Immunosenescence: a key player in cancer development

In the paper

“T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species.”

• Also stated in: § Concept, process, and hallmarks of immunosenescence · plain

  “Additionally, inflammation related to advanced age will produce a senescence-associated secretory phenotype (SASP), which also leads to immune system senescence [15, 23, 25].”

What the sources say

• Partly supported

  The Background says senescent cells secrete inflammatory cytokines and chemokines, supporting the secretory aspect of the claim. But it describes this as contributing to inflamm-ageing; it does not identify SASP production as an important feature of immunosenescence. The Background lists other principal hallmarks of immunosenescence, including reduced T-cell generation and accumulation of senescent cells. (LLM, conf=0.84)

  cites [15] Accardi G, Caruso C. Immune-inflammatory responses in the elderly: an update. Immun Ageing. 2018;15:11. sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction (page not specified) describes SASP as a hallmark of senescent cells and says their secretions may activate the immune system. It does not identify SASP production as an important feature of immunosenescence itself; it presents senescent cells as a possible contributor to age-related inflammation. (LLM, conf=0.82)

  cites [23] Pinti M, Appay V, Campisi J, Frasca D, Fülöp T, Sauce D, Larbi A, Weinberger B, Cossarizza A. Aging of the immune system: Focus on inflammation and vaccination. Eur J Immunol. 2016;46(10):2286–301. sourceExperimental — accuracy not yet measured
• Partly supported

  The ‘Intersection of Immunosenescence and Inflammaging’ section says diminished immune clearance of senescent cells leads to increased SASP production. It identifies SASP as a contributor to inflammaging, however, rather than as an important feature or primary hallmark of immunosenescence. Page numbers were not provided. (LLM, conf=0.85)

  cites [25] Thomas R, Wang W, Su D-M. Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging. Immun Ageing. 2020;17:2. sourceExperimental — accuracy not yet measured

In the paper

“P53 can cause cellular senescence [42] by regulating the cell cycle via inhibition of cyclin-dependent kinase (CDK) 4 and CDK6 [5, 43] (Fig. 2).”

What the sources say

• Supported

  In “Cellular Senescence > The INK4a/ARF locus and p53,” the paper explicitly describes p53’s role in inducing cellular senescence. The citation to this source is attached to that part of the sentence; the CDK4/CDK6 mechanism is cited separately to other sources. (LLM, conf=0.93)

  cites [5] Lopez-Otin C, Blasco MA, Partridge L, Serrano M, Kroemer G. The hallmarks of aging. Cell. 2013;153(6):1194–217. source
• ?Could not verify

  The citation is attached to the CDK4/CDK6 inhibition clause. The Introduction discusses p16INK4a as a tumor suppressor and an age-associated marker, but our copy does not state that p53 inhibits CDK4 or CDK6. Searches for p53, CDK4, CDK6, and cyclin-dependent kinase inhibition did not locate the attributed mechanism. (LLM, conf=0.74)

  cites [43] Liu Y, Sanoff HK, Cho H, Burd CE, Torrice C, Ibrahim JG, Thomas NE, Sharpless NE. Expression of p16(INK4a) in peripheral blood T-cells is a biomarker of human aging. Aging Cell. 2009;8(4):439–48. sourceExperimental — accuracy not yet measured

In the paper

“Furthermore, the activation of Toll-like receptor 8 signaling in tumor cells can enhance antitumor immunity by blocking the induction of senescent T cells and tumor-specific T cells in vitro and in vivo and reversing their inhibitory effect [63].”

What the sources say

• Supported

  The Discussion states that TLR8 signaling in tumor cells blocks senescence in naïve and tumor-specific effector T cells, reverses their suppressive effects in vitro and in vivo, and enhances antitumor immunity. The citing sentence is awkwardly worded, but its substantive claim matches this passage. (LLM, conf=0.92)

  cites [63] Ye J, Ma C, Hsueh EC, Dou J, Mo W, Liu S, Han B, Huang Y, Zhang Y, Varvares MA, et al. TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence. EMBO Mol Med. 2014;6(10):1294–311. source

In the paper

“Furthermore, IFN signaling and antigen presentation were reduced in the TME of aged mice and patients with triple-negative breast cancer [68].”

What the sources say

• Supported

  The Discussion reports that tumors from aged mice and TNBC patients over 65 lack enrichment for genes associated with antigen presentation and IFN response pathways, compared with younger groups. It identifies these changes as features of the age-dependent tumor microenvironment. (LLM, conf=0.93)

  cites [68] Sceneay J, Goreczny GJ, Wilson K, Morrow S, DeCristo MJ, Ubellacker JM, Qin Y, Laszewski T, Stover DG, Barrera V, et al. Interferon signaling is diminished with age and is associated with immune checkpoint blockade efficacy in triple-negative breast cancer. Cancer Discov. 2019;9(9):1208–27. source

In the paper

“In subsequent recent studies, in the relatively long-lived C57BL/6 mice and genetic hybrid mice, a similar phenomenon was observed [179, 180].”

What the sources say

• Partly supported

  The Discussion (page unavailable) reports increased mean lifespan with metformin in male C57BL/6 mice and a smaller, suggestive increase in male B6C3F1 hybrid mice. It also says this paper’s own metformin result in genetically heterogeneous mice was not statistically significant. Thus the copy supports a similar observed trend in both mouse stocks, but not an established lifespan benefit in both. (LLM, conf=0.78)

  cites [179] Strong R, Miller RA, Antebi A, Astle CM, Bogue M, Denzel MS, Fernandez E, Flurkey K, Hamilton KL, Lamming DW, et al. Longer lifespan in male mice treated with a weakly estrogenic agonist, an antioxidant, an α-glucosidase inhibitor or a Nrf2-inducer. Aging Cell. 2016;15(5):872–84. sourceExperimental — accuracy not yet measured
• Supported

  The Results section (‘Metformin increases healthspan and longevity of mice’; page unavailable) reports increased mean lifespan with 0.1% metformin in both male C57BL/6 mice and B6C3F1 mice. The increase in B6C3F1 mice was observed but was not statistically significant (p=0.064). (LLM, conf=0.90)

  cites [180] Martin-Montalvo A, Mercken EM, Mitchell SJ, Palacios HH, Mote PL, Scheibye-Knudsen M, Gomes AP, Ward TM, Minor RK, Blouin M-J, et al. Metformin improves healthspan and lifespan in mice. Nat Commun. 2013;4:2192. source

In the paper

“T cell–output decline is an important feature of immunosenescence as well as the production of senescence-associated secretory phenotype, increased glycolysis, and reactive oxygen species.”

