Immunosenescence and Its Hallmarks: How to Oppose Aging Strategically? A Review of Potential Options for Therapeutic Intervention

In the paper

“The age-related involvement of immune system leads to a progressive reduction in the ability to trigger effective antibody and cellular responses against infections and vaccinations.”

What the sources say

• Not checked yetcites [4] Walford, 1969 source

In the paper

“HCMV status has a greater impact than age on the immune system, because the virus contributes to shape the immune profile and function during normal human aging (16–18).”

What the sources say

• Not checked yetcites [16] Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol Rev. source
• Not checked yetcites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source
• Not checked yetcites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source

In the paper

“Several factors, such as genetics, nutrition, exercise, previous exposure to microorganisms, biological and cultural sex, and human cytomegalovirus (HCMV) status can influence immunosenescence (3, 6–11).”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source
• Not checked yetcites [7] Aiello, 2019, Role of immunogenetics in the outcome of HCMV infection: implications for ageing, Int J Mol Sci source
• Not checked yetcites [8] Caruso, 2013, Sex, gender and immunosenescence: a key to understand the different lifespan between men and women?, Immun Ageing source
• Not checked yetcites [9] Accardi, 2018, Immune-inflammatory responses in the elderly: an update, Immun Ageing source
• Not checked yetcites [10] Turner, 2016, Is immunosenescence influenced by our lifetime “dose” of exercise?, Biogerontology source
• Not checked yetcites [11] Maijó, 2014, Nutrition, diet and immunosenescence, Mech Ageing Dev source

In the paper

“In particular, HCMV seropositivity seems related to many functional T cell changes.”

What the sources say

• Not checked yetcites [16] Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol Rev. source
• Not checked yetcites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source
• Not checked yetcites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source

In the paper

“In fact, aging process more extensively affects acquired immunity than innate immunity (3, 5).”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [5] Nikolich-Žugich, 2018, The twilight of immunity: emerging concepts in aging of the immune system, Nat Immunol source

In the paper

“Follow-up of 2-, 4-, and 6-years mortality revealed significantly higher all-cause mortality in the IRP group than in the majority of other octogenarians and non-agenarians.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source
• Not checked yetcites [16] Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol Rev. source

In the paper

“Subsequently, the data were implemented and related to HCMV seropositivity, because HCMV seropositivity is closely related to the reversal of CD4/CD 8 T-cell ratio.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source
• Not checked yetcites [16] Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol Rev. source

In the paper

“Therefore, immune system might also be prone to intervention.”

In the paper

“In fact, the different parameters observed between young and older people could also be a product of the adaption vs. the exposome, i.e., all the stimuli that the immune system has undergone during life.”

What the sources say

• Not checked yetcites [21] Ponnappan, 2011, Aging and immune function: molecular mechanisms to interventions, Antioxid Redox Signal. source

In the paper

“Accordingly, DCs together with naïve T cells represent the most restrictive elements for the immune response to primary viral infections in older people (33).”

What the sources say

• Not checked yetcites [33] Schulz, 2015, Low thymic activity and dendritic cell numbers are associated with the immune response to primary viral infection in elderly humans, J Immunol source

In the paper

“Peripheral blood mononuclear cells (PBMCs) isolated from older individuals (≥65 years) exhibited a delayed and altered response to stimulation with TLR agonists compared with cells obtained from young adults (≤ 40 years).”

What the sources say

• Not checked yetcites [29] Gambino, 2017, Triggering of Toll-like receptors in the elderly. A pilot stdudy relevant for vaccination

In the paper

“This delayed response to agonists results in the reduced production of cytokines and chemokines (29).”

What the sources say

• Not checked yetcites [29] Gambino, 2017, Triggering of Toll-like receptors in the elderly. A pilot stdudy relevant for vaccination

In the paper

“As the expression of TLRs remains constant during life, defects in signal transduction should be responsible for this impairment, as discussed by (24).”

What the sources say

• Not checked yetcites [24] Pinti, 2016, Aging of the immune system: focus on inflammation and vaccination, Eur J Immunol source

In the paper

“As critically reviewed by (3, 6, 16), a number of longitudinal studies of octogenarians and non-agenarians performed in Sweden defined an immunological risk phenotype (IRP).”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source
• Not checked yetcites [16] Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol Rev. source

In the paper

“As the expression of TLRs remains constant during life, defects in signal transduction should be responsible for this impairment, as discussed by (24).”

What the sources say

• Not checked yetcites [24] Pinti, 2016, Aging of the immune system: focus on inflammation and vaccination, Eur J Immunol source

In the paper

“Thus, immune parameters associated with survival may vary in diverse populations at different ages (6).”

What the sources say

• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source

In the paper

“Participants with the reversal of CD4/CD 8 T-cell ratio, a reduced proliferative response to mitogenic stimuli, and severe reduced B cells number showed reduced survival.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source
• Not checked yetcites [16] Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol Rev. source

In the paper

“However, this IRP was not confirmed in the Leiden 85-Plus study, a prospective population-based cohort study of individuals at the age of 85 years living in Leiden (NL).”

What the sources say

• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source

In the paper

“However, all possible therapies aimed at non-specifically “rejuvenating” the immune system might be counterproductive.”

What the sources say

• Not checked yetcites [21] Ponnappan, 2011, Aging and immune function: molecular mechanisms to interventions, Antioxid Redox Signal. source

In the paper

“On the other hand, the addition of PAMPs to a subunit vaccine, triggering their corresponding pattern-recognition receptors (e.g., TLRs) improves vaccine efficacy in older humans and mice (25, 30–32).”

What the sources say

• Not checked yetcites [25] Metcalf, 2015, Global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors, Aging Cell source
• Not checked yetcites [30] Miyaji, 2011, Trends in adjuvant development for vaccines: DAMPs and PAMPs as potential new adjuvants, Braz J Med Biol Res source
• Not checked yetcites [31] Lal, 2015, Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults, N Engl J Med source
• Not checked yetcites [32] Sharma, 2008, CpG-ODN but not other TLR-ligands restore the antitumor responses in old mice: the implications for vaccinations in the aged, Cancer Immunol Immunother source

In the paper

“pDCs are instead characterized by a marked impairment of cytokine release in older people (27, 29).”

What the sources say

• Not checked yetcites [27] Collin, 2018, Human dendritic cell subsets: an update, Immunology source
• Not checked yetcites [29] Gambino, 2017, Triggering of Toll-like receptors in the elderly. A pilot stdudy relevant for vaccination

In the paper

“The IRP was present in around 15% of 85-years-olds in these studies at baseline.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source
• Not checked yetcites [16] Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol Rev. source

In the paper

“In fact, as discussed below, persistent HCMV infection leads to chronic stimulation of CD8 T cells, which expand clonally showing an effector memory phenotype characterized by low CD28 expression.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source
• Not checked yetcites [16] Pawelec, 2005, Human immunosenescence: is it infectious?, Immunol Rev. source

In the paper

“Aging per se leads only to a relative accumulation of memory cell subsets, linked to the decrease in naïve cell populations.”

