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

In the paper

“although some data show that immunosenescence develops earlier in men than in women.”

What the sources say

• 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 [13] Hirokawa, 2013, Slower immune system aging in women versus men in the Japanese population, Immun Ageing source
• Not checked yetcites [14] Dudkowska, 2017, The role of gender and labour status in immunosenescence of 65+ Polish population, Biogerontology. source

In the paper

“This phenomenon, called immunosenescence, a term coined by Roy Walford, is multifactorial, and affects both natural and acquired immunity, although T lymphocytes are dramatically affected (4).”

What the sources say

• Not checked yetcites [4] Walford, 1969 source

In the paper

“In general, while estrogens increase the immune response, progesterone and androgens have immune suppressive actions.”

What the sources say

• Not checked yetcites [12] Ostan, 2016, Gender, aging and longevity in humans: an update of an intriguing/neglected scenario paving the way to a gender-specific medicine, Clin Sci source

In the paper

“The apparently inevitable consequence of this complex scenario is the reduced ability of older individuals to respond to novel antigens and to vaccines, resulting in an increased susceptibility to infection and in the development of age-related diseases, including cancer (3).”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source

In the paper

“Briefly, natural killer (NK) cell cytotoxicity is well-preserved in centenarians, and an increase in the actual number of NK cells is observed in healthy aging.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• 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 [26] Müller, 2013, Immunosenescence in vertebrates and invertebrates, Immun Ageing. source

In the paper

“Neutrophils show reduced function in bacteria phagocytosis and in the oxidative burst while macrophages show reduced chemotaxis and phagocytosis, and decreased cytokine production.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• 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 [26] Müller, 2013, Immunosenescence in vertebrates and invertebrates, Immun Ageing. source

In the paper

“The hallmarks of immunosenescence include: (i) a reduced ability to respond to new antigens; (ii) the accumulation of memory T cells; (iii) a lingering level of low-grade inflammation termed “inflamm-aging.””

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

“Neutrophils show reduced function in bacteria phagocytosis and in the oxidative burst while macrophages show reduced chemotaxis and phagocytosis, and decreased cytokine production.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• 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 [26] Müller, 2013, Immunosenescence in vertebrates and invertebrates, Immun Ageing. source

In the paper

“The quality and quantity of the T and B cell responses change with increasing age, with consequent changes on the effectiveness of the immune response.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source

In the paper

“The general picture of innate immunity in older people, which emerges from several studies, is that of the down-regulation of some functions and the up-regulation of others.”

What the sources say

• Not checked yetcites [3] Caruso, 2016, Immunity and aging source
• 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 [26] Müller, 2013, Immunosenescence in vertebrates and invertebrates, Immun Ageing. source

In the paper

“Aging is a malleable process, affected by both nutritional and pharmacological interventions (19, 20).”

What the sources say

• Not checked yetcites [19] Longo, 2015, Interventions to Slow aging in humans: are we ready?, Aging Cell. source
• Not checked yetcites [20] Aiello, 2019, Slow-aging diets source

In the paper

“The life-long chronic antigen load causes the filling of the immunological space by a population of T lymphocytes with a late-differentiated phenotype and the shrinkage of the T cell repertoire.”

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

“Naïve T cells are abundant in youth but may become “used up” by exposures to microorganisms over the course of life, hence differentiating into memory lymphocyte subsets.”

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

“This process seems related to the increase of sex hormones and to the decrease of IL-7, a hematopoietic growth factor secreted by stromal cells in the bone marrow and thymus.”

What the sources say

• Not checked yetcites [34] Jiang, 2005, Cell biology of IL-7, a key lymphotrophin, Cytokine Growth Factor Rev source
• Not checked yetcites [35] Noguchi, 1993, Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor, Science. source

In the paper

“Irrespective of thymic activity, the naïve compartment only moderately decreases in size during the following life decades, while mostly maintaining overall diversity and distribution of clonal sizes.”