• Also stated in: § Concept, process, and hallmarks of immunosenescence · plain

  “Moreover, an important distinguishing feature is that the thymus gradually recedes and degenerates with age, resulting in a decrease in T cell output [24, 25].”

What the sources say

• Not checked yetcites [24] Palmer S, Albergante L, Blackburn CC, Newman TJ. Thymic involution and rising disease incidence with age. Proc Natl Acad Sci U S A. 2018;115(8):1883–8. source
• Not checked yetcites [25] Thomas R, Wang W, Su D-M. Contributions of Age-Related Thymic Involution to Immunosenescence and Inflammaging. Immun Ageing. 2020;17:2. source

In the paper

“Therefore, the T cell phenotype of CD27−CD28−CD57+KLRG-1+ is also an indicator of immunosenescence.”

What the sources say

• Not checked yetcites [41] Huff WX, Kwon JH, Henriquez M, Fetcko K, Dey M. The evolving role of CD8CD28 Immunosenescent T cells in cancer immunology. Int J Mol Sci. 2019;20(11):2810. source

In the paper

“The role of immunosenescence in tumors is sophisticated: the many factors involved include cAMP, glucose competition, and oncogenic stress in the tumor microenvironment, which can induce the senescence of T cells, macrophages, natural killer cells, and dendritic cells.”

• Also stated in: § Immunosenescence and cancer · plain

  “Many factors in the TME can induce the senescence of immune cells and dramatically affect their function.”

What the sources say

• Not checked yetcites [51] Ye J, Huang X, Hsueh EC, Zhang Q, Ma C, Zhang Y, Varvares MA, Hoft DF, Peng G. Human regulatory T cells induce T-lymphocyte senescence. Blood. 2012;120(10):2021–31. source
• Not checked yetcites [52] Ye J, Ma C, Hsueh EC, Eickhoff CS, Zhang Y, Varvares MA, Hoft DF, Peng G. Tumor-derived γδ regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence. J Immunol. 2013;190(5):2403–14. source
• Not checked yetcites [53] Liu X, Mo W, Ye J, Li L, Zhang Y, Hsueh EC, Hoft DF, Peng G. Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition. Nat Commun. 2018;9(1):249. source
• Not checked yetcites [54] Wang D, Yang L, Yue D, Cao L, Li L, Wang D, Ping Y, Shen Z, Zheng Y, Wang L, et al. Macrophage-derived CCL22 promotes an immunosuppressive tumor microenvironment via IL-8 in malignant pleural effusion. Cancer Lett. 2019;452:244–53. source
• Not checked yetcites [55] Yang L, Zhang Y. Tumor-associated macrophages: from basic research to clinical application. J Hematol Oncol. 2017;10(1):58. source
• Not checked yetcites [56] Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A. Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res. 2008;14(19):5947–52. source
• Not checked yetcites [57] Vang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, Skålhegg BS, Hansson V, Mustelin T, Taskén K. Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J Exp Med. 2001;193(4):497–507. source
• Not checked yetcites [58] Salminen A, Kauppinen A, Kaarniranta K. Myeloid-derived suppressor cells (MDSC): an important partner in cellular/tissue senescence. Biogerontology. 2018;19(5):325–39. source
• Not checked yetcites [59] Wang W, Chen JX, Liao R, Deng Q, Zhou JJ, Huang S, Sun P. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol. 2002;22(10):3389–403. source
• Not checked yetcites [60] Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011;30(8):1536–48. source

In the paper

“Indeed, some potential targets were already investigated: a recent study has reported that interleukin (IL)-7 and its receptors play a key role in immunosenescence, affecting the balance of the immune system [30] (Fig. 2).”

What the sources say

• Not checked yetcites [30] Nguyen V, Mendelsohn A, Larrick JW. Interleukin-7 and Immunosenescence. J Immunol Res. 2017;2017:4807853. source

In the paper

“However, the main obstacle to achieving efficacious immunotherapy is the tumor microenvironment (TME), which may accelerate senescence of the immune system [18, 19]: potential targets for rejuvenating the immune system are still a hypothesis.”

What the sources say

• Not checked yetcites [18] Fane M, Weeraratna AT. How the ageing microenvironment influences tumour progression. Nat Rev Cancer. 2020;20(2):89–106. source
• Not checked yetcites [19] Su D-M, Aw D, Palmer DB. Immunosenescence: a product of the environment? Curr Opin Immunol. 2013;25(4):498–503. source

In the paper

“These studies also documented that cellular senescence is a cellular state closely associated with various physiological processes and aging-related diseases [4, 5] and is a double-edged sword in cancer [6].”

What the sources say

• Not checked yetcites [6] Nacarelli T, Lau L, Fukumoto T, Zundell J, Fatkhutdinov N, Wu S, Aird KM, Iwasaki O, Kossenkov AV, Schultz D, et al. NAD metabolism governs the proinflammatory senescence-associated secretome. Nat Cell Biol. 2019;21(3):397–407. source

In the paper

“It should be noted that aging is generally defined as a decline of function in living organisms that occurs in a time-dependent manner and is associated with cancer progression [3].”

What the sources say

• Not checked yetcites [3] Munoz-Espin D, Serrano M. Cellular senescence: from physiology to pathology. Nat Rev Mol Cell Biol. 2014;15(7):482–96. source

In the paper

“Moreover, with the loss of CD27 and CD28, there is an increase in the expression of P16 and P21, which are involved in cell cycle regulation [42] (Fig. 2).”

What the sources say

• Not checked yetcites [42] Mondal AM, Horikawa I, Pine SR, Fujita K, Morgan KM, Vera E, Mazur SJ, Appella E, Vojtesek B, Blasco MA, et al. p53 isoforms regulate aging- and tumor-associated replicative senescence in T lymphocytes. J Clin Invest. 2013;123(12):5247–57. source

In the paper

“In fact, the process of immunosenescence is regulated by many factors, including aging, chronic inflammation, and changes in the microenvironment (Fig. 1).”