What the sources say

• Not checked yetcites [40] Wertheimer, 2014, Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans, J Immunol. source

In the paper

“Due to the lifelong and chronic exposure to pathogens, T cells replicate several times and become late-differentiated effector memory T cells with features of replicative senescence (38).”

What the sources say

• Not checked yetcites [38] Lanna, 2014, The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells, Nat Immunol source

In the paper

“The loss of CD28 occurs following cell proliferation, according to the observation that the CD28− T cells have shorter telomeres than CD28+ cells.”

What the sources say

• Not checked yetcites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source
• Not checked yetcites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source
• Not checked yetcites [41] Effros, 1994, Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence, Exp Gerontol source
• Not checked yetcites [42] Posnett, 1999, Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones, Int Immu source
• Not checked yetcites [43] Voehringer, 2002, Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1), Blood. source
• Not checked yetcites [44] Plunkett, 2007, The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation, J Immunol source
• Not checked yetcites [45] Derhovanessian, 2009, Biomarkers of human immunosenescence: impact of cytomegalovirus infection, Curr Opin Immunol. source
• Not checked yetcites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source
• Not checked yetcites [47] Pawelec, 2014, Immunosenenescence: role of cytomegalovirus, Exp Gerontol source

In the paper

“Therefore, at the age of 50, T cell production is <10% of its previous peak levels.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [22] Pawelec, 2018, Age and immunity: What is “immunosenescence”?, Exp Gerontol source
• Not checked yetcites [36] Shanley, 2009, An evolutionary perspective on the mechanisms of immunosenescence, Trends Immunol. source

In the paper

“Mechanistically, immunosenescence is only partially explained by organismal and cellular senescence.”

What the sources say

• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source
• Not checked yetcites [23] Goronzy, 2013, Understanding immunosenescence to improve responses to vaccines, Nat Immunol source

In the paper

“These T cells do not express the co-stimulatory molecule CD28, required for the activation of T cells.”

What the sources say

• Not checked yetcites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source
• Not checked yetcites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source
• Not checked yetcites [41] Effros, 1994, Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence, Exp Gerontol source
• Not checked yetcites [42] Posnett, 1999, Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones, Int Immu source
• Not checked yetcites [43] Voehringer, 2002, Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1), Blood. source
• Not checked yetcites [44] Plunkett, 2007, The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation, J Immunol source
• Not checked yetcites [45] Derhovanessian, 2009, Biomarkers of human immunosenescence: impact of cytomegalovirus infection, Curr Opin Immunol. source
• Not checked yetcites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source
• Not checked yetcites [47] Pawelec, 2014, Immunosenenescence: role of cytomegalovirus, Exp Gerontol source

In the paper

“In addition, their number decreases following the involution of primary lymphoid organs, because age-related defects have been observed in their stroma.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [22] Pawelec, 2018, Age and immunity: What is “immunosenescence”?, Exp Gerontol source
• Not checked yetcites [36] Shanley, 2009, An evolutionary perspective on the mechanisms of immunosenescence, Trends Immunol. source

In the paper

“Therefore, these hallmarks of immunosenescence would be markedly affected by the history of the individual exposure to pathogens (6, 23).”

What the sources say

• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source
• Not checked yetcites [23] Goronzy, 2013, Understanding immunosenescence to improve responses to vaccines, Nat Immunol source

In the paper

“As previously stated, an age-related decrease in absolute number of peripheral blood naïve T cells is consistently found in all studies and in different human populations (22, 37).”

What the sources say

• Not checked yetcites [22] Pawelec, 2018, Age and immunity: What is “immunosenescence”?, Exp Gerontol source
• Not checked yetcites [37] Franceschi, 2000, Human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space, Vaccine. source

In the paper

“The absolute increase in memory T cells, called memory inflation, is observed only in older people infected by HCMV (40).”

What the sources say

• Not checked yetcites [40] Wertheimer, 2014, Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans, J Immunol. source

In the paper

“The reduced ability to respond to new antigens is linked to a decreased number of peripheral naïve T and B cells (see last paragraph of this section).”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [22] Pawelec, 2018, Age and immunity: What is “immunosenescence”?, Exp Gerontol source
• Not checked yetcites [36] Shanley, 2009, An evolutionary perspective on the mechanisms of immunosenescence, Trends Immunol. source

In the paper

“An abrupt contraction is seen in later life.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [22] Pawelec, 2018, Age and immunity: What is “immunosenescence”?, Exp Gerontol source
• Not checked yetcites [36] Shanley, 2009, An evolutionary perspective on the mechanisms of immunosenescence, Trends Immunol. source

In the paper

“In addition, they are producers of pro-inflammatory cytokines (17, 18, 41–47).”

What the sources say

• Not checked yetcites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source
• Not checked yetcites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source
• Not checked yetcites [41] Effros, 1994, Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence, Exp Gerontol source
• Not checked yetcites [42] Posnett, 1999, Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones, Int Immu source
• Not checked yetcites [43] Voehringer, 2002, Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1), Blood. source
• Not checked yetcites [44] Plunkett, 2007, The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation, J Immunol source
• Not checked yetcites [45] Derhovanessian, 2009, Biomarkers of human immunosenescence: impact of cytomegalovirus infection, Curr Opin Immunol. source
• Not checked yetcites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source
• Not checked yetcites [47] Pawelec, 2014, Immunosenenescence: role of cytomegalovirus, Exp Gerontol source

In the paper

“However, a longitudinal study of 249 research participants followed for 10 years has strongly suggested that HCMV infection is not a primary causative factor in the age-related increase in systemic inflammation (48).”

What the sources say

• Not checked yetcites [48] Bartlett, The age-related increase in low-grade systemic inflammation (Inflammaging) is not driven by cytomegalovirus infection, Aging Cell. source

In the paper

“CD28 seems a good biomarker of immunosenescence, as further suggested by findings that late-differentiated CD8+/CD28− T cells tend to accumulate particularly in older people, frail or affected by age-related diseases.”

