Immunosenescence

Last updated

Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. A 2020 review concluded that the adaptive immune system is affected more than the innate immune system. [1] Immunosenescence involves both the host's capacity to respond to infections and the development of long-term immune memory. Age-associated immune deficiency is found in both long- and short-lived species as a function of their age relative to life expectancy rather than elapsed time. [2]

Contents

It has been studied in animal models including mice, marsupials and monkeys. [3] [4] [5] Immunosenescence is a contributory factor to the increased frequency of morbidity and mortality among the elderly. Along with anergy and T-cell exhaustion, immunosenescence belongs among the major immune system dysfunctional states. However, while T-cell anergy is a reversible condition, as of 2020 no techniques for immunosenescence reversal had been developed. [6] [7]

Immunosenescence is not a random deteriorative phenomenon, rather it appears to inversely recapitulate an evolutionary pattern. Most of the parameters affected by immunosenescence appear to be under genetic control. [8] Immunosenescence can be envisaged as the result of the continuous challenge of the unavoidable exposure to a variety of antigens such as viruses and bacteria. [9]

Age-associated decline in immune function

Aging of the immune system is a controversial phenomenon. Senescence refers to replicative senescence from cell biology, which describes the condition when the upper limit of cell divisions (Hayflick limit) has been exceeded, and such cells commit apoptosis or lose their functional properties. Immunosenescence generally means a robust shift in both structural and functional parameters that has a clinically relevant outcome. [10] Thymus involution is probably the most relevant factor responsible for immunosenescence. Thymic involution is common in most mammals; in humans it begins after puberty, as the immunological defense against most novel antigens is necessary mainly during infancy and childhood. [11]

The major characteristic of the immunosenescent phenotype is a shift in T-cell subpopulation distribution. As the thymus involutes, the number of naive T cells (especially CD8+) decreases, thus naive T cells homeostatically proliferate into memory T cells as a compensation. [5] It is believed that the conversion to memory phenotype can be accelerated by restimulation of the immune system by persistent pathogens such as CMV and HSV. By age 40, an estimated 50% to 85% of adults have contracted human cytomegalovirus (HCMV). [1] Recurring infections by latent herpes viruses can exhaust the immune system of elderly persons. [12] Consistent, repeated stimulation by such pathogens leads to preferential differentiation of the T-cell memory phenotype, and a 2020 review reported that CD8+ T-cell precursors, specific for the most rare and less frequently present antigens shed the most. [5] Such a distribution shift leads to increased susceptibility to non-persistent infection, cancer, autoimmune diseases, cardiovascular health conditions and many others. [13] [14]

T cells are not the only immune cells affected by aging:

In addition to changes in immune responses, the beneficial effects of inflammation devoted to the neutralisation of dangerous and harmful agents early in life and in adulthood become detrimental late in life in a period largely not foreseen by evolution, according to the antagonistic pleiotropy theory of aging. [25] Changes in the lymphoid compartment are not solely responsible for the malfunctioning of the immune system. Although myeloid cell production does not seem to decline with age, macrophages become dysregulated as a consequence of environmental changes. [26]

T-cell biomarkers of age-dependent dysfunction

T cells' functional capacity is most influenced by aging effects. Age-related alterations are evident in all T-cell development stages, making them a significant factor in immunosenescence. [27] T-cell function decline begins with the progressive involution of the thymus, which is the organ essential for T-cell maturation. This decline in turn reduces IL-2 production [28] [29] and reduction/exhaustion on the number of thymocytes (i.e. immature T cells), thus reducing peripheral naïve T cell output. [30] [31] Once matured and circulating throughout the peripheral system, T cells undergo deleterious age-dependent changes. This leaves the body practically devoid of virgin T cells, which makes it more prone to a variety of diseases. [9]

Challenges

The elderly frequently present with non-specific signs and symptoms, and clues of focal infection are often absent or obscured by chronic conditions. [2] This complicates diagnosis and treatment.