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

“Thymus involution occurs at the time of puberty, and is characterized by atrophy and replacement by adipose tissue.”

What the sources say

• Not checked yetcites [34] Jiang, 2005, Cell biology of IL-7, a key lymphotrophin, Cytokine Growth Factor Rev source
• Not checked yetcites [35] Noguchi, 1993, Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor, Science. source

In the paper

“CD127 is expressed on lymphoid lineage cells at different stages of development, whereas CD132 is shared with other cytokine receptors and expressed on most hematopoietic cells (34, 35).”

What the sources say

• Not checked yetcites [34] Jiang, 2005, Cell biology of IL-7, a key lymphotrophin, Cytokine Growth Factor Rev source
• Not checked yetcites [35] Noguchi, 1993, Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor, Science. source

In the paper

“IL-7 exerts its action through the binding to a heterodimeric receptor composed of an α chain (IL-7Rα or CD127) and the common cytokine receptor γ chain (γc or CD132).”

What the sources say

• Not checked yetcites [34] Jiang, 2005, Cell biology of IL-7, a key lymphotrophin, Cytokine Growth Factor Rev source
• Not checked yetcites [35] Noguchi, 1993, Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor, Science. source

In the paper

“This process seems related to the increase of sex hormones and to the decrease of IL-7, a hematopoietic growth factor secreted by stromal cells in the bone marrow and thymus.”

What the sources say

• Not checked yetcites [34] Jiang, 2005, Cell biology of IL-7, a key lymphotrophin, Cytokine Growth Factor Rev source
• Not checked yetcites [35] Noguchi, 1993, Interleukin-2 receptor gamma chain: a functional component of the interleukin-7 receptor, Science. source

In the paper

“Senescent T cells also express CD57 displaying a high cytotoxic potential, and killer cell lectin-like receptor subfamily G member 1.”

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

“These CD28− cells express high levels of the adhesion molecule integrin CD11a/CD18 and have high levels of perforin and granzyme, responsible for the killing of the target 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

“These cells display a highly differentiated phenotype, expressing CD27, another co-stimulatory molecule, but not CD28 (however, in CD28+ subset, CD28−CD27− seem to be more frequent).”

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

“They also carry short telomeres, lack telomerase and express negative signaling receptors, such as programmed cell death protein (PD)-1, which is involved in the down-regulation of the immune system (see paragraph on checkpoints inhibitors; the example of PD-1 and CTLA-4).”

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

“Age-related B cell changes are similar to those observed in T cell compartment and the effects on humoral immune response are detrimental as well.”

What the sources say

• Not checked yetcites [71] Bulati, 2011, B cells and immunosenescence: a focus on IgG+IgD−CD27− (DN) B cells in aged humans, Ageing Res Rev source

In the paper

“This term defines the systemic state of chronic low-grade inflammation considered a central biological pillar of the aging process and a common pathogenetic mechanism of age-related diseases, as well as a worse prognostic factor for all causes of death (9, 57–59).”

What the sources say

• 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
• Not checked yetcites [58] Leonardi, 2018, Ageing: from inflammation to cancer, Immun Ageing. source
• Not checked yetcites [59] Puzianowska-Kuznicka, 2016, Interleukin-6 and C-reactive protein, successful aging, and mortality: the PolSenior study, Immun Ageing source

In the paper

“T cell clones specific for HCMV dominate the repertoire in the older people and contribute to the contraction in diversity in the memory compartment (23).”

What the sources say

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

In the paper

“Therefore, the virus is responsible for the generation of a large population of HCMV-specific CD8+ T cells, with a significant increase in highly differentiated CD8+ effector memory T cells, which expand clonally showing an effector memory phenotype characterized by low CD28 expression.”

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

“Our immune system is quite efficient in fighting acute infections in young people, but not particularly efficient in responding to chronic stimuli, especially when they occur late in life.”