What the sources say

• Not checked yetcites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source
• Not checked yetcites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source
• Not checked yetcites [41] Effros, 1994, Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence, Exp Gerontol source
• Not checked yetcites [42] Posnett, 1999, Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones, Int Immu source
• Not checked yetcites [43] Voehringer, 2002, Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1), Blood. source
• Not checked yetcites [44] Plunkett, 2007, The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation, J Immunol source
• Not checked yetcites [45] Derhovanessian, 2009, Biomarkers of human immunosenescence: impact of cytomegalovirus infection, Curr Opin Immunol. source
• Not checked yetcites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source
• Not checked yetcites [47] Pawelec, 2014, Immunosenenescence: role of cytomegalovirus, Exp Gerontol source

In the paper

“Late-stage memory senescent T-cells may also acquire new functions, such as suppressive activity, as demonstrated in vitro.”

What the sources say

• Not checked yetcites [17] Jergović, 2019, Impact of CMV upon immune aging: facts and fiction, Med Microbiol Immunol source
• Not checked yetcites [18] Nikolich-Žugich, 2017, Cytomegalovirus (CMV) research in immune senescence comes of age: overview of the 6th international workshop on CMV and immunosenescence, Geroscience source
• Not checked yetcites [41] Effros, 1994, Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence, Exp Gerontol source
• Not checked yetcites [42] Posnett, 1999, Differentiation of human CD8 T cells: implications for in vivo persistence of CD8+ CD28− cytotoxic effector clones, Int Immu source
• Not checked yetcites [43] Voehringer, 2002, Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1), Blood. source
• Not checked yetcites [44] Plunkett, 2007, The loss of telomerase activity in highly differentiated CD8+CD28−CD27− T cells is associated with decreased Akt (Ser473) phosphorylation, J Immunol source
• Not checked yetcites [45] Derhovanessian, 2009, Biomarkers of human immunosenescence: impact of cytomegalovirus infection, Curr Opin Immunol. source
• Not checked yetcites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source
• Not checked yetcites [47] Pawelec, 2014, Immunosenenescence: role of cytomegalovirus, Exp Gerontol source

In the paper

“As previously stated, this determines the phenomenon of memory cell inflation, leading to the emergence of vast populations of resting effector CD8+ and, to a lesser extent, CD4+ cells.”

What the sources say

• Not checked yetcites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source
• Not checked yetcites [51] Khan, 2002, Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals, J Immunol source

In the paper

“In addition, the long-term chronic microbial burden induces progressive activation of macrophages, hence contributing to the chronic state of low-grade inflammation, inflamm-aging, another hallmark of immunosenescence (3, 9, 57).”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• Not checked yetcites [9] Accardi, 2018, Immune-inflammatory responses in the elderly: an update, Immun Ageing source
• Not checked yetcites [57] Franceschi, 2014, Chronic inflammation (inflammaging) and its potential contribution to age-associated diseases, J Gerontol A Biol Sci Med Sci source

In the paper

“This leads to an increased production of pro-inflammatory cytokines and acute phase proteins (59, 60).”

What the sources say

• Not checked yetcites [59] Puzianowska-Kuznicka, 2016, Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study, Immun Ageing source
• Not checked yetcites [60] Licastro, 2005, Innate immunity and inflammation in ageing: a key for understanding age-related diseases, Immun Ageing source

In the paper

“However, the memory responses can be unsustained, because T cell memory established in humans during early age can deteriorate during the second half of life.”

What the sources say

• Not checked yetcites [49] Gilden, 2014, Varicella-zoster, Handb Clin Neurol source

In the paper

“These inflated HCMV-specific memory T cells maintain their efficient effector functions for the lifetime of the individual (40, 46, 52).”

What the sources say

• Not checked yetcites [40] Wertheimer, 2014, Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans, J Immunol. source
• Not checked yetcites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source
• Not checked yetcites [52] Riddell, 2015, Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults, Immunology source

In the paper

“Therefore, the accumulation of memory T cells, especially late-stage differentiated CD8+ cells is viewed as the result of depletion of the reservoir of naïve cells over time by contact with pathogens and their conversion to memory cells.”

In the paper

“In older people, one or a few clonal populations can occupy more than 25% of the entire CD8+ cell pool (46, 51).”

What the sources say

• Not checked yetcites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source
• Not checked yetcites [51] Khan, 2002, Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals, J Immunol source

In the paper

“In fact, HCMV load in blood markedly increases in healthy people over the age of 70 years (53).”

What the sources say

• Not checked yetcites [53] Parry, 2016, Cytomegalovirus viral load within blood increases markedly in healthy people over the age of 70 years, Immun Ageing. source

In the paper

“In the course of aging, there is a reduction in the ability to endure consequences of antigenic, chemical, physical, and nutritional triggers of inflammation.”

What the sources say

• Not checked yetcites [59] Puzianowska-Kuznicka, 2016, Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study, Immun Ageing source
• Not checked yetcites [60] Licastro, 2005, Innate immunity and inflammation in ageing: a key for understanding age-related diseases, Immun Ageing source

In the paper

“A steady decline of VZV-specific CD4+ T cells over time has been documented, which is only very transiently boosted with zoster vaccination or reactivation (49).”

What the sources say

• Not checked yetcites [49] Gilden, 2014, Varicella-zoster, Handb Clin Neurol source

In the paper

“However, there may be a slight loss of control of HCMV replication in older compared with younger people.”

What the sources say

• Not checked yetcites [53] Parry, 2016, Cytomegalovirus viral load within blood increases markedly in healthy people over the age of 70 years, Immun Ageing. source

In the paper

“However, the correlation between HCMV positivity and impaired responses is controversial because this relationship is observed in some but not all studies (54–56).”

What the sources say

• Not checked yetcites [54] Frasca, 2015, Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine, Vaccine. source
• Not checked yetcites [55] Furman, 2015, Cytomegalovirus infection enhances the immune response to influenza, Sci Transl Med source
• Not checked yetcites [56] Weltevrede, 2016, Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: a systematic review, Exp Gerontol source

In the paper

“In contrast, high frequencies of antigen-specific T cells reactive to HCMV persist throughout life.”

What the sources say

• Not checked yetcites [23] Goronzy, 2013, Understanding immunosenescence to improve responses to vaccines, Nat Immunol source

In the paper

“The most obvious example of unsustained memory responses is the reactivation of latent varicella zoster virus (VZV) infection that manifests as herpes zoster.”

What the sources say

• Not checked yetcites [49] Gilden, 2014, Varicella-zoster, Handb Clin Neurol source

In the paper

“Inflationary CD8+ cells, after proper activation stimuli, can divide, secrete cytokines, and execute cytolysis, i.e., they are not exhausted.”

What the sources say

• Not checked yetcites [40] Wertheimer, 2014, Aging and cytomegalovirus infection differentially and jointly affect distinct circulating T cell subsets in humans, J Immunol. source
• Not checked yetcites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source
• Not checked yetcites [52] Riddell, 2015, Multifunctional cytomegalovirus (CMV)-specific CD8(+) T cells are not restricted by telomere-related senescence in young or old adults, Immunology source

In the paper

“Chronic and low-grade inflammation can lead to tissue dysfunction and degeneration.”