In the paper

“Accordingly, these senescent immune cells could also affect tumor progression.”

• Also stated in: § Immunosenescence and cancer · hedged

  “Altogether, these findings indicate that immunosenescence is linked to the occurrence and progression of tumors.”

In the paper

“Another hallmark of senescent T cells is telomere shortening [21, 44] (Fig. 2), which is caused by the continuous replication of T cells and the decrease in expression of the human telomerase RNA component.”

What the sources say

• Not checked yetcites [21] Nikolich-Zugich J. The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol. 2018;19(1):10–9. source
• Not checked yetcites [44] Bernadotte A, Mikhelson VM, Spivak IM. Markers of cellular senescence. Telomere shortening as a marker of cellular senescence. Aging. 2016;8(1):3–11. source

In the paper

“Therefore, these lines of evidence indicate that the underlying mechanism of tumorigenesis is closely associated with immunosenescence.”

In the paper

“Generally, the risk of malignant tumors increases with age.”

• Also stated in: § Immunosenescence and cancer · plain

  “DeSantis et al. [49] found a higher risk of tumorigenesis in the elderly group.”

What the sources say

• Not checked yetcites [49] DeSantis CE, Miller KD, Dale W, Mohile SG, Cohen HJ, Leach CR, Goding Sauer A, Jemal A, Siegel RL. Cancer statistics for adults aged 85 years and older, 2019. CA: a cancer journal for clinicians. 2019;69(6):452–67. source

In the paper

“Decreased expression of IFN signaling in CD8+ T cells in aged mice was identified in a mouse model of breast cancer [68].”

What the sources say

• Not checked yetcites [68] Sceneay J, Goreczny GJ, Wilson K, Morrow S, DeCristo MJ, Ubellacker JM, Qin Y, Laszewski T, Stover DG, Barrera V, et al. Interferon signaling is diminished with age and is associated with immune checkpoint blockade efficacy in triple-negative breast cancer. Cancer Discov. 2019;9(9):1208–27. source

In the paper

“P38 inhibits cell cycle progression by activating P53, P21, and P16 [64].”

What the sources say

• Not checked yetcites [64] Lanna A, Gomes DCO, Muller-Durovic B, McDonnell T, Escors D, Gilroy DW, Lee JH, Karin M, Akbar AN. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat Immunol. 2017;18(3):354–63. source

In the paper

“Chemotherapy can also induce CD8+ T cell senescence in patients with breast cancer [67].”

What the sources say

• Not checked yetcites [67] Onyema OO, Decoster L, Njemini R, Forti LN, Bautmans I, De Waele M, Mets T. Chemotherapy-induced changes and immunosenescence of CD8+ T-cells in patients with breast cancer. Anticancer Res. 2015;35(3):1481–9.

In the paper

“Moreover, NKp30, NKp46, and DNAM-1 are NK activation receptors involved in the recognition and lysis of different tumors, such as hematological malignancies [82], melanoma [83], and ovarian cancer [84].”

What the sources say

• Not checked yetcites [82] Fauriat C, Just-Landi S, Mallet F, Arnoulet C, Sainty D, Olive D, Costello RT. Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction. Blood. 2007;109(1):323–30. source
• Not checked yetcites [83] Lakshmikanth T, Burke S, Ali TH, Kimpfler S, Ursini F, Ruggeri L, Capanni M, Umansky V, Paschen A, Sucker A, et al. NCRs and DNAM-1 mediate NK cell recognition and lysis of human and mouse melanoma cell lines in vitro and in vivo. J Clin Invest. 2009;119(5):1251–63. source
• Not checked yetcites [84] Carlsten M, Björkström NK, Norell H, Bryceson Y, van Hall T, Baumann BC, Hanson M, Schedvins K, Kiessling R, Ljunggren H-G, et al. DNAX accessory molecule-1 mediated recognition of freshly isolated ovarian carcinoma by resting natural killer cells. Cancer Res. 2007;67(3):1317–25. source

In the paper

“The increased age-related sFRP2 secreted by fibroblasts also promoted angiogenesis and metastasis of melanoma cells [70].”

What the sources say

• Not checked yetcites [70] Kaur A, Webster MR, Marchbank K, Behera R, Ndoye A, Kugel CH, Dang VM, Appleton J, O’Connell MP, Cheng P, et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature. 2016;532(7598):250–4. source

In the paper

“Compared with young patients with melanoma, ECM rearrangement resulting from Hyaluronan And Proteoglycan Link Protein 1 changes in elderly patients can cause melanoma cells to be more invasive and prone to distant metastasis [69].”

What the sources say

• Not checked yetcites [69] Ecker BL, Kaur A, Douglass SM, Webster MR, Almeida FV, Marino GE, Sinnamon AJ, Neuwirth MG, Alicea GM, Ndoye A, et al. Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis. Cancer Discov. 2019;9(1):82–95. source

In the paper

“By analyzing the age distributions of 100 different tumors, Palmer et al. [24] concluded that the immune system may play an important role in tumor development.”

What the sources say

• Not checked yetcites [24] Palmer S, Albergante L, Blackburn CC, Newman TJ. Thymic involution and rising disease incidence with age. Proc Natl Acad Sci U S A. 2018;115(8):1883–8. source

In the paper

“The NFκB, C/EBPβ, and cGAS-STING pathways also play a key role in the induction of T cell senescence [66].”

What the sources say

• Not checked yetcites [66] Goronzy JJ, Weyand CM. Mechanisms underlying T cell ageing. Nat Rev Immunol. 2019;19(9):573–83. source

In the paper

“In addition, tumor cells activate the PKA-CREB and P38 pathways by producing cAMP, thereby causing DNA damage and senescence of T cells [51, 53, 58–63].”