Vaccination in the elderly

The reduced efficacy of vaccination in the elderly stems from their restricted ability to respond to immunization with novel non-persistent pathogens, and correlates with both CD4:CD8 alterations and impaired dendritic cell function. [48] Therefore, vaccination in earlier life stages seems more likely to be effective, although the duration of the effect varies by pathogen. [49] [10]

Rescue of the advanced-age phenotype

Removal of senescent cells with senolytic compounds has been proposed as a method of enhancing immunity during aging. [50]

Immune system aging in mice can be partly restricted by restoring thymus growth, which can be achieved by transplantation of proliferative thymic epithelial cells from young mice. [51] Metformin has been proven to moderate aging in preclinical studies. [52] Its protective effect is probably caused primarily by impaired mitochondria metabolism, particularly decreased reactive oxygen production [53] or increased AMP:ATP ratio [54] and lower NAD/NADH ratio. Coenzyme NAD+ is reduced in various tissues in an age-dependent manner, and thus redox potential associated changes seem to be critical in the aging process, [55] and NAD+ supplements may have protective effects. [56] Rapamycin, an antitumor and immunosuppresant, acts similarly. [57]

Related Research Articles

<span class="mw-page-title-main">T cell</span> White blood cells of the immune system

T cells are one of the important types of white blood cells of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell surface.

<span class="mw-page-title-main">T helper cell</span> Type of immune cell

The T helper cells (Th cells), also known as CD4+ cells or CD4-positive cells, are a type of T cell that play an important role in the adaptive immune system. They aid the activity of other immune cells by releasing cytokines. They are considered essential in B cell antibody class switching, breaking cross-tolerance in dendritic cells, in the activation and growth of cytotoxic T cells, and in maximizing bactericidal activity of phagocytes such as macrophages and neutrophils. CD4+ cells are mature Th cells that express the surface protein CD4. Genetic variation in regulatory elements expressed by CD4+ cells determines susceptibility to a broad class of autoimmune diseases.

The regulatory T cells (Tregs or Treg cells), formerly known as suppressor T cells, are a subpopulation of T cells that modulate the immune system, maintain tolerance to self-antigens, and prevent autoimmune disease. Treg cells are immunosuppressive and generally suppress or downregulate induction and proliferation of effector T cells. Treg cells express the biomarkers CD4, FOXP3, and CD25 and are thought to be derived from the same lineage as naïve CD4+ cells. Because effector T cells also express CD4 and CD25, Treg cells are very difficult to effectively discern from effector CD4+, making them difficult to study. Research has found that the cytokine transforming growth factor beta (TGF-β) is essential for Treg cells to differentiate from naïve CD4+ cells and is important in maintaining Treg cell homeostasis.

Memory T cells are a subset of T lymphocytes that might have some of the same functions as memory B cells. Their lineage is unclear.

<span class="mw-page-title-main">Interleukin 21</span> Mammalian protein found in humans

Interleukin 21 (IL-21) is a protein that in humans is encoded by the IL21 gene.

<span class="mw-page-title-main">CD86</span> Mammalian protein found in Homo sapiens

Cluster of Differentiation 86 is a protein constitutively expressed on dendritic cells, Langerhans cells, macrophages, B-cells, and on other antigen-presenting cells. Along with CD80, CD86 provides costimulatory signals necessary for T cell activation and survival. Depending on the ligand bound, CD86 can signal for self-regulation and cell-cell association, or for attenuation of regulation and cell-cell disassociation.

<span class="mw-page-title-main">CD83</span>

CD83 is a human protein encoded by the CD83 gene.

<span class="mw-page-title-main">B3GAT1</span> Protein-coding gene in the species Homo sapiens

3-beta-glucuronosyltransferase 1 (B3GAT1) is an enzyme that in humans is encoded by the B3GAT1 gene, whose enzymatic activity creates the CD57 epitope on other cell surface proteins. In immunology, the CD57 antigen is also known as HNK1 or LEU7. It is expressed as a carbohydrate epitope that contains a sulfoglucuronyl residue in several adhesion molecules of the nervous system.