What the sources say

• Not checked yetcites [59] Puzianowska-Kuznicka, 2016, Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study, Immun Ageing source
• Not checked yetcites [60] Licastro, 2005, Innate immunity and inflammation in ageing: a key for understanding age-related diseases, Immun Ageing source

In the paper

“Immune changes associated with HCMV may have significant impact during co-infection and vaccination, as well as on general and immunological fitness.”

What the sources say

• Not checked yetcites [54] Frasca, 2015, Cytomegalovirus (CMV) seropositivity decreases B cell responses to the influenza vaccine, Vaccine. source
• Not checked yetcites [55] Furman, 2015, Cytomegalovirus infection enhances the immune response to influenza, Sci Transl Med source
• Not checked yetcites [56] Weltevrede, 2016, Cytomegalovirus persistence and T-cell immunosenescence in people aged fifty and older: a systematic review, Exp Gerontol source

In the paper

“Increased serum levels of TNF-α are also linked to a defective T cell response, in part due to reduced expression of CD28 (21).”

What the sources say

• Not checked yetcites [21] Ponnappan, 2011, Aging and immune function: molecular mechanisms to interventions, Antioxid Redox Signal. source

In the paper

“Accordingly, in monocytes, the pre-vaccination expression of genes related to inflammation and innate immune response is negatively correlated to vaccination-induced activation of influenza-specific antibody responses (70).”

What the sources say

• Not checked yetcites [70] Nakaya, 2015, Systems analysis of immunity to influenza vaccination across multiple years and in diverse populations reveals shared molecular signatures, Immunity. source

In the paper

“In the latent state, the intermittent production of viral antigens prevents contraction of virus-specific T cells.”

What the sources say

• Not checked yetcites [46] Nikolich-Zugich, 2017, Known unknowns: how might the persistent herpesvirome shape immunity and aging?, Curr Opin Immunol. source
• Not checked yetcites [51] Khan, 2002, Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals, J Immunol source

In the paper

“Many existing data demonstrate the key role of foods as regulators of immune response and inflammatory status, hence as possible modulators of the rate of immunosenescence, particularly inflamm-aging (11, 80).”

What the sources say

• Not checked yetcites [11] Maijó, 2014, Nutrition, diet and immunosenescence, Mech Ageing Dev source
• Not checked yetcites [80] Xia, 2016, An update on inflamm-aging: mechanisms, prevention, and treatment, J Immunol Res source

In the paper

“Other data have demonstrated the importance of following a specific, even personally tailored, dietary pattern (81).”

What the sources say

• Not checked yetcites [81] Choi, 2017, Nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseases and immunosenescence, Mol Cell Endocrinol source

In the paper

“It is due to the higher expression of the inflammatory mi-RNAs 16 and 155, which bind to the 3'-untranslated region of E47 and AID mRNA, respectively, inducing mRNA degradation (69).”

What the sources say

• Not checked yetcites [69] Frasca, 2015, MicroRNAs miR-155 and miR-16 decrease AID and E47 in B cells from elderly individuals, J Immunol. source

In the paper

“The reduced levels of E47 and AID mRNA in B cells from older individuals are also due to the reduced mRNA stability.”

What the sources say

• Not checked yetcites [69] Frasca, 2015, MicroRNAs miR-155 and miR-16 decrease AID and E47 in B cells from elderly individuals, J Immunol. source

In the paper

“There is a mutual interaction between nutrition, intake of particular bioactive dietary components, immune function, and inflammatory status, hence a close relation with the hallmarks of immunosenescence (78, 79).”

What the sources say

• Not checked yetcites [78] Maggini, 2018, Immune function and micronutrient requirements change over the life course, Nutrients source
• Not checked yetcites [79] Lesourd, 2006, Nutritional factors and immunological ageing, Proc Nutr Soc source

In the paper

“This is the key transcription factor, for the induction of activation-induced cytidine deaminase (AID), involved in class switching and somatic hypermutation.”

What the sources say

• Not checked yetcites [72] Frasca, 2004, Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase, J Immunol. source
• Not checked yetcites [73] Frasca, 2016, The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations, Vaccine. source

In the paper

“The main barrier to better clarity remains the wide heterogeneity among human beings, linked to different life-style and genetic factors that influence the rate of immunosenescence (6, 10, 11, 82).”

What the sources say

• Not checked yetcites [6] Pawelec, 2012, Hallmarks of human “immunosenescence”: adaptation or dysregulation?, Immun Ageing source
• Not checked yetcites [10] Turner, 2016, Is immunosenescence influenced by our lifetime “dose” of exercise?, Biogerontology source
• Not checked yetcites [11] Maijó, 2014, Nutrition, diet and immunosenescence, Mech Ageing Dev source
• Not checked yetcites [82] Ongrádi, 2010, Factors that may impact on immunosenescence: an appraisal, Immun Ageing source

In the paper

“NF-κB, mechanistic target of rapamycin (mTOR), and MAPK, pathways closely related to aging and inflammation are modulated by caloric restriction that downregulates the activation of IL-1β, IL-6, and tumor necrosis factor (TNF)-α genes, hence the pro-inflammatory state (20, 91, 92).”

What the sources say

• Not checked yetcites [20] Aiello, 2019, Slow-aging diets source
• Not checked yetcites [91] Chung, 2013, Recent advances in calorie restriction research on aging, Exp Gerontol source
• Not checked yetcites [92] Chung, 2001, The inflammation hypothesis of aging: molecular modulation by calorie restriction, Ann N Y Acad Sci source

In the paper

“Activated B cells isolated from older adults display a reduced induction of E47, a class I basic helix-loop-helix protein encoded by the E2A gene.”

What the sources say

• Not checked yetcites [72] Frasca, 2004, Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase, J Immunol. source
• Not checked yetcites [73] Frasca, 2016, The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations, Vaccine. source

In the paper

“In particular, the Mediterranean diet down-regulates the levels of inflammatory mediators, such as soluble intercellular adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM-1), C reactive protein, and IL-6, as well as many other biomarkers of inflammation (87–90).”

What the sources say

• Not checked yetcites [87] Gambino, 2018, Effect of extra virgin olive oil and table olives on the immuneinflammatory responses: potential clinical applications, Endocr Metab Immune Disord Drug Targets source
• Not checked yetcites [88] Accardi, 2016, Mediterranean nutraceutical foods: Strategy to improve vascular ageing, Mech Ageing Dev source
• Not checked yetcites [89] Accardi, 2016, Nutraceutical effects of table green olives: a pilot study with Nocellara del Belice olives, Immun Ageing source
• Not checked yetcites [90] Casas, 2016, Long-term immunomodulatory effects of a mediterranean diet in adults at high risk of cardiovascular disease in the PREvención con DIeta MEDiterránea (PREDIMED) randomized controlled trial, J Nutr source

In the paper

“More specifically, the results obtained by administration of different cycles of fasting, mimicking diet or long-term fasting influences inflamm-aging (20).”