What the sources say

• Not checked yetcites [51] Ye J, Huang X, Hsueh EC, Zhang Q, Ma C, Zhang Y, Varvares MA, Hoft DF, Peng G. Human regulatory T cells induce T-lymphocyte senescence. Blood. 2012;120(10):2021–31. source
• Not checked yetcites [53] Liu X, Mo W, Ye J, Li L, Zhang Y, Hsueh EC, Hoft DF, Peng G. Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition. Nat Commun. 2018;9(1):249. source
• Not checked yetcites [58] Salminen A, Kauppinen A, Kaarniranta K. Myeloid-derived suppressor cells (MDSC): an important partner in cellular/tissue senescence. Biogerontology. 2018;19(5):325–39. source
• Not checked yetcites [59] Wang W, Chen JX, Liao R, Deng Q, Zhou JJ, Huang S, Sun P. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol Cell Biol. 2002;22(10):3389–403. source
• Not checked yetcites [60] Freund A, Patil CK, Campisi J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 2011;30(8):1536–48. source
• Not checked yetcites [61] Van Nguyen T, Puebla-Osorio N, Pang H, Dujka ME, Zhu C. DNA damage-induced cellular senescence is sufficient to suppress tumorigenesis: a mouse model. J Exp Med. 2007;204(6):1453–61. source
• Not checked yetcites [62] Rodier F, Coppé J-P, Patil CK, Hoeijmakers WAM, Muñoz DP, Raza SR, Freund A, Campeau E, Davalos AR, Campisi J. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat Cell Biol. 2009;11(8):973–9. source
• Not checked yetcites [63] Ye J, Ma C, Hsueh EC, Dou J, Mo W, Liu S, Han B, Huang Y, Zhang Y, Varvares MA, et al. TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence. EMBO Mol Med. 2014;6(10):1294–311. source

In the paper

“In various mouse models, tumor proliferation was found to be slower in elderly mice, such as MC38, B16, and 4T1 tumor models [71].”

What the sources say

• Not checked yetcites [71] Oh J, Magnuson A, Benoist C, Pittet MJ, Weissleder R. Age-related tumor growth in mice is related to integrin α 4 in CD8+ T cells. JCI insight. 2018;3(21):e122961. source

In the paper

“Another study retrospectively analyzed the histological report of 1869 women with breast cancer and found that the incidence of invasive ductal carcinoma increased in patients < 39 years of age [76].”

What the sources say

• Not checked yetcites [76] Fisher CJ, Egan MK, Smith P, Wicks K, Millis RR, Fentiman IS. Histopathology of breast cancer in relation to age. Br J Cancer. 1997;75(4):593–6. source

In the paper

“Overall, these different research results indicate that age is closely associated with tumorigenesis.”

In the paper

“Studies have shown that immunosenescence, especially that of CD8+ T cells, plays a pivotal role in the pathogenesis and treatment of patients with breast cancer [67].”

What the sources say

• Not checked yetcites [67] Onyema OO, Decoster L, Njemini R, Forti LN, Bautmans I, De Waele M, Mets T. Chemotherapy-induced changes and immunosenescence of CD8+ T-cells in patients with breast cancer. Anticancer Res. 2015;35(3):1481–9.

In the paper

“Vatter et al. [50] performed a phenotypic analysis of mammary epithelial cells from 57 women (16–91 years old) and showed that accumulation of lumen and progenitor cells with age may lead to an increased risk of carcinogenesis.”

What the sources say

• Not checked yetcites [50] Pelissier Vatter FA, Schapiro D, Chang H, Borowsky AD, Lee JK, Parvin B, Stampfer MR, LaBarge MA, Bodenmiller B, Lorens JB. High-dimensional phenotyping identifies age-emergent cells in human mammary epithelia. Cell Rep. 2018;23(4):1205–19. source

In the paper

“Several studies have reported that tumor-derived endogenous cyclic adenosine monophosphate (cAMP) induces T cell senescence by inhibiting tumor-specific effector T cells in hypoxic microenvironment [56, 57].”

What the sources say

• Not checked yetcites [56] Sitkovsky MV, Kjaergaard J, Lukashev D, Ohta A. Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin Cancer Res. 2008;14(19):5947–52. source
• Not checked yetcites [57] Vang T, Torgersen KM, Sundvold V, Saxena M, Levy FO, Skålhegg BS, Hansson V, Mustelin T, Taskén K. Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J Exp Med. 2001;193(4):497–507. source

In the paper

“Altogether, these findings indicate that immunosenescence is linked to the occurrence and progression of tumors.”

In the paper

“In 1973, a retrospective study of 226 patients with colorectal cancer aged 80 years and older found that the prognosis of elderly patients was better than that of young patients [72].”

What the sources say

• Not checked yetcites [72] Calabrese CT, Adam YG, Volk H. Geriatric colon cancer. Am J Surg. 1973;125(2):181–4. source

In the paper

“The function of NK cells, such as immune surveillance, is also affected by age-related changes.”

In the paper

“It has been reported that CAR-T cell therapy shows high response rates to B-ALL patients in different age groups [117–119].”

What the sources say

• Not checked yetcites [117] Sidaway P. Immunotherapy: CAR T cell therapy efficacious against B-ALL across age groups. Nat Rev Clin Oncol. 2018;15(4):199. source
• Not checked yetcites [118] Maude SL, Laetsch TW, Buechner J, Rives S, Boyer M, Bittencourt H, Bader P, Verneris MR, Stefanski HE, Myers GD, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439–48. source
• Not checked yetcites [119] Park JH, Rivière I, Gonen M, Wang X, Sénéchal B, Curran KJ, Sauter C, Wang Y, Santomasso B, Mead E, et al. Long-term follow-up of CD19 CAR therapy in acute lymphoblastic Leukemia. N Engl J Med. 2018;378(5):449–59. source

In the paper

“These findings do suggest therapeutic potential of CAR-T cells for senescence-related diseases.”

In the paper

“Therefore, degeneration of the thymus is the cause of age-related failure of the adaptive immune system [95, 96].”

What the sources say

• Not checked yetcites [95] Palmer DB. The effect of age on thymic function. Frontiers in immunology. 2013;4:316. source
• Not checked yetcites [96] Chinn IK, Blackburn CC, Manley NR, Sempowski GD. Changes in primary lymphoid organs with aging. Semin Immunol. 2012;24(5):309–20. source

In the paper

“Some studies also documented that memory T cells gradually accumulate with age [66, 97–99].”

