Immunosenescence

From Wikipedia, the free encyclopedia

Immunosenescence is the gradual deterioration of the immune system, brought on by natural age advancement. Generally, it is believed 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. This age-associated immune deficiency is found in both long- and short-living species as a function of their age relative to life expectancy rather than chronological time.[2] It has been studied in various animal models such mice, marsupials and monkeys.[3][4][5] It is considered a major contributory factor to the increased frequency of morbidity and mortality among the elderly. Besides anergy and T-cell exhaustion, immunosenescence belongs among the major immune system dysfunctional states. However, while T-cell anergy or exhaustion are reversible condition, immunosenescence is believed to be a state that can not be reversed.[6][7]

Immunosenescence is not a random deteriorative phenomenon, rather it appears to inversely repeat an evolutionary pattern and most of the parameters affected by immunosenescence appear to be under genetic control.[8] Immunosenescence can also be sometimes 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 in the term immunosenescence 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 eventually degenerate in their functional properties.[10] However, an immunological term "immunosenescence" generally means a robust shift in both the structural and functional parameters of the immune cells that has a clinically relevant outcome.[10] Thymus involution is probably the most relevant factor responsible for immunosenescence. Involution of the thymus is common in most mammals and in humans it begins after puberty, as the immunological defense against most of the novel antigens is necessary mainly during infancy and childhood.[11]

The major characteristic of the immunosenescent phenotype is a shift in the T-cell subpopulation counts. As the thymus involutes with advanced age, the number of naive T cells (especially CD8+) decreases, thus naive T cells homeostatically proliferate into a late-stage (memory) T cells as a compensation for the cell loss.[5] It is believed that the progression of the conversion to memory phenotype can be accelerated by restimulation of the immune system by persistent pathogens causing lifelong infections such as (CMV, and HSV). By age 40, an estimated 50% to 85% of adults have contracted human cytomegalovirus (HCMV).[1] Consistent, repeated stimulation by such pathogens leads to preferential differentiation of the T-cell memory phenotype, and it seems that the CD8+ T-cell precursors, specific for the most rare and less frequently present antigens do shed the most.[5] However, such shift in T-cell counts leads to the increased susceptibility to non-persistent infection, cancer, autoimmune diseases, cardiovascular health conditions and many others.[12][13]

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

  • Hematopoietic stem cells (HSC), which provide the regulated lifelong supply of leukocyte progenitors that are in turn able to differentiate into a diversity of specialised immune cells (including lymphocytes, antigen-presenting dendritic cells, and phagocytes) diminish in their self-renewal capacity. This is due to the accumulation of oxidative damage to DNA by aging and cellular metabolic activity[14] and the shortening of telomeric terminals of chromosomes.
  • There is a notable decline in the total number of phagocytes in aged hosts, coupled with an intrinsic reduction of their bactericidal activity.[15][16]
  • The cytotoxicity of natural killer (NK) cells and the antigen-presenting function of dendritic cells is known to diminish with old age.[17][18][19][20] The age-associated impairment of dendritic antigen-presenting cells (APCs) has profound implications as this translates into a deficiency in cell-mediated immunity and thus, the inability for effector T-lymphocytes to modulate an adaptive immune response.
  • A decline in humoral immunity caused by a reduction in the population of antibody producing B-cells along with a smaller immunoglobulin diversity and affinity.[21][22]

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.[23] It should be further noted that changes in the lymphoid compartment is not solely responsible for the malfunctioning of the immune system in the elderly. Although myeloid cell production does not seem to decline with age, macrophages become dysregulated as a consequence of environmental changes.[24]

T-cell biomarkers of age-dependent dysfunction[]

The functional capacity of T cells is most influenced by the effects of aging. In fact, age-related alterations are evident in all stages of T-cell development, making them a significant factor in the development of immunosenescence.[25] After birth, the decline of T-cell function begins with the progressive involution of the thymus, which is the organ essential for T-cell maturation following the migration of precursor cells from the bone marrow. This age-associated decrease of thymic epithelial volume results in the decrease of IL-2 production[26][27] and reduction/exhaustion on the number of thymocytes (i.e. pre-mature T cells), thus reducing output of peripheral naïve T cells.[28][29] Once matured and circulating throughout the peripheral system, T cells still undergo deleterious age-dependent changes. Together with the age-related thymic involution, and the consequent age-related decrease of thymic output of new T cells, this situation leaves the body practically devoid of virgin T cells, which makes the body more prone to a variety of infectious and non-infectious diseases.[9]