What the sources say

• Not checked yetcites [20] Aiello, 2019, Slow-aging diets source

In the paper

“The high rate of long living people and the low incidence of cardiovascular disease in many Mediterranean countries suggest the importance of a diet rich in fruits, vegetables, whole grains, legumes, and olive oil (probably the main anti-aging food in this area).”

What the sources say

• Not checked yetcites [68] Vasto, 2014, Mediterranean diet and healthy ageing: a Sicilian perspective, Gerontology. source
• Not checked yetcites [83] Trichopoulou, 2019, Impact of Mediterranean diet on longevity source
• Not checked yetcites [84] Martinez-Gonzalez, 2009, Mediterranean food pattern and the primary prevention of chronic disease: recent developments, Nutr Rev source
• Not checked yetcites [85] Mitsou, 2017, Adherence to the Mediterranean diet is associated with the gut microbiota pattern and gastrointestinal characteristics in an adult population, Br J Nutr source
• Not checked yetcites [86] Sofi, 2010, Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis, Am J Clin Nutr source

In the paper

“The reduced expression of E2A might be responsible for the decreased avidity of antibodies and diminished antibody-mediated protection (72, 73).”

What the sources say

• Not checked yetcites [72] Frasca, 2004, Reduced Ig class switch in aged mice correlates with decreased E47 and activation-induced cytidine deaminase, J Immunol. source
• Not checked yetcites [73] Frasca, 2016, The generation of memory B cells is maintained, but the antibody response is not, in the elderly after repeated influenza immunizations, Vaccine. source

In the paper

“New insights may also come from the use of caloric restriction mimetics, such as metformin, an activator of 5′ AMP-activated protein kinase (AMPK).”

What the sources say

• Not checked yetcites [94] Barzilai, 2016, Metformin as a tool to target aging, Cell Metab source

In the paper

“The reduced consumption of animal proteins, in particular red and cured meat, is also important.”

What the sources say

• Not checked yetcites [68] Vasto, 2014, Mediterranean diet and healthy ageing: a Sicilian perspective, Gerontology. source
• Not checked yetcites [83] Trichopoulou, 2019, Impact of Mediterranean diet on longevity source
• Not checked yetcites [84] Martinez-Gonzalez, 2009, Mediterranean food pattern and the primary prevention of chronic disease: recent developments, Nutr Rev source
• Not checked yetcites [85] Mitsou, 2017, Adherence to the Mediterranean diet is associated with the gut microbiota pattern and gastrointestinal characteristics in an adult population, Br J Nutr source
• Not checked yetcites [86] Sofi, 2010, Accruing evidence on benefits of adherence to the Mediterranean diet on health: an updated systematic review and meta-analysis, Am J Clin Nutr source

In the paper

“Minor effects on immune function, after a brief starvation period of 72 hours, were seen in ten healthy, normal-weight, young volunteers.”

What the sources say

• Not checked yetcites [93] Neuvonen, 1984, Effects of short-term starvation on the immune response, Nutr Res. source

In the paper

“This defect might be linked to a reduced interaction with CD40L+ T helper cells, because, in older adults, the memory/effector T cells show a reduced expression of CD40L, necessary for B cells cooperation (74).”

What the sources say

• Not checked yetcites [74] Colonna-Romano, 2003, B cells in the aged: CD27, CD5, and CD40 expression, Mech Ageing Dev source

In the paper

“after zinc supplementation for 12 months (45 mg elemental Zn gluconate/day), the incidence of infections was significantly lower, plasma zinc was significantly higher, and generation of TNF-α and oxidative stress markers was significantly lower in the zinc-supplemented participants than in the placebo group”

In the paper

“Even slight deficiencies in zinc can have important consequences (104–107).”

What the sources say

• Not checked yetcites [104] Haase, 2009, The immune system and the impact of zinc during aging, Immun Ageing source
• Not checked yetcites [105] Prasad, 2008, Clinical, immunological, anti-inflammatory and antioxidant roles of zinc, Exp Gerontol source
• Not checked yetcites [106] Prasad, 2008, Zinc in human health: effect of zinc on immune cells, Mol Med source
• Not checked yetcites [107] Maywald, 2017, Zinc signals and immunity, Int J Mol Sci source

In the paper

“Nutritional status is crucial for the health status of older adults.”

What the sources say

• Not checked yetcites [100] Leslie, 2015, Aging, nutritional status and health, Healthcare (Basel) source

In the paper

“lower CD25 expression by resting T lymphocytes (123)”

What the sources say

• Not checked yetcites [123] Landete, 2017, Probiotic bacteria for healthier aging: immunomodulation and metabolism of phytoestrogens, Biomed Res Int source

In the paper

“In addition, these biotics improve the innate immune responses by the modulation of phagocytosis and cytotoxicity against specific bacteria, such as Staphylococcus aureus”

What the sources say

• Not checked yetcites [123] Landete, 2017, Probiotic bacteria for healthier aging: immunomodulation and metabolism of phytoestrogens, Biomed Res Int source

In the paper

“As shown in a randomized, doubleblind, placebo-controlled trial, after zinc supplementation for 12 months (45 mg elemental Zn gluconate/day), the incidence of infections was significantly lower, plasma zinc was significantly higher, and generation of TNF-α and oxidative stress markers was significantly lower in the zinc-supplemented participants than in the placebo group (both groups composed of 5”

In the paper

“Moreover, healthy status, including absence of disease and nutritional status, seems to be crucial for their action as demonstrated by null results on immunomodulation after administration of prebiotics in older adults vaccinated with influenza or pneumococcal vaccines (125).”

What the sources say

• Not checked yetcites [125] Bunout, 2002, Effects of prebiotics on the immune response to vaccination in the elderly, JPEN J Parenter Enteral Nutr source

In the paper

“Jyonouchi et al. observed that lutein and astaxanthin increased the ex vivo antibody response of mouse splenocytes to T-cell antigens (136).”

What the sources say

• Not checked yetcites [136] Jyonouchi, 1994, Immunomodulating actions of carotenoids: enhancement of in vivo and in vitro antibody production to T-dependent antigens, Nutr Cancer source

In the paper

“Given the dose-dependent effect of zinc, both as a pro- and anti-oxidant, its presence in the normal range is essential for regulating the levels of reactive oxygen species (112).”