What the sources say

• Not checked yetcites [66] Goronzy JJ, Weyand CM. Mechanisms underlying T cell ageing. Nat Rev Immunol. 2019;19(9):573–83. source
• Not checked yetcites [97] Fukushima Y, Minato N, Hattori M. The impact of senescence-associated T cells on immunosenescence and age-related disorders. Inflamm Regen. 2018;38:24. source
• Not checked yetcites [98] Pawelec G. Immunosenescence and cancer. Biogerontology. 2017;18(4):717–21. source
• Not checked yetcites [99] Goronzy JJ, Weyand CM. Successful and maladaptive T cell aging. Immunity. 2017;46(3):364–78. source

In the paper

“A study showed that there was no difference in the frequency of TSCM between the young and old groups [105].”

What the sources say

• Not checked yetcites [105] Van Epps P, Banks R, Aung H, Betts MR, Canaday DH. Age-related differences in polyfunctional T cell responses. Immun Ageing. 2014;11:14. source

In the paper

“Collectively, these studies have demonstrated that central memory CD8+ T cells represent the majority of memory CD8+ T cells in aged mice [101, 102].”

What the sources say

• Not checked yetcites [101] Chiu B-C, Martin BE, Stolberg VR, Chensue SW. Cutting edge: Central memory CD8 T cells in aged mice are virtual memory cells. J Immunol. 2013;191(12):5793–6. source
• Not checked yetcites [102] Quinn KM, Fox A, Harland KL, Russ BE, Li J, Nguyen THO, Loh L, Olshanksy M, Naeem H, Tsyganov K, et al. Age-related decline in primary CD8(+) T cell responses is associated with the development of senescence in virtual memory CD8(+) T cells. Cell Rep. 2018;23(12):3512–24. source

In the paper

“Gabriele et al. reported that CD57, a T cell senescence marker, can quickly and efficiently transfer from glioblastoma stem cells to CAR-T cells, leading to its senescence [124].”

What the sources say

• Not checked yetcites [124] Zhu X, Niedermann G. Rapid and efficient transfer of the T cell aging marker CD57 from glioblastoma stem cells to CAR T cells. Oncoscience. 2015;2(5):476–82. source

In the paper

“The reconstructed and expanded CAR-T cells are exposed to the patient's tumor microenvironment, thereby inducing the senescent phenotype of CAR-T [122, 123].”

What the sources say

• Not checked yetcites [122] Ye B, Stary CM, Li X, Gao Q, Kang C, Xiong X. Engineering chimeric antigen receptor-T cells for cancer treatment. Mol Cancer. 2018;17(1):32. source
• Not checked yetcites [123] Yao D, Xu L, Tan J, Zhang Y, Lu S, Li M, Lu S, Yang L, Chen S, Chen J, et al. Re-balance of memory T cell subsets in peripheral blood from patients with CML after TKI treatment. Oncotarget. 2017;8(47):81852–9. source

In the paper

“In general, restoring the function of senescent CAR-T cells is the key to enhancing the antitumor effect of modified T cells.”

In the paper

“Overall, these results indicate that TSCM exists throughout the life process.”

In the paper

“The low survival rate of patients with glioblastoma is associated with immunosenescence of postoperative CD4+ T cells [128].”

What the sources say

• Not checked yetcites [128] Fornara O, Odeberg J, Wolmer Solberg N, Tammik C, Skarman P, Peredo I, Stragliotto G, Rahbar A, Soderberg-Naucler C. Poor survival in glioblastoma patients is associated with early signs of immunosenescence in the CD4 T-cell compartment after surgery. Oncoimmunology. 2015;4(9):e1036211. source

In the paper

“Therefore, changes in the expression of these activated receptors in the elderly may affect the immune monitoring function of NK cells [85, 86].”

What the sources say

• Not checked yetcites [85] Campos C, López N, Pera A, Gordillo JJ, Hassouneh F, Tarazona R, Solana R. Expression of NKp30, NKp46 and DNAM-1 activating receptors on resting and IL-2 activated NK cells from healthy donors according to CMV-serostatus and age. Biogerontology. 2015;16(5):671–83. source
• Not checked yetcites [86] Campos C, Pera A, Sanchez-Correa B, Alonso C, Lopez-Fernandez I, Morgado S, Tarazona R, Solana R. Effect of age and CMV on NK cell subpopulations. Exp Gerontol. 2014;54:130–7. source

In the paper

“their inclusion in clinical studies is usually insufficient, as patients over 75 years of age represent less than 10% of patients with cancer [150, 151]”

What the sources say

• Not checked yetcites [150] Scher KS, Hurria A. Under-representation of older adults in cancer registration trials: known problem, little progress. J Clin Oncol. 2012;30(17):2036–8. source
• Not checked yetcites [151] Mohile SG, Dale W, Somerfield MR, Hurria A. Practical assessment and management of vulnerabilities in older patients receiving chemotherapy: ASCO guideline for geriatric oncology summary. J Oncol Pract. 2018;14(7):442–6. source

In the paper

“It has been reported that CD39 expression during aging reduces the number of CD4+ T cells [130].”

What the sources say

• Not checked yetcites [130] Fang F, Yu M, Cavanagh MM, Hutter Saunders J, Qi Q, Ye Z, Le Saux S, Sultan W, Turgano E, Dekker CL, et al. Expression of CD39 on activated T cells impairs their survival in older individuals. Cell Rep. 2016;14(5):1218–31. source

In the paper

“One study reported that age limits ICB antibody therapy efficacy in aged triple-negative breast cancer-bearing mice [68].”

What the sources say

• Not checked yetcites [68] Sceneay J, Goreczny GJ, Wilson K, Morrow S, DeCristo MJ, Ubellacker JM, Qin Y, Laszewski T, Stover DG, Barrera V, et al. Interferon signaling is diminished with age and is associated with immune checkpoint blockade efficacy in triple-negative breast cancer. Cancer Discov. 2019;9(9):1208–27. source

In the paper

“The age-related remodeling of the B cell compartment may be the result of unbalanced fate selection in the hematopoietic progenitor cell population, autonomous changes in B cells, and external signals [138, 139].”

What the sources say

• Not checked yetcites [138] Hagen M, Derudder E. Inflammation and the alteration of B-Cell physiology in aging. Gerontology. 2020;66(2):105–13. source
• Not checked yetcites [139] Labi V, Derudder E. Cell signaling and the aging of B cells. Exp Gerontol. 2020;138:110985. source

In the paper

“A meta-analysis of randomized trials showed that although anti-PD-1 drugs are effective for both young and elderly patients, the risk of death among elderly patients is comparable or improved compared to that of patients subjected to control interventions, with no increased toxicity [155–158].”