<span class="mw-page-title-main">Lymphocyte-activation gene 3</span>

Lymphocyte-activation gene 3, also known as LAG-3, is a protein which in humans is encoded by the LAG3 gene. LAG3, which was discovered in 1990 and was designated CD223 after the Seventh Human Leucocyte Differentiation Antigen Workshop in 2000, is a cell surface molecule with diverse biological effects on T cell function but overall has an immune inhibitory effect. It is an immune checkpoint receptor and as such is the target of various drug development programs by pharmaceutical companies seeking to develop new treatments for cancer and autoimmune disorders. In soluble form it is also being developed as a cancer drug in its own right.

<span class="mw-page-title-main">BTLA</span> Protein-coding gene in the species Homo sapiens

B- and T-lymphocyte attenuator or BTLA is a protein that belongs to the CD28 immunoglobulin superfamily (IgSF) which is encoded by the BTLA gene located on the 3rd human chromosome. BTLA was first discovered in 2003 as an inhibitor of Th1 expansion and it became the 3rd member of the CD28 IgSF. However, its discovered ligand herpes virus entry mediator or HVEM belongs to the tumor necrosis factor receptor superfamily (TNFRSF). This finding was surprising because until the discovery of HVEM it was believed that receptors and ligands always belong to the same family.

<span class="mw-page-title-main">KLRG1</span> Protein-coding gene in humans

Killer cell lectin-like receptor subfamily G member 1 is a protein that in humans is encoded by the KLRG1 gene.

<span class="mw-page-title-main">CD8A</span> Protein-coding gene in the species Homo sapiens

CD8a, is a human gene.

<span class="mw-page-title-main">Follicular B helper T cells</span>

Follicular helper T cells (also known as T follicular helper cells and abbreviated as TFH), are antigen-experienced CD4+ T cells found in the periphery within B cell follicles of secondary lymphoid organs such as lymph nodes, spleen and Peyer's patches, and are identified by their constitutive expression of the B cell follicle homing receptor CXCR5. Upon cellular interaction and cross-signaling with their cognate follicular (Fo B) B cells, TFH cells trigger the formation and maintenance of germinal centers through the expression of CD40 ligand (CD40L) and the secretion of IL-21 and IL-4. TFH cells also migrate from T cell zones into these seeded germinal centers, predominantly composed of rapidly dividing B cells mutating their Ig genes. Within germinal centers, TFH cells play a critical role in mediating the selection and survival of B cells that go on to differentiate either into long-lived plasma cells capable of producing high affinity antibodies against foreign antigen, or germinal center-dependent memory B cells capable of quick immune re-activation in the future if ever the same antigen is re-encountered. TFH cells are also thought to facilitate negative selection of potentially autoimmune-causing mutated B cells in the germinal center. However, the biomechanisms by which TFH cells mediate germinal center tolerance are yet to be fully understood.

Thymic involution is the shrinking (involution) of the thymus with age, resulting in changes in the architecture of the thymus and a decrease in tissue mass. Thymus involution is one of the major characteristics of vertebrate immunology, and occurs in almost all vertebrates, from birds, teleosts, amphibians to reptiles, though the thymi of a few species of sharks are known not to involute. This process is genetically regulated, with the nucleic material responsible being an example of a conserved sequence — one maintained through natural selection since it arose in a common ancestor of all species now exhibiting it, via a phenomenon known to bioinformaticists as an orthologic sequence homology.

MHC multimers are oligomeric forms of MHC molecules, designed to identify and isolate T-cells with high affinity to specific antigens amid a large group of unrelated T-cells. Multimers generally range in size from dimers to octamers; however, some companies use even higher quantities of MHC per multimer. Multimers may be used to display class 1 MHC, class 2 MHC, or nonclassical molecules from species such as monkeys, mice, and humans.

