223. Fried, L. P. et al. Frailty in older adults: evidence for a phenotype. J. Gerontol. A Biol. Sci. Med. Sci. 56, M146–M156 (2001).

    Article  CAS  PubMed  Google Scholar 

  224. Fried, L. P., Ferrucci, L., Darer, J., Williamson, J. D. & Anderson, G. Untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care. J. Gerontol. A Biol. Sci. Med. Sci. 59, 255–263 (2004).

    Article  PubMed  Google Scholar 

  225. Motta, F., Sica, A. & Selmi, C. Frailty in rheumatic diseases. Front. Immunol. 11, 576134 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  226. Gijsen, R. et al. Causes and consequences of comorbidity: a review. J. Clin. Epidemiol. 54, 661–674 (2001).

    Article  CAS  PubMed  Google Scholar 

  227. Cacciatore, F. et al. Long-term mortality in frail elderly subjects with osteoarthritis. Rheumatology 53, 293–299 (2014).

    Article  PubMed  Google Scholar 

  228. Bergman, H. et al. Frailty: an emerging research and clinical paradigm–issues and controversies. J. Gerontol. A Biol. Sci. Med. Sci. 62, 731–737 (2007).

    Article  PubMed  Google Scholar 

  229. Hoogendijk, E. O. et al. Frailty: implications for clinical practice and public health. Lancet 394, 1365–1375 (2019).

    Article  PubMed  Google Scholar 

  230. Meessen, J. et al. Frailty in end-stage hip or knee osteoarthritis: validation of the Groningen Frailty Indicator (GFI) questionnaire. Rheumatol. Int. 38, 917–924 (2018).

    Article  PubMed  Google Scholar 

  231. Castell, M. V. et al. Osteoarthritis and frailty in elderly individuals across six European countries: results from the European Project on OSteoArthritis (EPOSA). BMC Musculoskelet. Disord. 16, 359 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  232. Veronese, N. et al. Pain increases the risk of developing frailty in older adults with osteoarthritis. Pain. Med. 18, 414–427 (2017).

    PubMed  Google Scholar 

  233. Salaffi, F., Di Carlo, M., Farah, S., Di Donato, E. & Carotti, M. Prevalence of frailty and its associated factors in patients with rheumatoid arthritis: a cross-sectional analysis. Clin. Rheumatol. 38, 1823–1830 (2019).

    Article  PubMed  Google Scholar 

  234. Katz, P. P. et al. Is frailty a relevant concept in SLE? Lupus Sci. Med. 4, e000186 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  235. Haider, S. et al. Frailty in seropositive rheumatoid arthritis patients of working age: a cross-sectional study. Clin. Exp. Rheumatol. 37, 585–592 (2019).

    PubMed  Google Scholar 

  236. Guler, S. A. et al. Severity and features of frailty in systemic sclerosis-associated interstitial lung disease. Respir. Med. 129, 1–7 (2017).

    Article  PubMed  Google Scholar 

  237. Nurmohamed, M. T., Heslinga, M. & Kitas, G. D. Cardiovascular comorbidity in rheumatic diseases. Nat. Rev. Rheumatol. 11, 693–704 (2015).

    Article  CAS  PubMed  Google Scholar 

  238. Radner, H., Yoshida, K., Smolen, J. S. & Solomon, D. H. Multimorbidity and rheumatic conditions-enhancing the concept of comorbidity. Nat. Rev. Rheumatol. 10, 252–256 (2014).

    Article  PubMed  Google Scholar 

  239. Conti, P., Gallenga, C. E., Caraffa, A., Ronconi, G. & Kritas, S. K. Impact of mast cells in fibromyalgia and low-grade chronic inflammation: can IL-37 play a role? Dermatol. Ther. 33, e13191 (2020).

    Article  CAS  PubMed  Google Scholar 

  240. Wang, W., Zhou, H. & Liu, L. Side effects of methotrexate therapy for rheumatoid arthritis: a systematic review. Eur. J. Med. Chem. 158, 502–516 (2018).

    Article  CAS  PubMed  Google Scholar 

  241. Silvagni, E. et al. One year in review 2020: novelties in the treatment of rheumatoid arthritis. Clin. Exp. Rheumatol. 38, 181–194 (2020).

    Article  PubMed  Google Scholar 

  242. Gomez-Garcia, L. et al. Reduced numbers of circulating CD28-negative CD4+ cells in patients with rheumatoid arthritis chronically treated with abatacept. Int. J. Rheum. Dis. 16, 469–471 (2013).

    Article  CAS  PubMed  Google Scholar 

  243. Scarsi, M., Ziglioli, T. & Airo, P. Decreased circulating CD28-negative T cells in patients with rheumatoid arthritis treated with abatacept are correlated with clinical response. J. Rheumatol. 37, 911–916 (2010).