What the sources say

• Not checked yetcites [155] Elias R, Giobbie-Hurder A, McCleary NJ, Ott P, Hodi FS, Rahma O. Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis. J Immunother Cancer. 2018;6(1):26. source
• Not checked yetcites [156] Li P, Yang X, Feng Y, Wu L, Ma W, Ding G, Wei Y, Sun L. The impact of immunosenescence on the efficacy of immune checkpoint inhibitors in melanoma patients: a meta-analysis. Onco Targets Ther. 2018;11:7521–7. source
• Not checked yetcites [157] Marur S, Singh H, Mishra-Kalyani P, Larkins E, Keegan P, Sridhara R, Blumenthal GM, Pazdur R. FDA analyses of survival in older adults with metastatic non-small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies. Semin Oncol. 2018;45(4):220–5. source
• Not checked yetcites [158] Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30–7. source

In the paper

“The ability of neutrophils to phagocytose pathogens decreases with age [147].”

What the sources say

• Not checked yetcites [147] Jackaman C, Tomay F, Duong L, Abdol Razak NB, Pixley FJ, Metharom P, Nelson DJ. Aging and cancer: the role of macrophages and neutrophils. Ageing Res Rev. 2017;36:105–16. source

In the paper

“As shown in Fig. 5, the loose arrangement of the ECM in the aging microenvironment may be one of the causes of metastasis in elderly patients with tumors [69, 70].”

What the sources say

• Not checked yetcites [69] Ecker BL, Kaur A, Douglass SM, Webster MR, Almeida FV, Marino GE, Sinnamon AJ, Neuwirth MG, Alicea GM, Ndoye A, et al. Age-related changes in HAPLN1 increase lymphatic permeability and affect routes of melanoma metastasis. Cancer Discov. 2019;9(1):82–95. source
• Not checked yetcites [70] Kaur A, Webster MR, Marchbank K, Behera R, Ndoye A, Kugel CH, Dang VM, Appleton J, O’Connell MP, Cheng P, et al. sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature. 2016;532(7598):250–4. source

In the paper

“a preclinical study highlights that the efficacy is poorer in older mouse models than in younger mouse models, indicating that age may have a significant effect on different tumor types and various physiological states [153].”

What the sources say

• Not checked yetcites [153] Padron A, Hurez V, Gupta HB, Clark CA, Pandeswara SL, Yuan B, Svatek RS, Turk MJ, Drerup JM, Li R, et al. Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model. Exp Gerontol. 2018;105:146–54. source

In the paper

“Furthermore, in aging TME, changes in immune cell function and secretion of SASP molecules dramatically affect tumor progression [18].”

What the sources say

• Not checked yetcites [18] Fane M, Weeraratna AT. How the ageing microenvironment influences tumour progression. Nat Rev Cancer. 2020;20(2):89–106. source

In the paper

“Similarly, in Lewis lung cancer mouse models and patients with lung cancer, Tregs infiltration and Foxp3 mRNA expression levels were higher in the elderly group than in the younger group [135, 136].”

What the sources say

• Not checked yetcites [135] Pan X-D, Mao Y-Q, Zhu L-J, Li J, Xie Y, Wang L, Zhang G-B. Changes of regulatory T cells and FoxP3 gene expression in the aging process and its relationship with lung tumors in humans and mice. Chin Med J (Engl). 2012;125(11):2004–11.
• Not checked yetcites [136] Gong Z, Jia Q, Chen J, Diao X, Gao J, Wang X, Zhu B. Impaired cytolytic activity and loss of clonal neoantigens in elderly patients with lung adenocarcinoma. J Thorac Oncol. 2019;14(5):857–66. source

In the paper

“In mice, the turnover of mature spleen B cells also decreases with age [143, 144].”

What the sources say

• Not checked yetcites [143] Johnson KM, Owen K, Witte PL. Aging and developmental transitions in the B cell lineage. Int Immunol. 2002;14(11):1313–23. source
• Not checked yetcites [144] Kline GH, Hayden TA, Klinman NR. B cell maintenance in aged mice reflects both increased B cell longevity and decreased B cell generation. J Immunol. 1999;162(6):3342–9. source

In the paper

“Kugel et al. [154] analyzed the relationship between age and anti-PD-1 response in 538 patients with melanoma and found that those over 60 years of age exhibited a better response to anti-PD-1 than those aged < 60 years.”

What the sources say

• Not checked yetcites [154] Kugel CH 3rd, Douglass SM, Webster MR, Kaur A, Liu Q, Yin X, Weiss SA, Darvishian F, Al-Rohil RN, Ndoye A, et al. Age Correlates with response to Anti-PD1, reflecting age-related differences in intratumoral effector and regulatory T-cell populations. Clin Cancer Res. 2018;24(21):5347–56. source

In the paper

“Immunosenescence may affect the response to blocking antibody therapy in patients with non-small cell lung cancer [152].”

What the sources say

• Not checked yetcites [152] Ferrara R, Mezquita L, Auclin E, Chaput N, Besse B. Immunosenescence and immunecheckpoint inhibitors in non-small cell lung cancer patients: does age really matter? Cancer Treat Rev. 2017;60:60–8. source

In the paper

“Moreover, their functions such as antigen presentation, endocytosis, and IFN production, are also reduced in aged individuals [145, 146].”

What the sources say

• Not checked yetcites [145] Agrawal A, Gupta S. Impact of aging on dendritic cell functions in humans. Ageing Res Rev. 2011;10(3):336–45. source
• Not checked yetcites [146] Gardner JK, Mamotte CDS, Jackaman C, Nelson DJ. Modulation of dendritic cell and T cell cross-talk during aging: the potential role of checkpoint inhibitory molecules. Ageing Res Rev. 2017;38:40–51. source

In the paper

“Padron et al. [153] found that in a melanoma mouse model, anti-CTLA-4, anti-PD-1, and anti-PD-L1 antibodies were very effective in treating young mice.”