T-cell receptor revision is a process in the peripheral immune system which is used by mature T cells to alter their original antigenic specificity based on rearranged T cell receptors (TCR). This process can lead either to continuous appearance of potentially self-reactive T cells in the body, not controlled by the central tolerance mechanism in the thymus or better eliminate such self-reactive T cells on the other hand and thus contributing to peripheral tolerance – the extent of each has not been completely understood yet. This process occurs during follicular helper T cell formation in lymph node germinal centers.

The CD4+/CD8+ ratio is the ratio of T helper cells (with the surface marker CD4) to cytotoxic T cells (with the surface marker CD8). Both CD4+ and CD8+ T cells contain several subsets.

Tissue-resident memory T cells or TRM cells represent a subset of a long-lived memory T cells that occupies epithelial, mucosal and other tissues without recirculating. TRM cells are transcriptionally, phenotypically and functionally distinct from central memory (TCM) and effector memory (TEM) T cells which recirculate between blood, the T cell zones of secondary lymphoid organ, lymph and nonlymphoid tissues. Moreover, TRM cells themself represent a diverse populations because of the specializations for the resident tissues. The main role of TRM cells is to provide superior protection against infection in extralymphoid tissues.

<span class="mw-page-title-main">Franca Ronchese</span> Italian-New Zealand immunologist

Franca Ronchese is an Italian-New Zealand immunologist. She currently leads the immune cell biology programme at the Malaghan Institute of Medical Research in Wellington, New Zealand and is a research professor at Victoria University of Wellington.

<span class="mw-page-title-main">Inflammaging</span> Chronic low-grade inflammation that develops with advanced age

Inflammaging is a chronic, sterile, low-grade inflammation that develops with advanced age, in the absence of overt infection, and may contribute to clinical manifestations of other age-related pathologies. Inflammaging is thought to be caused by a loss of control over systemic inflammation resulting in chronic overstimulation of the innate immune system. Inflammaging is a significant risk factor in mortality and morbidity in aged individuals.