    Article  CAS  PubMed  Google Scholar 

  244. Gerli, R. et al. CD4+CD28− T lymphocytes contribute to early atherosclerotic damage in rheumatoid arthritis patients. Circulation 109, 2744–2748 (2004).

    Article  CAS  PubMed  Google Scholar 

  245. Kageyama, Y., Takahashi, M., Ichikawa, T., Torikai, E. & Nagano, A. Reduction of oxidative stress marker levels by anti-TNF-α antibody, infliximab, in patients with rheumatoid arthritis. Clin. Exp. Rheumatol. 26, 73–80 (2008).

    CAS  PubMed  Google Scholar 

  246. Kageyama, Y., Takahashi, M., Nagafusa, T., Torikai, E. & Nagano, A. Etanercept reduces the oxidative stress marker levels in patients with rheumatoid arthritis. Rheumatol. Int. 28, 245–251 (2008).

    Article  CAS  PubMed  Google Scholar 

  247. Hirao, M. et al. Serum level of oxidative stress marker is dramatically low in patients with rheumatoid arthritis treated with tocilizumab. Rheumatol. Int. 32, 4041–4045 (2012).

    Article  CAS  PubMed  Google Scholar 

  248. Harty, L. C. et al. Mitochondrial mutagenesis correlates with the local inflammatory environment in arthritis. Ann. Rheum. Dis. 71, 582–588 (2012).

    Article  CAS  PubMed  Google Scholar 

  249. Bruyn, G. A. et al. Everolimus in patients with rheumatoid arthritis receiving concomitant methotrexate: a 3-month, double-blind, randomised, placebo-controlled, parallel-group, proof-of-concept study. Ann. Rheum. Dis. 67, 1090–1095 (2008).

    Article  CAS  PubMed  Google Scholar 

  250. Lai, Z. W. et al. Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial. Lancet 391, 1186–1196 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  251. Kopf, H., de la Rosa, G. M., Howard, O. M. & Chen, X. Rapamycin inhibits differentiation of Th17 cells and promotes generation of FoxP3+ T regulatory cells. Int. Immunopharmacol. 7, 1819–1824 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Mo, C., Zeng, Z., Deng, Q., Ding, Y. & Xiao, R. Imbalance between T helper 17 and regulatory T cell subsets plays a significant role in the pathogenesis of systemic sclerosis. Biomed. Pharmacother. 108, 177–183 (2018).

    Article  CAS  PubMed  Google Scholar 

  253. Papotto, P. H., Reinhardt, A., Prinz, I. & Silva-Santos, B. Innately versatile: γδ17 T cells in inflammatory and autoimmune diseases. J. Autoimmun. 87, 26–37 (2018).

    Article  CAS  PubMed  Google Scholar 

  254. Radstake, T. R. et al. The pronounced Th17 profile in systemic sclerosis (SSc) together with intracellular expression of TGFβ and IFNγ distinguishes SSc phenotypes. PLoS One 4, e5903 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  255. Moon, J. et al. Metformin ameliorates scleroderma via inhibiting Th17 cells and reducing mTOR-STAT3 signaling in skin fibroblasts. J. Transl. Med. 19, 192 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Kulkarni, A. S., Gubbi, S. & Barzilai, N. Benefits of metformin in attenuating the hallmarks of aging. Cell Metab. 32, 15–30 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. American Federation for Aging Research. The TAME trial; targeting the biology of aging. Ushering a new era of interventions [online], https://www.afar.org/tame-trial (2022).

  258. Wang, Y. et al. Association between metformin use and disease progression in obese people with knee osteoarthritis: data from the Osteoarthritis Initiative — a prospective cohort study. Arthritis Res. Ther. 21, 127 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  259. Gharib, M., Elbaz, W., Darweesh, E., Sabri, N. A. & Shawki, M. A. Efficacy and safety of metformin use in rheumatoid arthritis: a randomized controlled study. Front. Pharmacol. 12, 726490 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  260. Zhang, L. X. et al. Resveratrol (RV): a pharmacological review and call for further research. Biomed. Pharmacother. 143, 112164 (2021).

    Article  CAS  PubMed  Google Scholar 

  261. Rubinsztein, D. C., Marino, G. & Kroemer, G. Autophagy and aging. Cell 146, 682–695 (2011).

    Article  CAS  PubMed  Google Scholar 

  262. Carmona-Gutierrez, D., Hughes, A. L., Madeo, F. & Ruckenstuhl, C. The crucial impact of lysosomes in aging and longevity. Ageing Res. Rev. 32, 2–12 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Eisenberg, T. et al. Induction of autophagy by spermidine promotes longevity. Nat. Cell Biol. 11, 1305–1314 (2009).