What the sources say

• Not checked yetcites [112] Lee, 2018, Critical role of zinc as either an antioxidant or a prooxidant in cellular systems, Oxid Med Cell Longev source

In the paper

“Vitamin supplementation studies in older adults have demonstrated a role for vitamin E in the production of IL-2 as well as the activation induced T cell proliferation in naïve but not in memory T cells (78, 113–115).”

What the sources say

• Not checked yetcites [78] Maggini, 2018, Immune function and micronutrient requirements change over the life course, Nutrients source
• Not checked yetcites [113] Meydani, 1997, Vitamin E supplementation and in vivo immune response in healthy elderly subjects. A randomized controlled trial, JAMA source
• Not checked yetcites [114] De la Fuente, 2008, Vitamin E ingestion improves several immune functions in elderly men and women, Free Radic Res source
• Not checked yetcites [115] Pallast, 1999, Effect of 50- and 100-mg vitamin E supplements on cellular immune function in noninstitutionalized elderly persons, Am J Clin Nutr source

In the paper

“Therefore, the administration of specific strains of Lactobacilli and Bifidobacteria as probiotics as well as fructooligosaccharides, galactooligosaccharides, and other prebiotics, or the combination of both might constitute a benefit for immunocompromised people (118–122).”

What the sources say

• Not checked yetcites [118] Markowiak, 2017, Effects of probiotics, prebiotics, and synbiotics on human health, Nutrients source
• Not checked yetcites [119] Gill, 2001, Enhancement of immunity in the elderly by dietary supplementation with the probiotic Bifidobacterium lactis HN019, Am J Clin Nutr source
• Not checked yetcites [120] Dong, 2013, Immunomodulatory effects of a probiotic drink containing Lactobacillus casei Shirota in healthy older volunteers, Eur J Nutr source
• Not checked yetcites [121] Vulevic, 2008, Modulation of the fecal microflora profile and immune function by a novel trans-galactooligosaccharide mixture (B-GOS) in healthy elderly volunteers, Am J Clin Nutr source
• Not checked yetcites [122] Lefevre, 2015, Probiotic strain Bacillus subtilis CU1 stimulates immune system of elderly during common infectious disease period: a randomized, double-blind placebo-controlled study, Immun Ageing source

In the paper

“However, this response is variable, depending on genetics and immune functionality (102).”

What the sources say

• Not checked yetcites [102] Pae, 2012, The role of nutrition in enhancing immunity in aging, Aging Dis

In the paper

“Micronutrients, such as vitamins and minerals, are essential for the efficient performance of the immune system.”

What the sources say

• Not checked yetcites [78] Maggini, 2018, Immune function and micronutrient requirements change over the life course, Nutrients source
• Not checked yetcites [103] Elmadfa, 2009, European Nutrition and Health Report 2009, Ann Nutr Metab source

In the paper

“These food compounds, mainly found in plant-based foods and fatty fish, have been implicated in offering physiological health benefits over and above basic nutritional requirements (126–128).”

What the sources say

• Not checked yetcites [126] Aiello, 2016, Nutrigerontology: a key for achieving successful ageing and longevity, Immun Ageing source
• Not checked yetcites [127] Ferrari, 2004, Functional foods, herbs and nutraceuticals: towards biochemical mechanisms of healthy aging, Biogerontology source
• Not checked yetcites [128] Davinelli, 2016, Dietary phytochemicals and neuro-inflammaging: from mechanistic insights to translational challenges, Immun Ageing source

In the paper

“This makes older people enable to trigger an efficient immune response to newly encountered pathogens.”

What the sources say

• Not checked yetcites [98] Nova, 2007, Immunomodulatory effects of probiotics in different stages of life, Br J Nutr source
• Not checked yetcites [99] Shlisky, 2017, Nutritional considerations for healthy aging and reduction in age-related chronic disease, Adv Nutr source

In the paper

“generation of TNF-α and oxidative stress markers was significantly lower in the zinc-supplemented participants than in the placebo group”

In the paper

“Data from supplementation studies with pro- or prebiotics in older adults show a control of inflammatory status because their use is responsible for a lower production of TNF-α, IL-1β, and IL-6 as well as an increase of anti-inflammatory cytokine IL-10, by PBMCs.”

What the sources say

• Not checked yetcites [123] Landete, 2017, Probiotic bacteria for healthier aging: immunomodulation and metabolism of phytoestrogens, Biomed Res Int source

In the paper

“In mice with collagen-induced arthritis, metformin administration had an anti-inflammatory effect on arthritis due to the inhibition of Th17 cell differentiation, a subset of pro-inflammatory cells producing IL-17, and the upregulation of T regulatory cells (Tregs) differentiation along with the suppression of osteoclast differentiation (96, 97).”

What the sources say

• Not checked yetcites [96] Saisho, 2015, Metformin and inflammation: its potential beyond glucose-lowering effect, Endocr Metab Immune Disord Drug Targets source
• Not checked yetcites [97] Son, 2014, Metformin attenuates experimental autoimmune arthritis through reciprocal regulation of Th17/Treg balance and osteoclastogenesis, Mediat Inflamm source

In the paper

“Older adults supplemented with carotenoids (30 mg β-carotene, 15 mg lycopene and 9 mg lutein) had a shift to T cells expressing a mature phenotype”

What the sources say

• Not checked yetcites [137] Farges, 2012, Immune status is more affected by age than by carotenoid depletion-repletion in healthy human subjects, Br J Nutr source

In the paper

“Zinc deficiency can cause decreased levels of serum thymulin, a zinc dependent peptide hormone produced by thymic epithelial cells, with an activity that is progressively reduced with age, with a peak in pre-adolescence (78, 104, 108).”

What the sources say

• Not checked yetcites [78] Maggini, 2018, Immune function and micronutrient requirements change over the life course, Nutrients source
• Not checked yetcites [104] Haase, 2009, The immune system and the impact of zinc during aging, Immun Ageing source
• Not checked yetcites [108] Fraker, 2004, Reprogramming of the immune system during zinc deficiency, Annu Rev Nutr source

In the paper

“increase activity of peripheral blood NK cells”

What the sources say

• Not checked yetcites [123] Landete, 2017, Probiotic bacteria for healthier aging: immunomodulation and metabolism of phytoestrogens, Biomed Res Int source

In the paper

“Mutations in the IL-7Rα or γc in humans lead to severe combined immunodeficiency, confirming the importance of the IL-7 signaling pathway in the development of T cells (158, 159).”