References

  1. 1 2 Pangrazzi L, Weinberger B (February 2020). "T cells, aging and senescence". Experimental Gerontology. 134: 110887. doi:10.1016/j.exger.2020.110887. PMID   32092501. S2CID   211237913.
  2. 1 2 Ginaldi L, Loreto MF, Corsi MP, Modesti M, De Martinis M (August 2001). "Immunosenescence and infectious diseases". Microbes and Infection. 3 (10): 851–857. doi:10.1016/S1286-4579(01)01443-5. PMID   11580980.
  3. ↑ Letendre C, Sawyer E, Young LJ, Old JM (2018). "Immunosenescence in a captive semelparous marsupial, the red-tailed phascogale (Phascogale calura)". BMC Zoology. 3: 10. doi: 10.1186/s40850-018-0036-3 . S2CID   53496572.
  4. ↑ Letendre C, Young LJ, Old JM (October 2018). "Limitations in the isolation and stimulation of splenic mononuclear cells in a dasyurid marsupial, Phascogale calura". BMC Research Notes. 11 (1): 712. doi: 10.1186/s13104-018-3824-5 . PMC   6180634 . PMID   30305168.
  5. 1 2 3 Nikolich-Zugich J, Rudd BD (August 2010). "Immune memory and aging: an infinite or finite resource?". Current Opinion in Immunology. 22 (4): 535–540. doi:10.1016/j.coi.2010.06.011. PMC   2925022 . PMID   20674320.
  6. 1 2 Crespo J, Sun H, Welling TH, Tian Z, Zou W (April 2013). "T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment". Current Opinion in Immunology. 25 (2): 214–221. doi:10.1016/j.coi.2012.12.003. PMC   3636159 . PMID   23298609.
  7. ↑ Zhang Z, Liu S, Zhang B, Qiao L, Zhang Y, Zhang Y (2020). "T Cell Dysfunction and Exhaustion in Cancer". Frontiers in Cell and Developmental Biology. 8: 17. doi: 10.3389/fcell.2020.00017 . PMC   7027373 . PMID   32117960.
  8. 1 2 3 Franceschi C, Valensin S, Fagnoni F, Barbi C, Bonafè M (December 1999). "Biomarkers of immunosenescence within an evolutionary perspective: the challenge of heterogeneity and the role of antigenic load". Experimental Gerontology. 34 (8): 911–921. doi:10.1016/S0531-5565(99)00068-6. PMID   10673145. S2CID   32614875.
  9. 1 2 Franceschi C, Bonafè M, Valensin S (February 2000). "Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space". Vaccine. 18 (16): 1717–1720. doi:10.1016/S0264-410X(99)00513-7. PMID   10689155.
  10. 1 2 3 Pawelec G (May 2018). "Age and immunity: What is "immunosenescence"?". Experimental Gerontology. 105: 4–9. doi:10.1016/j.exger.2017.10.024. PMID   29111233. S2CID   46819839.
  11. ↑ Shanley DP, Aw D, Manley NR, Palmer DB (July 2009). "An evolutionary perspective on the mechanisms of immunosenescence". Trends in Immunology. 30 (7): 374–381. doi:10.1016/j.it.2009.05.001. PMID   19541538.
  12. ↑ Nikolich-Zugich J (2008). "Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections". Nature Reviews Immunology . 8 (7): 512–522. doi:10.1038/nri2318. PMC   5573867 . PMID   18469829.
  13. ↑ Hakim FT, Gress RE (September 2007). "Immunosenescence: deficits in adaptive immunity in the elderly". Tissue Antigens. 70 (3): 179–189. doi: 10.1111/j.1399-0039.2007.00891.x . PMID   17661905.
  14. ↑ Haq K, McElhaney JE (August 2014). "Immunosenescence: Influenza vaccination and the elderly". Current Opinion in Immunology. 29: 38–42. doi:10.1016/j.coi.2014.03.008. PMID   24769424.
  15. ↑ Monga I, Kaur K, Dhanda S (March 2022). "Revisiting hematopoiesis: applications of the bulk and single-cell transcriptomics dissecting transcriptional heterogeneity in hematopoietic stem cells". Briefings in Functional Genomics. 21 (3): 159–176. doi:10.1093/bfgp/elac002. PMID   35265979.
  16. ↑ High frequency electromagnetic waves such as gamma and xrays can penetrate and damage DNA. Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, et al. (October 2004). "Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells". Nature. 431 (7011): 997–1002. Bibcode:2004Natur.431..997I. doi:10.1038/nature02989. PMID   15496926. S2CID   4370804.