    Article  CAS  PubMed  Google Scholar 

  264. Zhang, H. et al. Polyamines control eIF5A hypusination, TFEB translation, and autophagy to reverse B cell senescence. Mol. Cell 76, 110–125 e119 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Puleston, D. J. et al. Autophagy is a critical regulator of memory CD8+ T cell formation. Elife 3, e03706 (2014).

    Article  PubMed Central  Google Scholar 

  266. Sacitharan, P. K., Lwin, S., Gharios, G. B. & Edwards, J. R. Spermidine restores dysregulated autophagy and polyamine synthesis in aged and osteoarthritic chondrocytes via EP300. Exp. Mol. Med. 50, 123 (2018).

    Article  PubMed Central  Google Scholar 

  267. Zheng, W. et al. Fisetin inhibits IL-1β-induced inflammatory response in human osteoarthritis chondrocytes through activating SIRT1 and attenuates the progression of osteoarthritis in mice. Int. Immunopharmacol. 45, 135–147 (2017).

    Article  CAS  PubMed  Google Scholar 

  268. Lee, J. D. et al. Flavonol-rich RVHxR from Rhus verniciflua Stokes and its major compound fisetin inhibits inflammation-related cytokines and angiogenic factor in rheumatoid arthritic fibroblast-like synovial cells and in vivo models. Int. Immunopharmacol. 9, 268–276 (2009).

    Article  CAS  PubMed  Google Scholar 

  269. Xu, S. P. & Li, Y. S. Fisetin inhibits pristine-induced systemic lupus erythematosus in a murine model through CXCLs regulation. Int. J. Mol. Med. 42, 3220–3230 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  270. Cribbs, A. P. et al. Methotrexate restores regulatory T cell function through demethylation of the FoxP3 upstream enhancer in patients with rheumatoid arthritis. Arthritis Rheumatol. 67, 1182–1192 (2015).

    Article  CAS  PubMed  Google Scholar 

  271. de Andres, M. C. et al. Assessment of global DNA methylation in peripheral blood cell subpopulations of early rheumatoid arthritis before and after methotrexate. Arthritis Res. Ther. 17, 233 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  272. Garaud, S. et al. IL-6 modulates CD5 expression in B cells from patients with lupus by regulating DNA methylation. J. Immunol. 182, 5623–5632 (2009).

    Article  CAS  PubMed  Google Scholar 

  273. Chen, Y. M. et al. Association between autophagy and inflammation in patients with rheumatoid arthritis receiving biologic therapy. Arthritis Res. Ther. 20, 268 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  274. Krasselt, M., Baerwald, C., Wagner, U. & Rossol, M. CD56+ monocytes have a dysregulated cytokine response to lipopolysaccharide and accumulate in rheumatoid arthritis and immunosenescence. Arthritis Res. Ther. 15, R139 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  275. Smolen, J. S. et al. EULAR recommendations for the management of rheumatoid arthritis with synthetic and biological disease-modifying antirheumatic drugs: 2016 update. Ann. Rheum. Dis. 76, 960–977 (2017).

    Article  PubMed  Google Scholar 

  276. Aletaha, D. & Smolen, J. S. Diagnosis and management of rheumatoid arthritis: a review. JAMA 320, 1360–1372 (2018).

    Article  PubMed  Google Scholar 

  277. Fleischmann, R. et al. Placebo-controlled trial of tofacitinib monotherapy in rheumatoid arthritis. N. Engl. J. Med. 367, 495–507 (2012).

    Article  CAS  PubMed  Google Scholar 

  278. Fleischmann, R. et al. Baricitinib, methotrexate, or combination in patients with rheumatoid arthritis and no or limited prior disease-modifying antirheumatic drug treatment. Arthritis Rheumatol. 69, 506–517 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  279. Illei, G. G. et al. Tocilizumab in systemic lupus erythematosus: data on safety, preliminary efficacy, and impact on circulating plasma cells from an open-label phase I dosage-escalation study. Arthritis Rheum. 62, 542–552 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Shirota, Y. et al. Impact of anti-interleukin-6 receptor blockade on circulating T and B cell subsets in patients with systemic lupus erythematosus. Ann. Rheum. Dis. 72, 118–128 (2013).