  • shift in the CD4+/CD8+ ratio[30]
  • the accumulation and the clonal expansion of memory and effector T cells[8][31]
  • impaired development of CD4+ T follicular helper cells, which are specialized in facilitating peripheral B cell maturation, and the generation of antibody-producing plasma cells and memory B cells[32]
  • deregulation of intracellular signal transduction capabilities[33]
  • diminished capacity to produce effector lymphokines[34][31][35]
  • shrinkage of antigen-recognition repertoire of T-cell receptor (TcR) diversity[36][37]
  • down-regulation of CD28 costimulatory molecules[38]
  • cytotoxic activity of Natural Killer T cells (NKTs) decreases[18] due to reduction of the expression of cytotoxicity activating receptors (NKp30, NKp46, etc.) and simultaneously increase in the expression of the inhibitory (KIR, NKG2C, etc.) receptors of NK cells[39]
  • reduction of cytotoxic activity due to impaired expression of associated molecules such as IFN-γ, granzyme B or perforin[40][6]
  • impaired proliferation in response to antigenic stimulation[34][31][36][37]
  • the accumulation and the clonal expansion of memory and effector T cells[8][31]
  • hampered immune defences against viral pathogens, especially by cytotoxic CD8+ T cells[35]
  • changes in cytokine profile e.g. increased pro-inflammatory cytokines milieu present in the elderly[41] (IL-6)[10]
  • the expression of PD-1 increases[42]
  • glycolysis is employed as a preferential pathway of energetic metabolism and thus functionally impaired mitochondria produce ROS excessively[43]
  • presence of a T cell-specific biomarkers of senescence (circular RNA100783, micro-RNAs MiR-181a)[44][45]

Research challenges of immunosenescence[]

A problem of infections in the elderly is that they frequently present with non-specific signs and symptoms, and clues of focal infection are often absent or obscured by underlying chronic conditions.[2] This causes problems in 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 function of dendritic cells.[46] Therefore, the immunization with novel antigens in an earlier life stages seems to be more reasonable but, on the other hand, the lifetime of the established memory differ from a pathogen to the other one.[47][10]

Rescue of the advanced-age phenotype[]

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 to the aged or defective thymus.[48] Metformin is an antidiabetic drug that has been proven to moderate aging in preclinical studies.[49] Its aging protective effect is probably caused primarily by impaired mitochondria metabolism, particularly decreased reactive oxygen production[50] or increased AMP:ATP ratio[51] and lower NAD/NADH ratio. The coenzyme NAD+ has also shown to be reduced in various tissues in an age-dependent manner, and thus redox potential associated changes seem to be critical in the aging process,[52] and NAD+ supplements may have protective effects.[53] Rapamycin, an antitumor and immunosuppresant, is also shown to act similarly.[54]

References[]