  17. ↑ Lord JM, Butcher S, Killampali V, Lascelles D, Salmon M (September 2001). "Neutrophil ageing and immunesenescence". Mechanisms of Ageing and Development. 122 (14): 1521–1535. doi:10.1016/S0047-6374(01)00285-8. PMID   11511394. S2CID   1898942.
  18. ↑ Stout RD, Suttles J (June 2005). "Immunosenescence and macrophage functional plasticity: dysregulation of macrophage function by age-associated microenvironmental changes". Immunological Reviews. 205: 60–71. doi:10.1111/j.0105-2896.2005.00260.x. PMC   1201508 . PMID   15882345.
  19. ↑ Bruunsgaard H, Pedersen AN, Schroll M, Skinhøj P, Pedersen BK (December 2001). "Decreased natural killer cell activity is associated with atherosclerosis in elderly humans". Experimental Gerontology. 37 (1): 127–136. doi:10.1016/S0531-5565(01)00162-0. PMID   11738153. S2CID   32717204.
  20. 1 2 Mocchegiani E, Malavolta M (August 2004). "NK and NKT cell functions in immunosenescence". Aging Cell. 3 (4): 177–184. doi: 10.1111/j.1474-9728.2004.00107.x . PMID   15268751. S2CID   19710282.
  21. ↑ Uyemura K, Castle SC, Makinodan T (April 2002). "The frail elderly: role of dendritic cells in the susceptibility of infection". Mechanisms of Ageing and Development. 123 (8): 955–962. doi:10.1016/S0047-6374(02)00033-7. PMID   12044944. S2CID   11558962.
  22. ↑ Sanchez-Correa B, Campos C, Pera A, Bergua JM, Arcos MJ, Bañas H, et al. (April 2016). "Natural killer cell immunosenescence in acute myeloid leukaemia patients: new targets for immunotherapeutic strategies?". Cancer Immunology, Immunotherapy. 65 (4): 453–463. doi:10.1007/s00262-015-1720-6. PMID   26059279. S2CID   20498123.
  23. ↑ Gibson KL, Wu YC, Barnett Y, Duggan O, Vaughan R, Kondeatis E, et al. (February 2009). "B-cell diversity decreases in old age and is correlated with poor health status". Aging Cell. 8 (1): 18–25. doi:10.1111/j.1474-9726.2008.00443.x. PMC   2667647 . PMID   18986373.
  24. ↑ Han S, Yang K, Ozen Z, Peng W, Marinova E, Kelsoe G, Zheng B (February 2003). "Enhanced differentiation of splenic plasma cells but diminished long-lived high-affinity bone marrow plasma cells in aged mice". Journal of Immunology. 170 (3): 1267–1273. doi: 10.4049/jimmunol.170.3.1267 . PMID   12538685.
  25. ↑ 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): 244–254. Bibcode:2000NYASA.908..244F. doi:10.1111/j.1749-6632.2000.tb06651.x. PMID   10911963. S2CID   1843716.
  26. ↑ Cambier J (June 2005). "Immunosenescence: a problem of lymphopoiesis, homeostasis, microenvironment, and signaling". Immunological Reviews. 205: 5–6. doi:10.1111/j.0105-2896.2005.00276.x. PMID   15882340. S2CID   39130596.
  27. ↑ Linton PJ, Lustgarten J, Thoman M (2006). "T cell function in the aged: Lessons learned from animal models". Clinical and Applied Immunology Reviews. 6 (2): 73–97. doi:10.1016/j.cair.2006.06.001.
  28. ↑ Effros RB (April 2004). "Replicative senescence of CD8 T cells: effect on human ageing". Experimental Gerontology. 39 (4): 517–524. doi:10.1016/j.exger.2003.09.024. PMID   15050285. S2CID   2954461.
  29. ↑ Malek TR, Bayer AL (September 2004). "Tolerance, not immunity, crucially depends on IL-2". Nature Reviews. Immunology. 4 (9): 665–674. doi:10.1038/nri1435. PMID   15343366. S2CID   8449323.
  30. ↑ Aspinall R, Andrew D (July 2000). "Thymic involution in aging". Journal of Clinical Immunology. 20 (4): 250–256. doi:10.1023/A:1006611518223. PMID   10939712. S2CID   25042349.
  31. ↑ Min H, Montecino-Rodriguez E, Dorshkind K (July 2004). "Reduction in the developmental potential of intrathymic T cell progenitors with age". Journal of Immunology. 173 (1): 245–250. doi: 10.4049/jimmunol.173.1.245 . PMID   15210781.