    Article  CAS  PubMed  Google Scholar 

  281. Shima, Y. et al. The skin of patients with systemic sclerosis softened during the treatment with anti-IL-6 receptor antibody tocilizumab. Rheumatology 49, 2408–2412 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Su, T. I. et al. Rapamycin versus methotrexate in early diffuse systemic sclerosis: results from a randomized, single-blind pilot study. Arthritis Rheum. 60, 3821–3830 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  283. Reitamo, S. et al. Efficacy of sirolimus (rapamycin) administered concomitantly with a subtherapeutic dose of cyclosporin in the treatment of severe psoriasis: a randomized controlled trial. Br. J. Dermatol. 145, 438–445 (2001).

    Article  CAS  PubMed  Google Scholar 

  284. Sun, F. et al. Effects of metformin on disease flares in patients with systemic lupus erythematosus: post hoc analyses from two randomised trials. Lupus Sci. Med. 7, e000429 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  285. Wang, H., Li, T., Chen, S., Gu, Y. & Ye, S. Neutrophil extracellular trap mitochondrial DNA and its autoantibody in systemic lupus erythematosus and a proof-of-concept trial of metformin. Arthritis Rheumatol. 67, 3190–3200 (2015).

    Article  CAS  PubMed  Google Scholar 

  286. Khojah, H. M., Ahmed, S., Abdel-Rahman, M. S. & Elhakeim, E. H. Resveratrol as an effective adjuvant therapy in the management of rheumatoid arthritis: a clinical study. Clin. Rheumatol. 37, 2035–2042 (2018).

    Article  PubMed  Google Scholar 

  287. Marouf, B. H., Hussain, S. A., Ali, Z. S. & Ahmmad, R. S. Resveratrol supplementation reduces pain and inflammation in knee osteoarthritis patients treated with meloxicam: a randomized placebo-controlled study. J. Med. Food https://doi.org/10.1089/jmf.2017.4176 (2018).

    Article  PubMed  Google Scholar 

  288. Justice, J. N. et al. Senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label, pilot study. EBioMedicine 40, 554–563 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  289. Hus, B. E. A. S. Tolerability, pharmacokinetics, and clinical outcomes following single-dose IA administration of UBX0101, a senolytic MDM2/p53 interaction inhibitor, in patients with knee OA [abstract]. Arthritis Rheumatol. https://doi.org/10.1002/art.41108 (2019).

    Article  Google Scholar 

  290. Smolen, J. S. et al. Effect of interleukin-6 receptor inhibition with tocilizumab in patients with rheumatoid arthritis (OPTION study): a double-blind, placebo-controlled, randomised trial. Lancet 371, 987–997 (2008).

    Article  CAS  PubMed  Google Scholar 

  291. Richette, P. et al. Efficacy of tocilizumab in patients with hand osteoarthritis: double blind, randomised, placebo-controlled, multicentre trial. Ann. Rheum. Dis. 80, 349–355 (2020).

    Article  PubMed  Google Scholar 

  292. Khanna, D. et al. Safety and efficacy of subcutaneous tocilizumab in adults with systemic sclerosis (faSScinate): a phase 2, randomised, controlled trial. Lancet 387, 2630–2640 (2016).

    Article  CAS  PubMed  Google Scholar 

  293. Khanna, D. et al. Long-term safety and efficacy of tocilizumab in early systemic sclerosis-interstitial lung disease: open label extension of a phase 3 randomized controlled trial. Am. J. Respir. Crit. Care Med. 205, 674–684 (2021).

    Article  Google Scholar 

  294. Opoka-Winiarska, V. et al. Long-term, interventional, open-label extension study evaluating the safety of tocilizumab treatment in patients with polyarticular-course juvenile idiopathic arthritis from Poland and Russia who completed the global, international CHERISH trial. Clin. Rheumatol. 37, 1807–1816 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  295. Mease, P. J. et al. The efficacy and safety of clazakizumab, an anti-interleukin-6 monoclonal antibody, in a phase IIb study of adults with active psoriatic arthritis. Arthritis Rheumatol. 68, 2163–2173 (2016).

    Article  CAS  PubMed  Google Scholar 

  296. Wallace, D. J. et al. Efficacy and safety of an interleukin 6 monoclonal antibody for the treatment of systemic lupus erythematosus: a phase II dose-ranging randomised controlled trial. Ann. Rheum. Dis. 76, 534–542 (2017).

    Article  CAS  PubMed  Google Scholar 

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Authors and Affiliations

  1. The Kennedy Institute of Rheumatology, NDORMS, University of Oxford, Oxford, UK

    Ghada Alsaleh, Felix C. Richter & Anna K. Simon

  2. Botnar Research Centre, NDORMS, University of Oxford, Oxford, UK

    Ghada Alsaleh

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Alsaleh, G., Richter, F.C. & Simon, A.K. Age-related mechanisms in the context of rheumatic disease. Nat Rev Rheumatol 18, 694–710 (2022). https://doi.org/10.1038/s41584-022-00863-8

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