What the sources say

• Not checked yetcites [158] Puel, 1998, Defective IL7R expression in T(-)B(+)NK(+) severe combined immunodeficiency, Nat Genet source
• Not checked yetcites [159] Roifman, 2000, A partial deficiency of interleukin-7R alpha is sufficient to abrogate T-cell development and cause severe combined immunodeficiency, Blood source

In the paper

“However, the major effects of polyphenols are associated with increased release of IL-2 and IFN-γ, hence enhancing immune response (146).”

What the sources say

• Not checked yetcites [146] Magrone, 2015, Nutraceuticals in immunosenescence source

In the paper

“These have anti-inflammatory properties inhibiting the formation of eicosanoids and synthesis of pro-inflammatory cytokines (IL-1β, TNF-α, IL-6), chemokines (IL-8, monocyte chemoattractant protein 1), and adhesion molecules (ICAM-1, VCAM-1, selectins) (148).”

What the sources say

• Not checked yetcites [148] Calder, 2010, The 2008 ESPEN Sir David Cuthbertson Lecture: fatty acids and inflammation–from the membrane to the nucleus and from the laboratory bench to the clinic, Clin Nutr source

In the paper

“A small scale (n = 23) pilot study has shown that daily consumption of 12 green olives, containing oleuropein and hydroxytyrosol, significantly reduced serum IL-6 and malondialdehyde (a lipid peroxidation marker) levels after 30 days of consumption by healthy adults (90).”

What the sources say

• Not checked yetcites [90] Casas, 2016, Long-term immunomodulatory effects of a mediterranean diet in adults at high risk of cardiovascular disease in the PREvención con DIeta MEDiterránea (PREDIMED) randomized controlled trial, J Nutr source

In the paper

“Therefore, IL-7 effect on T cell development probably should require the preceding restoration of the thymic architecture.”

In the paper

“an increase in NK cells (137)”

What the sources say

• Not checked yetcites [137] Farges, 2012, Immune status is more affected by age than by carotenoid depletion-repletion in healthy human subjects, Br J Nutr source

In the paper

“In fact, immunosenescence influences the efficacy of the immune checkpoint inhibitors in older people (169);”

What the sources say

• Not checked yetcites [169] Elias, 2016, Immune checkpoint inhibitors in older adults, Curr Oncol Rep source

In the paper

“Interestingly, responses were inversely correlated to the dose (144).”

What the sources say

• Not checked yetcites [144] Miles, 2005, Differential anti-inflammatory effects of phenolic compounds from extra virgin olive oil identified in human whole blood cultures, Nutrition source

In the paper

“Although higher doses of carotenoids are not easily achievable in the diet of population, these findings suggest that low doses are insufficient to affect immune responses.”

In the paper

“In another study, the administration of PD-L1 antibody Atezolizumab also shows positive results for all participants enrolled (172).”

What the sources say

• Not checked yetcites [172] Ghanizada, 2019, The effects of checkpoint inhibition on head and neck squamous cell carcinoma: a systematic review, Oral Oncol source

In the paper

“IL-7R down-regulation guarantees an efficient use of the limited amount of IL-7 to naïve T cells that need it, driving their proliferation and preserving their phenotype (160).”

What the sources say

• Not checked yetcites [160] Gao, 2015, Mechanism of action of IL-7 and its potential applications and limitations in cancer immunotherapy, Int J Mol Sci source

In the paper

“long-term β-carotene supplementation increased NK cell activity in older adults (139, 140).”

What the sources say

• Not checked yetcites [139] Prabhala, 1991, The effects of 13-cis-retinoic acid and beta-carotene on cellular immunity in humans, Cancer source
• Not checked yetcites [140] Santos, 1996, Natural killer cell activity in elderly men is enhanced by beta-carotene supplementation, Am J Clin Nutr source

In the paper

“The integrity of cortical and medullary thymic architecture and the presence of functional thymic epithelial cells are required to support and maintain thymopoiesis (164).”

What the sources say

• Not checked yetcites [164] Gui, 2007, The aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells, Int Immunol source

In the paper

“Enhanced NK cell cytotoxicity was observed in participants treated with oral β-carotene”

What the sources say

• Not checked yetcites [139] Prabhala, 1991, The effects of 13-cis-retinoic acid and beta-carotene on cellular immunity in humans, Cancer source
• Not checked yetcites [140] Santos, 1996, Natural killer cell activity in elderly men is enhanced by beta-carotene supplementation, Am J Clin Nutr source

In the paper

“In the metastatic melanoma, for example, the use of the MoAb Nivolumab, a PD-1 inhibitor, alone or in combination with other antagonists, has survival benefits independently on age (170, 171).”

What the sources say

• Not checked yetcites [170] Elias, 2017, Immunotherapy comes of age: immune aging & checkpoint inhibitors, J Geriatr Oncol. source
• Not checked yetcites [171] Hurez, 2017, Considerations for successful cancer immunotherapy in aged hosts, Clin Exp Immunol source

In the paper

“In fact, immune checkpoint inhibitors promote the immunological control of cancer cells by blocking the immune inhibitory responses that are evolutionary designed to prevent continuing immunological responses once an antigenic stimulus has been eradicated (165).”

What the sources say

• Not checked yetcites [165] Elias, 2018, Aging, immune senescence, and immunotherapy: a comprehensive review, Semin Oncol source

In the paper

“IL-7Rα is re-expressed at the memory stage, ensuring cell survival and proliferation in memory T cell pool too (156).”

What the sources say

• Not checked yetcites [156] Fry, 2005, The many faces of IL-7: from lymphopoiesis to peripheral T cell maintenance, J Immunol source

In the paper

“Moreover, there is evidence about the efficacy of anti PD-1/PD-L1 MoAbs in older patients with non-small cell lung cancer (NSCLC) compared with chemotherapy.”

What the sources say

• Not checked yetcites [173] Grossi, 2018, Use of nivolumab in elderly patients with advanced squamous non-small-cell lung cancer: results from the Italian cohort of an expanded access programme, Eur J Cancer source

In the paper

“In the first clinical trial in humans, patients with metastatic cancer (age range 20–59 years) treated with different doses of IL-7 showed a dose-dependent increase in circulating CD4+ and CD8+ lymphocytes along with a decrease in Tregs (162).”

What the sources say

• Not checked yetcites [162] Rosenberg, 2006, IL-7 administration to humans leads to expansion of CD8+ and CD4+ cells but a relative decrease of CD4+ T-regulatory cells, J Immunother source

In the paper

“Watson et al. report that higher doses of β-carotene (30 and 60 mg/day; instead of 15, 30, and 45) increase T helper cells and NK cells number (138).”

What the sources say

• Not checked yetcites [138] Watson, 1991, Effect of beta-carotene on lymphocyte subpopulations in elderly humans: evidence for a dose-response relationship, Am J Clin Nutr source

In the paper

“In HIV-infected patients, with persistently low CD4+ T-cell counts despite viral suppression, repeated cycles of recombinant human IL-7 induced a dose-dependent increase in circulating levels of both naïve and memory CD4+ and mostly naïve CD8+ T cells (163).”