  1. ^ a b 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. ^ a b Ginaldi L, Loreto MF, Corsi MP, Modesti M, De Martinis M (August 2001). "Immunosenescence and infectious diseases". Microbes and Infection. 3 (10): 851–7. 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. ^ a b c Nikolich-Zugich, Janko; Rudd, Brian D. (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. ISSN 0952-7915. PMC 2925022. PMID 20674320.
  6. ^ a b 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): 214–21. 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. ^ a b c 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): 911–21. doi:10.1016/S0531-5565(99)00068-6. PMID 10673145. S2CID 32614875.
  9. ^ a b 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): 1717–20. doi:10.1016/S0264-410X(99)00513-7. PMID 10689155.
  10. ^ a b c d Pawelec, Graham (May 2018). "Age and immunity: What is "immunosenescence"?". Experimental Gerontology. 105: 4–9. doi:10.1016/j.exger.2017.10.024. ISSN 1873-6815. PMID 29111233. S2CID 46819839.
  11. ^ Shanley, Daryl P.; Aw, Danielle; Manley, Nancy R.; Palmer, Donald B. (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. ISSN 1471-4981. PMID 19541538.
  12. ^ Hakim FT, Gress RE (September 2007). "Immunosenescence: deficits in adaptive immunity in the elderly". Tissue Antigens. 70 (3): 179–89. doi:10.1111/j.1399-0039.2007.00891.x. PMID 17661905.
  13. ^ 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.
  14. ^ 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.
  15. ^ Lord JM, Butcher S, Killampali V, Lascelles D, Salmon M (September 2001). "Neutrophil ageing and immunesenescence". Mechanisms of Ageing and Development. 122 (14): 1521–35. doi:10.1016/S0047-6374(01)00285-8. PMID 11511394. S2CID 1898942.
  16. ^ 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.
  17. ^ 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): 127–36. doi:10.1016/S0531-5565(01)00162-0. PMID 11738153. S2CID 32717204.
  18. ^ a b Mocchegiani E, Malavolta M (August 2004). "NK and NKT cell functions in immunosenescence". Aging Cell. 3 (4): 177–84. doi:10.1111/j.1474-9728.2004.00107.x. PMID 15268751. S2CID 19710282.
  19. ^ 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): 955–62. doi:10.1016/S0047-6374(02)00033-7. PMID 12044944. S2CID 11558962.
  20. ^ 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): 453–63. doi:10.1007/s00262-015-1720-6. PMID 26059279. S2CID 20498123.
  21. ^ 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.
  22. ^ 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): 1267–73. doi:10.4049/jimmunol.170.3.1267. PMID 12538685.
  23. ^ 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.
  24. ^ 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.
  25. ^ 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.
  26. ^ Effros, Rita B. (2004-04-01). "Replicative senescence of CD8 T cells: effect on human ageing". Experimental Gerontology. 39 (4): 517–524. doi:10.1016/j.exger.2003.09.024. ISSN 0531-5565. PMID 15050285. S2CID 2954461.
  27. ^ Malek, Thomas R.; Bayer, Allison L. (September 2004). "Tolerance, not immunity, crucially depends on IL-2". Nature Reviews. Immunology. 4 (9): 665–674. doi:10.1038/nri1435. ISSN 1474-1733. PMID 15343366. S2CID 8449323.
  28. ^ Aspinall R, Andrew D (July 2000). "Thymic involution in aging". Journal of Clinical Immunology. 20 (4): 250–6. doi:10.1023/A:1006611518223. PMID 10939712. S2CID 25042349.
  29. ^ 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): 245–50. doi:10.4049/jimmunol.173.1.245. PMID 15210781.
  30. ^ 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): 2645–53. doi:10.4049/jimmunol.176.4.2645. PMID 16456027.
  31. ^ a b c d 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): 3698–702. doi:10.1182/blood-2002-02-0657. PMID 12393723.
  32. ^ 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): 732–40. doi:10.1111/j.1474-9726.2012.00836.x. PMC 3444657. PMID 22607653.
  33. ^ 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.
  34. ^ a b 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.
  35. ^ a b 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): 911–20. doi:10.1016/S0531-5565(03)00134-7. PMID 12915213. S2CID 44591282.
  36. ^ a b 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): 7446–52. doi:10.4049/jimmunol.174.11.7446. PMID 15905594.
  37. ^ a b Weng NP (May 2006). "Aging of the immune system: how much can the adaptive immune system adapt?". Immunity. 24 (5): 495–9. doi:10.1016/j.immuni.2006.05.001. PMC 2266981. PMID 16713964.
  38. ^ 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). doi:10.3390/ijms20112810. PMC 6600236. PMID 31181772.
  39. ^ 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): 417–26. doi:10.1007/s00262-015-1750-0. PMID 26288343. S2CID 32642259.
  40. ^ 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): 16–9. doi:10.1016/j.virol.2004.11.028. PMID 15661136.
  41. ^ Sunderkötter C, Kalden H, Luger TA (October 1997). "Aging and the skin immune system". Archives of Dermatology. 133 (10): 1256–62. doi:10.1001/archderm.133.10.1256. PMID 9382564.
  42. ^ 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): 15807–12. Bibcode:2009PNAS..10615807S. doi:10.1073/pnas.0908805106. PMC 2739871. PMID 19805226.
  43. ^ 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): 4004–16. doi:10.1172/JCI75051. PMC 4151208. PMID 25083993.
  44. ^ 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): 5725–35. doi:10.4049/jimmunol.1500319. hdl:2433/202671. PMID 25972477. S2CID 12736294.
  45. ^ 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.
  46. ^ Schulz, Axel Ronald; Mälzer, Julia Nora; Domingo, Cristina; Jürchott, Karsten; Grützkau, Andreas; Babel, Nina; Nienen, Mikalai; Jelinek, Tomas; Niedrig, Matthias; Thiel, Andreas (2015-11-15). "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. ISSN 1550-6606. PMID 26459351. S2CID 24146051.
  47. ^ Fuertes Marraco, Silvia A.; Soneson, Charlotte; Cagnon, Laurène; Gannon, Philippe O.; Allard, Mathilde; Abed Maillard, Samia; Montandon, Nicole; Rufer, Nathalie; Waldvogel, Sophie; Delorenzi, Mauro; Speiser, Daniel E. (2015-04-08). "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. ISSN 1946-6242. PMID 25855494. S2CID 21394251.
  48. ^ 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): 4784–95. doi:10.4049/jimmunol.1403158. PMC 4481326. PMID 25870244.
  49. ^ 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.
  50. ^ Kane, Daniel A.; Anderson, Ethan J.; Price, Jesse W.; Woodlief, Tracey L.; Lin, Chien-Te; Bikman, Benjamin T.; Cortright, Ronald N.; Neufer, P. Darrell (2010-09-15). "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. ISSN 1873-4596. PMC 2921476. PMID 20600832.
  51. ^ El-Mir, M. Y.; Nogueira, V.; Fontaine, E.; Avéret, N.; Rigoulet, M.; Leverve, X. (2000-01-07). "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. ISSN 0021-9258. PMID 10617608.
  52. ^ Madiraju, Anila K.; Qiu, Yang; Perry, Rachel J.; Rahimi, Yasmeen; Zhang, Xian-Man; Zhang, Dongyan; Camporez, João-Paulo G.; Cline, Gary W.; Butrico, Gina M.; Kemp, Bruce E.; Casals, Gregori (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. ISSN 1546-170X. PMC 6129196. PMID 30038219.
  53. ^ 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.
  54. ^ 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): 586–92. doi:10.4161/cbt.28164. PMC 4026081. PMID 24556924.
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