Inflammaging

Inflamm-aging (also known as inflammaging or inflamm-ageing) is a chronic low-grade inflammation that develops with advanced age. It is believed to accelerate the process of biological aging and to worsen many age-related diseases.

Characteristics

The immune system declines as aging persists. This drastically affects an individual's adaptive immune system. It causes it to become less effective as the B and T lymphocyte numbers gradually reduce as time passes by. These cells can be seen in the bone marrow, thymus, and the mature lymphocytes found in the secondary lymphoid tissues. This was seen when the elderly were given vaccinations. They were very much less effective. [1]

While effectiveness of adaptive immune system declines, innate immune mechanisms become more active.[2] This is represented by increased number of natural killer cells and increased production of pro-inflammatory cytokines.[2] This chronic activation of innate immune system results in a low-grade chronic inflammation development in the elderly. This phenomenon was termed as inflamm-aging.[3] Inflamm-aging is described as a low grade, chronic, controlled and asymptomatic inflammation which occurs in the absence of infection and is primarily driven by endogenous signals.[3][4] Key molecules associated with inflamm-aging are elevated pro-inflammatory cytokines, especially IL-6, TNFα and C-reactive protein (CRP).[5][6] This chronic inflamed state has detrimental effect on health and contributes to biological ageing and development of age-related pathologies.[3] Inflamm-aging was shown to help development and worsen course of Alzheimer's disease,[7] atherosclerosis,[8] type II diabetes and chronic heart diseases.[9]

Causes

As inflamm-aging is a complex and systemic issue, it is likely that inflammaging is a result of several factors. It seems that the major cause of inflamm-aging is accumulation of misplaced and misfolded self-molecules from damaged cells.[10] These molecules are recognized by receptors of innate immune cells which leads to their activation and consequently to inflammation. Cell components which can stimulate innate cells include microRNAs, mitochondrial DNA or histones.

Senescent cells increase with aging, and senescent cells secrete a pro-inflammatory cocktail of chemicals, a condition known as senescence-associated secretory phenotype (SASP).[11]

Inflamm-aging has been also associated with persistent Cytomegalovirus infection. Cytomegalovirus drives up production of a variety of inflammatory cytokines and also results in expansion of CMV specific memory T cells.[12] Other possible factors that may lead to inflamm-aging include overnutrition, altered gut microbiome, impaired intestinal epithelial barrier, and chronic stress occurring in any stage of the individual's life.[13][14][15] Cytokines with inflammatory properties can also be secreted by fat tissue.[16]

Proposed interventions

Use of low-dose aspirin, exercise, and statins are therapies for inflammaging already in common use.[11] Possible future therapies include senolytic drugs, probiotics, cytomegalovirus vaccine, and thymic replacement.[11] or thymic rejuvenation[17]