What the sources say

• Not checked yetcites [163] Lévy, 2012, Effects of recombinant human interleukin 7 on T-cell recovery and thymic output in HIV-infected patients receiving antiretroviral therapy: results of a phase I/IIa randomized, placebo-controlled, multicenter study, Clin Infect Dis source

In the paper

“However, in the complex scenario of aging, the immunorestorative properties of IL-7 may not be as great as initially hoped, most probably due to the deterioration of the thymus structure.”

In the paper

“In these studies, T cells of older adults were still able to respond to the blockade of their inhibitory receptors with a recovery of cytotoxic activity.”

In the paper

“Consumption of cocoa polyphenols rich in flavonoids (40 g/day) with 500 ml of skimmed milk, by participants at high cardiovascular disease risk (≥55 years), significantly reduced the expression of cell adhesion molecule very late antigen-4, CD40, and CD36 on monocytes.”

What the sources say

• Not checked yetcites [143] Monagas, 2009, Effect of cocoa powder on the modulation of inflammatory biomarkers in patients at high risk of cardiovascular disease, Am J Clin Nutr source

In the paper

“Therefore, some data suggest that IL-7 could have a therapeutic potential in improving the clinical outcome in settings that require enhanced immunological responses.”

In the paper

“This treatment also lowered circulating levels of the inflammatory markers P-selectin and ICAM-1, compared with monocytes from the control group (only skimmed milk) (143).”

What the sources say

• Not checked yetcites [143] Monagas, 2009, Effect of cocoa powder on the modulation of inflammatory biomarkers in patients at high risk of cardiovascular disease, Am J Clin Nutr source

In the paper

“higher IgA serum levels”

What the sources say

• Not checked yetcites [137] Farges, 2012, Immune status is more affected by age than by carotenoid depletion-repletion in healthy human subjects, Br J Nutr source

In the paper

“In vitro studies have shown that administration of olive oil polyphenols (caffeic acid and oleuropein glycoside) to human whole blood cultures stimulated with lipopolysaccharides significantly reduced IL-1β levels compared with stimulated control cultures that were not incubated with olive oil polyphenols.”

What the sources say

• Not checked yetcites [144] Miles, 2005, Differential anti-inflammatory effects of phenolic compounds from extra virgin olive oil identified in human whole blood cultures, Nutrition source

In the paper

“In fact, the interaction between specific microorganisms molecular pathways and immune cells can regulate local or systemic inflammation, hence influencing immune response (177).”

What the sources say

• Not checked yetcites [177] Cani, 2018, Gut microbiota-mediated inflammation in obesity: a link with gastrointestinal cancer, Nat Rev Gastroenterol Hepatol source

In the paper

“In 2009, Eisenberg et al. identified the use of spermidine, a polyamine compound, to promote longevity, via autophagy, using PBMCs as model.”

What the sources say

• Not checked yetcites [190] Eisenberg, 2009, Induction of autophagy by spermidine promotes longevity, Nat Cell Biol source

In the paper

“These data demonstrated that, in responding patients, there was a relative abundance of bacteria of the Ruminococcaceae family.”

What the sources say

• Not checked yetcites [179] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science source

In the paper

“This pathway is not active in Th2 cells (186).”

What the sources say

• Not checked yetcites [186] Jackson, 2010, Role of mitogen-activated protein kinase and PI3K pathways in the regulation of IL-12-family cytokines in dendritic cells and the generation of T H-responses, Eur Cytokine Netw source

In the paper

“On the contrary, tumors in antibiotic-treated or germ-free mice did not respond to CTLA blockade (180).”

What the sources say

• Not checked yetcites [180] Vétizou, 2015, Anticancer immunotherapy by CTLA-4 blockade relies on the gut microbiota, Science source

In the paper

“Each one is separately regulated within individual cells (184)”

What the sources say

• Not checked yetcites [184] Johnson, 2002, Mitogen-activated protein kinase pathways mediated by ERK, JNK, and p38 protein kinases, Science source

In the paper

“Recently, the role of MAPKs pathways in the functional competence of the immune system has been demonstrated (183).”

What the sources say

• Not checked yetcites [183] Patterson, 2014, Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases, Clin Exp Immunol source

In the paper

“However, these complex systems also regulate several functions of the innate and acquired immunity.”

What the sources say

• Not checked yetcites [183] Patterson, 2014, Protein kinase inhibitors in the treatment of inflammatory and autoimmune diseases, Clin Exp Immunol source

In the paper

“The authors demonstrated a 37% reduction of the risk of death in favor of immune checkpoint inhibitors compared with control arm (175).”

What the sources say

• Not checked yetcites [175] Nishijima, 2016, Comparison of efficacy of immune checkpoint inhibitors (ICIs) between younger and older patients: a systematic review and meta-analysis, Cancer Treat Rev source

In the paper

“The p38-MAPK pathway plays a pleiotropic role in cell survival, both sustaining proliferation, and inducing apoptosis in a cell type-specific manner, depending on the type of stimulus (185).”

What the sources say

• Not checked yetcites [185] Henson, 2014, p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells, J Clin Invest. source

In the paper

“In fact, studies carried out on HIV, hepatitis B and hepatitis C infections have shown that blocking the interaction PD-1/PD-L1 has a positive effect on the effector functions of T cells.”

What the sources say

• Not checked yetcites [182] Kulpa, 2013, PD-1 coinhibitory signals: the link between pathogenesis and protection, Semin Immunol source

In the paper

“The analysis of 112 buccal and fecal samples from patients with metastatic melanoma also showed that the response to anti-PD-1 therapy depends on differences in the diversity and composition of the patient gut microbiota of responders vs. non-responders (179).”

What the sources say

• Not checked yetcites [179] Gopalakrishnan, 2018, Gut microbiome modulates response to anti-PD-1 immunotherapy in melanoma patients, Science source

In the paper

“The benefit of immunotherapy in terms of response is stackable between younger and older patients (173).”

What the sources say

• Not checked yetcites [173] Grossi, 2018, Use of nivolumab in elderly patients with advanced squamous non-small-cell lung cancer: results from the Italian cohort of an expanded access programme, Eur J Cancer source

In the paper

“Baseline gut microbiota enriched with Faecalibacterium and other Firmicutes was associated with beneficial clinical response to Ipilimumab (181).”

What the sources say

• Not checked yetcites [181] Chaput, 2017, Baseline gut microbiota predicts clinical response and colitis in metastatic melanoma patients treated with ipilimumab, Ann Oncol source