What the sources say

• Not checked yetcites [153] Padron A, Hurez V, Gupta HB, Clark CA, Pandeswara SL, Yuan B, Svatek RS, Turk MJ, Drerup JM, Li R, et al. Age effects of distinct immune checkpoint blockade treatments in a mouse melanoma model. Exp Gerontol. 2018;105:146–54. source

In the paper

“Recently, it has been proven that drug intervention can slow down the aging phenotype to alleviate age-related functional decline [176].”

What the sources say

• Not checked yetcites [176] Partridge L, Fuentealba M, Kennedy BK. The quest to slow ageing through drug discovery. Nat Rev Drug Discov. 2020;19(8):513–32. source

In the paper

“patients who experienced lethal toxic effects appeared to be older than those not suffering from lethal toxic effects [159].”

What the sources say

• Not checked yetcites [159] Wang DY, Salem JE, Cohen JV, Chandra S, Menzer C, Ye F, Zhao S, Das S, Beckermann KE, Ha L, et al. Fatal toxic effects associated with immune checkpoint inhibitors: a systematic review and meta-analysis. JAMA Oncol. 2018;4(12):1721–8. source

In the paper

“Similarly, a report has shown that the injection of a plasmid vector carrying FOXN1-cDNA into the thymus of elderly mice would cause a partial rescue in the size of the thymus and the number of thymocytes [172].”

What the sources say

• Not checked yetcites [172] Sun L, Guo J, Brown R, Amagai T, Zhao Y, Su D-M. Declining expression of a single epithelial cell-autonomous gene accelerates age-related thymic involution. Aging Cell. 2010;9(3):347–57. source

In the paper

“it was reported that the IL-7 fusion protein, that is, IL-7 binding to the N-terminal extracellular domain of CCR9, could restore the thymus structure in elderly individuals [173]”

What the sources say

• Not checked yetcites [173] Henson SM, Snelgrove R, Hussell T, Wells DJ, Aspinall R. An IL-7 fusion protein that shows increased thymopoietic ability. J Immunol. 2005;175(6):4112–8. source

In the paper

“Moreover, in an oral cancer tumor-bearing mouse model, the tumor regression of aged mice after anti-PD-L1 treatment was faster than that of young mice [161].”

What the sources say

• Not checked yetcites [161] Sekido K, Tomihara K, Tachinami H, Heshiki W, Sakurai K, Moniruzzaman R, Imaue S, Fujiwara K, Noguchi M. Alterations in composition of immune cells and impairment of anti-tumor immune response in aged oral cancer-bearing mice. Oral Oncol. 2019;99:104462. source

In the paper

“Much of the literature suggests that the genetic regulation of mTOR signal transduction can slow the aging of many organisms [183–185].”

What the sources say

• Not checked yetcites [183] Ha CW, Huh W-K. Rapamycin increases rDNA stability by enhancing association of Sir2 with rDNA in Saccharomyces cerevisiae. Nucleic Acids Res. 2011;39(4):1336–50. source
• Not checked yetcites [184] Harrison DE, Strong R, Sharp ZD, Nelson JF, Astle CM, Flurkey K, Nadon NL, Wilkinson JE, Frenkel K, Carter CS, et al. Rapamycin fed late in life extends lifespan in genetically heterogeneous mice. Nature. 2009;460(7253):392–5. source
• Not checked yetcites [185] Miller RA, Harrison DE, Astle CM, Baur JA, Boyd AR, de Cabo R, Fernandez E, Flurkey K, Javors MA, Nelson JF, et al. Rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice. J Gerontol Ser A Biol Sci Med Sci. 2011;66(2):191–201. source

In the paper

“Metformin, a widely prescribed antidiabetic drug, has been shown to alleviate aging in preclinical studies [177].”

What the sources say

• Not checked yetcites [177] Barzilai N, Crandall JP, Kritchevsky SB, Espeland MA. Metformin as a Tool to Target Aging. Cell Metab. 2016;23(6):1060–5. source

In the paper

“with no increased toxicity [155–158].”

What the sources say

• Not checked yetcites [155] Elias R, Giobbie-Hurder A, McCleary NJ, Ott P, Hodi FS, Rahma O. Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis. J Immunother Cancer. 2018;6(1):26. source
• Not checked yetcites [156] Li P, Yang X, Feng Y, Wu L, Ma W, Ding G, Wei Y, Sun L. The impact of immunosenescence on the efficacy of immune checkpoint inhibitors in melanoma patients: a meta-analysis. Onco Targets Ther. 2018;11:7521–7. source
• Not checked yetcites [157] Marur S, Singh H, Mishra-Kalyani P, Larkins E, Keegan P, Sridhara R, Blumenthal GM, Pazdur R. FDA analyses of survival in older adults with metastatic non-small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies. Semin Oncol. 2018;45(4):220–5. source
• Not checked yetcites [158] Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30–7. source

In the paper

“which proved for the first time that the aging process is plastic [167].”

What the sources say

• Not checked yetcites [167] McCay CM, Maynard LA, Sperling G, Barnes LL. The Journal of Nutrition. Volume 18 July--December, 1939. Pages 1--13. Retarded growth, life span, ultimate body size and age changes in the albino rat after feeding diets restricted in calories. Nutrit Rev. 1975;33(8):241–43. source

In the paper

“It has been reported that the reduction of senescent cells through genetic and pharmacological methods can prevent and alleviate various senescence-related diseases [165, 166].”

What the sources say

• Not checked yetcites [165] Pignolo RJ, Passos JF, Khosla S, Tchkonia T, Kirkland JL. Reducing senescent cell burden in aging and disease. Trends in molecular medicine. 2020;26(7):630–8. source
• Not checked yetcites [166] Campisi J, Kapahi P, Lithgow GJ, Melov S, Newman JC, Verdin E. From discoveries in ageing research to therapeutics for healthy ageing. Nature. 2019;571(7764):183–92. source

In the paper

“IL-7 targeting the thymus of the elderly may also restore the development of T cells in the elderly.”