References
  1. Montecino-Rodriguez, Encarnacion et al. “Causes, consequences, and reversal of immune system aging.” The Journal of clinical investigation vol. 123,3 (2013): 958-65. doi:10.1172/JCI64096
  2. Panda A, Arjona A, Sapey E, Bai F, Fikrig E, Montgomery RR, Lord JM, Shaw AC (July 2009). "Human innate immunosenescence: causes and consequences for immunity in old age". Trends in Immunology. 30 (7): 325–33. doi:10.1016/j.it.2009.05.004. PMC 4067971. PMID 19541535.
  3. Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (June 2000). "Inflamm-aging. An evolutionary perspective on immunosenescence". Annals of the New York Academy of Sciences. 908 (1): 244–54. Bibcode:2000NYASA.908..244F. doi:10.1111/j.1749-6632.2000.tb06651.x. PMID 10911963. S2CID 1843716.
  4. Giunta S (December 2006). "Is inflammaging an auto[innate]immunity subclinical syndrome?". Immunity & Ageing. 3: 12. doi:10.1186/1742-4933-3-12. OCLC 834287459. PMC 1716179. PMID 17173699.
  5. De Martinis M, Franceschi C, Monti D, Ginaldi L (April 2005). "Inflamm-ageing and lifelong antigenic load as major determinants of ageing rate and longevity". FEBS Letters. 579 (10): 2035–9. doi:10.1016/j.febslet.2005.02.055. PMID 15811314. S2CID 10250457.
  6. Scott WN, Strand FL (1984). First Colloquium in Biological Sciences. New York Academy of Sciences. ISBN 0897662644. OCLC 11649336.
  7. Giunta B, Fernandez F, Nikolic WV, Obregon D, Rrapo E, Town T, Tan J (November 2008). "Inflammaging as a prodrome to Alzheimer's disease". Journal of Neuroinflammation. 5 (1): 51. doi:10.1186/1742-2094-5-51. PMC 2615427. PMID 19014446.
  8. Boren E, Gershwin ME (July 2004). "Inflamm-aging: autoimmunity, and the immune-risk phenotype". Autoimmunity Reviews. 3 (5): 401–6. doi:10.1016/j.autrev.2004.03.004. PMID 15288008.
  9. Fülöp T, Dupuis G, Witkowski JM, Larbi A (2016-03-01). "The Role of Immunosenescence in the Development of Age-Related Diseases". Revista de Investigacion Clinica. 68 (2): 84–91. PMID 27103044.
  10. Franceschi C, Garagnani P, Vitale G, Capri M, Salvioli S (March 2017). "Inflammaging and 'Garb-aging'". Trends in Endocrinology and Metabolism. 28 (3): 199–212. doi:10.1016/j.tem.2016.09.005. hdl:11585/579512. PMID 27789101. S2CID 5914681.
  11. Franceschi C, Campisi J (2014). "Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases". Journal of Gerontology: Biological Sciences. 69 (Supp 1): s4–s9. doi:10.1093/gerona/glu057. PMID 24833586.
  12. Aiello AE, Chiu YL, Frasca D (June 2017). "How does cytomegalovirus factor into diseases of aging and vaccine responses, and by what mechanisms?". GeroScience. 39 (3): 261–271. doi:10.1007/s11357-017-9983-9. PMC 5505887. PMID 28624868.
  13. Franceschi C, Garagnani P, Parini P, Giuliani C, Santoro A (October 2018). "Inflammaging: a new immune-metabolic viewpoint for age-related diseases". Nature Reviews. Endocrinology. 14 (10): 576–590. doi:10.1038/s41574-018-0059-4. hdl:11585/675065. PMID 30046148. S2CID 50785788.
  14. Meier J, Sturm A (2009). "The intestinal epithelial barrier: does it become impaired with age?". Digestive Diseases. 27 (3): 240–5. doi:10.1159/000228556. PMID 19786747. S2CID 40407420.
  15. Kiecolt-Glaser JK, Preacher KJ, MacCallum RC, Atkinson C, Malarkey WB, Glaser R (July 2003). "Chronic stress and age-related increases in the proinflammatory cytokine IL-6". Proceedings of the National Academy of Sciences of the United States of America. 100 (15): 9090–5. Bibcode:2003PNAS..100.9090K. doi:10.1073/pnas.1531903100. PMC 166443. PMID 12840146.
  16. Pedersen M, Bruunsgaard H, Weis N, Hendel HW, Andreassen BU, Eldrup E, Dela F, Pedersen BK (April 2003). "Circulating levels of TNF-alpha and IL-6-relation to truncal fat mass and muscle mass in healthy elderly individuals and in patients with type-2 diabetes". Mechanisms of Ageing and Development. 124 (4): 495–502. doi:10.1016/s0047-6374(03)00027-7. PMID 12714258. S2CID 20234017.
  17. Oh, J., Wang, W., Thomas, R., & Su, D. M. (2020). Thymic rejuvenation via induced thymic epithelial cells (iTECs) from FOXN1-overexpressing fibroblasts to counteract inflammaging. bioRxiv. https://doi.org/10.1101/2020.03.17.995357
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