  32. ↑ Hadrup SR, Strindhall J, Køllgaard T, Seremet T, Johansson B, Pawelec G, et al. (February 2006). "Longitudinal studies of clonally expanded CD8 T cells reveal a repertoire shrinkage predicting mortality and an increased number of dysfunctional cytomegalovirus-specific T cells in the very elderly". Journal of Immunology. 176 (4): 2645–2653. doi: 10.4049/jimmunol.176.4.2645 . PMID   16456027.
  33. 1 2 3 4 Voehringer D, Koschella M, Pircher H (November 2002). "Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1)". Blood. 100 (10): 3698–3702. doi: 10.1182/blood-2002-02-0657 . PMID   12393723.
  34. ↑ Lefebvre JS, Maue AC, Eaton SM, Lanthier PA, Tighe M, Haynes L (October 2012). "The aged microenvironment contributes to the age-related functional defects of CD4 T cells in mice". Aging Cell. 11 (5): 732–740. doi:10.1111/j.1474-9726.2012.00836.x. PMC   3444657 . PMID   22607653.
  35. ↑ Fülöp T, Gagné D, Goulet AC, Desgeorges S, Lacombe G, Arcand M, Dupuis G (April 1999). "Age-related impairment of p56lck and ZAP-70 activities in human T lymphocytes activated through the TcR/CD3 complex". Experimental Gerontology. 34 (2): 197–216. doi:10.1016/S0531-5565(98)00061-8. PMID   10363787. S2CID   42659829.
  36. 1 2 Murciano C, Villamón E, Yáñez A, O'Connor JE, Gozalbo D, Gil ML (December 2006). "Impaired immune response to Candida albicans in aged mice". Journal of Medical Microbiology. 55 (Pt 12): 1649–1656. doi: 10.1099/jmm.0.46740-0 . PMID   17108267.
  37. 1 2 Ouyang Q, Wagner WM, Voehringer D, Wikby A, Klatt T, Walter S, et al. (August 2003). "Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1)". Experimental Gerontology. 38 (8): 911–920. doi:10.1016/S0531-5565(03)00134-7. PMID   12915213. S2CID   44591282.
  38. 1 2 Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E, et al. (June 2005). "The influence of age on T cell generation and TCR diversity". Journal of Immunology. 174 (11): 7446–7452. doi: 10.4049/jimmunol.174.11.7446 . PMID   15905594.
  39. 1 2 Weng NP (May 2006). "Aging of the immune system: how much can the adaptive immune system adapt?". Immunity. 24 (5): 495–499. doi:10.1016/j.immuni.2006.05.001. PMC   2266981 . PMID   16713964.
  40. ↑ Huff WX, Kwon JH, Henriquez M, Fetcko K, Dey M (June 2019). "The Evolving Role of CD8+CD28− Immunosenescent T Cells in Cancer Immunology". International Journal of Molecular Sciences. 20 (11): 2810. doi: 10.3390/ijms20112810 . PMC   6600236 . PMID   31181772.
  41. ↑ Manser AR, Uhrberg M (April 2016). "Age-related changes in natural killer cell repertoires: impact on NK cell function and immune surveillance". Cancer Immunology, Immunotherapy. 65 (4): 417–426. doi:10.1007/s00262-015-1750-0. PMID   26288343. S2CID   32642259.
  42. ↑ Yang OO, Lin H, Dagarag M, Ng HL, Effros RB, Uittenbogaart CH (February 2005). "Decreased perforin and granzyme B expression in senescent HIV-1-specific cytotoxic T lymphocytes". Virology. 332 (1): 16–19. doi: 10.1016/j.virol.2004.11.028 . PMID   15661136.
  43. ↑ Sunderkötter C, Kalden H, Luger TA (October 1997). "Aging and the skin immune system". Archives of Dermatology. 133 (10): 1256–1262. doi:10.1001/archderm.133.10.1256. PMID   9382564.
  44. ↑ Shimatani K, Nakashima Y, Hattori M, Hamazaki Y, Minato N (September 2009). "PD-1+ memory phenotype CD4+ T cells expressing C/EBPalpha underlie T cell immunodepression in senescence and leukemia". Proceedings of the National Academy of Sciences of the United States of America. 106 (37): 15807–15812. Bibcode:2009PNAS..10615807S. doi: 10.1073/pnas.0908805106 . PMC   2739871 . PMID   19805226.