What the sources say

• Not checked yetcites [173] Henson SM, Snelgrove R, Hussell T, Wells DJ, Aspinall R. An IL-7 fusion protein that shows increased thymopoietic ability. J Immunol. 2005;175(6):4112–8. source

In the paper

“a retrospective analysis showed that the life span of diabetic patients treated with metformin increased compared with individuals without diabetes [181]”

What the sources say

• Not checked yetcites [181] Bannister CA, Holden SE, Jenkins-Jones S, Morgan CL, Halcox JP, Schernthaner G, Mukherjee J, Currie CJ. Can people with type 2 diabetes live longer than those without? A comparison of mortality in people initiated with metformin or sulphonylurea monotherapy and matched, non-diabetic controls. Diabetes Obes Metab. 2014;16(11):1165–73. source

In the paper

“therefore, the effect of ICB antibody therapy on elderly patients has not been fully elucidated [162].”

What the sources say

• Not checked yetcites [162] Belgioia L, Desideri I, Errico A, Franzese C, Daidone A, Marino L, Fiore M, Borghetti P, Greto D, Fiorentino A, et al. Safety and efficacy of combined radiotherapy, immunotherapy and targeted agents in elderly patients: a literature review. Crit Rev Oncol Hematol. 2019;133:163–70. source

In the paper

“The clearest evidence of age being the biggest risk factor for age-related diseases, and the accumulation of senescent cells is closely related to the occurrence of many chronic diseases [163, 164].”

What the sources say

• Not checked yetcites [163] Niccoli T, Partridge L. Ageing as a risk factor for disease. Curr Biol. 2012;22(17):R741–52. source
• Not checked yetcites [164] St Sauver JL, Boyd CM, Grossardt BR, Bobo WV, Finney Rutten LJ, Roger VL, Ebbert JO, Therneau TM, Yawn BP, Rocca WA. Risk of developing multimorbidity across all ages in an historical cohort study: differences by sex and ethnicity. BMJ Open. 2015;5(2):e006413. source

In the paper

“the risk of death among elderly patients is comparable or improved compared to that of patients subjected to control interventions, with no increased toxicity [155–158].”

What the sources say

• Not checked yetcites [155] Elias R, Giobbie-Hurder A, McCleary NJ, Ott P, Hodi FS, Rahma O. Efficacy of PD-1 & PD-L1 inhibitors in older adults: a meta-analysis. J Immunother Cancer. 2018;6(1):26. source
• Not checked yetcites [156] Li P, Yang X, Feng Y, Wu L, Ma W, Ding G, Wei Y, Sun L. The impact of immunosenescence on the efficacy of immune checkpoint inhibitors in melanoma patients: a meta-analysis. Onco Targets Ther. 2018;11:7521–7. source
• Not checked yetcites [157] Marur S, Singh H, Mishra-Kalyani P, Larkins E, Keegan P, Sridhara R, Blumenthal GM, Pazdur R. FDA analyses of survival in older adults with metastatic non-small cell lung cancer in controlled trials of PD-1/PD-L1 blocking antibodies. Semin Oncol. 2018;45(4):220–5. source
• Not checked yetcites [158] Nishijima TF, Muss HB, Shachar SS, Moschos SJ. Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis. Cancer Treat Rev. 2016;45:30–7. source

In the paper

“Much of the literature suggests that NAD+ declines in many tissues during the aging process, including adipose tissue, skeletal muscle, brain, liver, pancreas, heart, spleen, kidney, and lungs, leading to various age-related pathophysiology developments [195–197].”

What the sources say

• Not checked yetcites [195] Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 2018;27(3):529–47. source
• Not checked yetcites [196] Verdin E. NAD+ in aging, metabolism, and neurodegeneration. Science (New York, NY). 2015;350(6265):1208–13. source
• Not checked yetcites [197] Yoshino J, Baur JA, Imai S-I. NAD intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 2018;27(3):513–28. source

In the paper

“According to reports, NR and NMN have a protective effect in a number of age-related disease models, by increasing the pool of precursors and thus NAD+ levels in the body, both of which have been tested in murine and invertebrate aging studies [195, 197, 199].”

What the sources say

• Not checked yetcites [195] Rajman L, Chwalek K, Sinclair DA. Therapeutic potential of NAD-boosting molecules: the in vivo evidence. Cell Metab. 2018;27(3):529–47. source
• Not checked yetcites [197] Yoshino J, Baur JA, Imai S-I. NAD intermediates: the biology and therapeutic potential of NMN and NR. Cell Metab. 2018;27(3):513–28. source
• Not checked yetcites [199] Hikosaka K, Yaku K, Okabe K, Nakagawa T. Implications of NAD metabolism in pathophysiology and therapeutics for neurodegenerative diseases. Nutr Neurosci. 2019;1–13. source

In the paper

“NMN treatment can also restore glucose-stimulated insulin secretion in elderly mice [207].”

What the sources say

• Not checked yetcites [207] Ramsey KM, Mills KF, Satoh A, Imai S-I. Age-associated loss of Sirt1-mediated enhancement of glucose-stimulated insulin secretion in beta cell-specific Sirt1-overexpressing (BESTO) mice. Aging Cell. 2008;7(1):78–88. source

In the paper

“First, the reduction of T cell output caused by thymic degeneration can be achieved through the intervention with immune regulatory factors, i.e., by supplementing IL-7 [30], thereby restoring T cell production and thymic function.”

What the sources say

• Not checked yetcites [30] Nguyen V, Mendelsohn A, Larrick JW. Interleukin-7 and Immunosenescence. J Immunol Res. 2017;2017:4807853. source

In the paper

“Furthermore, the rejuvenation strategy for the thymic matrix microenvironment has been proven to successfully restore the thymus function of the elderly.”

In the paper

“Second, genes that control aging are highly conserved in humans.”

In the paper

“Previous studies have demonstrated that NMN can effectively alleviate age-related physiological decline in wild-type mice fed with conventional feed [205]”

What the sources say

• Not checked yetcites [205] Mills KF, Yoshida S, Stein LR, Grozio A, Kubota S, Sasaki Y, Redpath P, Migaud ME, Apte RS, Uchida K, et al. Long-term administration of nicotinamide mononucleotide mitigates age-associated physiological decline in mice. Cell Metab. 2016;24(6):795–806. source

In the paper

“These signal modulations, including mRNA translation, transcription, autophagy, and mitochondrial function, have been shown to mediate extended lifespan [186].”

What the sources say

• Not checked yetcites [186] Kapahi P, Kaeberlein M, Hansen M. Dietary restriction and lifespan: Lessons from invertebrate models. Ageing Res Rev. 2017;39:3–14. source