  45. ↑ Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, et al. (September 2014). "p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8⁺ T cells". The Journal of Clinical Investigation. 124 (9): 4004–4016. doi:10.1172/JCI75051. PMC   4151208 . PMID   25083993.
  46. ↑ Tahir S, Fukushima Y, Sakamoto K, Sato K, Fujita H, Inoue J, et al. (June 2015). "A CD153+CD4+ T follicular cell population with cell-senescence features plays a crucial role in lupus pathogenesis via osteopontin production". Journal of Immunology. 194 (12): 5725–5735. doi:10.4049/jimmunol.1500319. hdl: 2433/202671 . PMID   25972477. S2CID   12736294.
  47. ↑ Wang YH, Yu XH, Luo SS, Han H (2015-10-08). "Comprehensive circular RNA profiling reveals that circular RNA100783 is involved in chronic CD28-associated CD8(+)T cell ageing". Immunity & Ageing. 12 (1): 17. doi: 10.1186/s12979-015-0042-z . PMC   4597608 . PMID   26451160.
  48. ↑ Schulz AR, Mälzer JN, Domingo C, Jürchott K, Grützkau A, Babel N, et al. (November 2015). "Low Thymic Activity and Dendritic Cell Numbers Are Associated with the Immune Response to Primary Viral Infection in Elderly Humans". Journal of Immunology. 195 (10): 4699–4711. doi: 10.4049/jimmunol.1500598 . PMID   26459351. S2CID   24146051.
  49. ↑ Fuertes Marraco SA, Soneson C, Cagnon L, Gannon PO, Allard M, Abed Maillard S, et al. (April 2015). "Long-lasting stem cell-like memory CD8+ T cells with a naïve-like profile upon yellow fever vaccination". Science Translational Medicine. 7 (282): 282ra48. doi:10.1126/scitranslmed.aaa3700. PMID   25855494. S2CID   21394251.
  50. ↑ Chambers ES, Akbar AN (2020). "Can blocking inflammation enhance immunity during aging?". The Journal of Allergy and Clinical Immunology . 145 (5): 1323–1331. doi:10.1016/j.jaci.2020.03.016. PMID   32386656.
  51. ↑ Kim MJ, Miller CM, Shadrach JL, Wagers AJ, Serwold T (May 2015). "Young, proliferative thymic epithelial cells engraft and function in aging thymuses". Journal of Immunology. 194 (10): 4784–4795. doi:10.4049/jimmunol.1403158. PMC   4481326 . PMID   25870244.
  52. ↑ Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA (June 2016). "Metformin as a Tool to Target Aging". Cell Metabolism. 23 (6): 1060–1065. doi:10.1016/j.cmet.2016.05.011. PMC   5943638 . PMID   27304507.
  53. ↑ Kane DA, Anderson EJ, Price JW, Woodlief TL, Lin CT, Bikman BT, et al. (September 2010). "Metformin selectively attenuates mitochondrial H2O2 emission without affecting respiratory capacity in skeletal muscle of obese rats". Free Radical Biology & Medicine. 49 (6): 1082–1087. doi:10.1016/j.freeradbiomed.2010.06.022. PMC   2921476 . PMID   20600832.
  54. ↑ El-Mir MY, Nogueira V, Fontaine E, Avéret N, Rigoulet M, Leverve X (January 2000). "Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I". The Journal of Biological Chemistry. 275 (1): 223–228. doi: 10.1074/jbc.275.1.223 . PMID   10617608.
  55. ↑ Madiraju AK, Qiu Y, Perry RJ, Rahimi Y, Zhang XM, Zhang D, et al. (September 2018). "Metformin inhibits gluconeogenesis via a redox-dependent mechanism in vivo". Nature Medicine. 24 (9): 1384–1394. doi:10.1038/s41591-018-0125-4. PMC   6129196 . PMID   30038219.
  56. ↑ Rajman L, Chwalek K, Sinclair DA (March 2018). "Therapeutic Potential of NAD-Boosting Molecules: The In Vivo Evidence". Cell Metabolism. 27 (3): 529–547. doi:10.1016/j.cmet.2018.02.011. PMC   6342515 . PMID   29514064.
  57. ↑ Popovich IG, Anisimov VN, Zabezhinski MA, Semenchenko AV, Tyndyk ML, Yurova MN, Blagosklonny MV (May 2014). "Lifespan extension and cancer prevention in HER-2/neu transgenic mice treated with low intermittent doses of rapamycin". Cancer Biology & Therapy. 15 (5): 586–592. doi:10.4161/cbt.28164. PMC   4026081 . PMID   24556924.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.