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

“In fact, inflamm-aging is responsible for a high expression of micro (mi)-RNAs that interfere with B cell activation, driving tumor necrosis factor (TNF)-α production and inhibiting B cell activation as measured in vitro (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

“Oxidative stress also plays an important role in determining and maintaining this low-grade inflammation, which, in turn contributes to oxidative stress (61, 62).”

What the sources say

• Not checked yetcites [61] De la Fuente, 2009, An update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging, Curr Pharm Des. source
• Not checked yetcites [62] Biswas, 2016, Does the Interdependence between oxidative stress and inflammation explain the antioxidant paradox?, Oxid Med Cell Longev. source

In the paper

“Persistent antigenic challenges lead to a poor response to newly encountered microbial antigens, as well as to a shift in the immune system toward an inflammatory, autoimmune, T helper (Th) 2 profile.”

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

“However, as previously stated, immunosenescence represents the most important contributor to inflamm-aging, in turn, contributing to impaired immune responses.”

In the paper

“This is accompanied by an impaired ability to produce high affinity protective antibodies against infectious agents and the shrinkage of the repertoire diversity.”

What the sources say

• Not checked yetcites [71] Bulati, 2011, B cells and immunosenescence: a focus on IgG+IgD−CD27− (DN) B cells in aged humans, Ageing Res Rev source
• Not checked yetcites [75] Bulati, 2017, From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by “inflamm-ageing”, Ageing Res Rev source
• Not checked yetcites [76] Listì, 2006, A study of serum immunoglobulin levels in elderly persons that provides new insights into B cell immunosenescence, Ann N Y Acad Sci. source
• Not checked yetcites [77] Colonna-Romano, 2009, A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people, Mech Ageing Dev source

In the paper

“They showed an increase in suppressor cell numbers but no change in the number of peripheral blood leucocytes or in the differential counts (93).”

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

“The reduced serum levels of IgM and IgD suggest a shift in the balance from the naïve (CD27) toward the memory compartment (CD27+), although this is not observed in all studies (71, 75–77).”

What the sources say

• Not checked yetcites [71] Bulati, 2011, B cells and immunosenescence: a focus on IgG+IgD−CD27− (DN) B cells in aged humans, Ageing Res Rev source
• Not checked yetcites [75] Bulati, 2017, From lymphopoiesis to plasma cells differentiation, the age-related modifications of B cell compartment are influenced by “inflamm-ageing”, Ageing Res Rev source
• Not checked yetcites [76] Listì, 2006, A study of serum immunoglobulin levels in elderly persons that provides new insights into B cell immunosenescence, Ann N Y Acad Sci. source
• Not checked yetcites [77] Colonna-Romano, 2009, A double-negative (IgD-CD27-) B cell population is increased in the peripheral blood of elderly people, Mech Ageing Dev source

In the paper

“Age also affects B cell numbers and B cell repertoire diversity, as well as immunoglobulin isotypes and receptor repertoire with a decrease in specific humoral immune responses against new extracellular pathogens (71).”

What the sources say

• Not checked yetcites [71] Bulati, 2011, B cells and immunosenescence: a focus on IgG+IgD−CD27− (DN) B cells in aged humans, Ageing Res Rev source

In the paper

“Data discussed below show that the main target of dietary strategies is inflamm-aging, because diet, biotics, and nutraceuticals can show anti-inflammatory and anti-oxidant properties.”

In the paper

“These dietary patterns explicate their activity, particularly, during the refeeding period, reducing the rate of aging because of their antioxidant and anti-inflammatory effects, and possibly counteracting some other aspects of immunosenescence.”

What the sources say

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

In the paper

“The efficacy of this diet results as an attenuation of inflammation and oxidative stress, and from the maintenance of a condition of eubiosis of the microbiota, involved in the general improvement of immune response in these populations (68, 83–86).”

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

“Changes in phenotypic features, mainly loss of teeth and alterations in taste receptors, and gut disorders as well, determine a variation in both quality and quantity of food intake, contributing to general alterations in metabolism (100).”

What the sources say

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

In the paper

“Because vitamin C is water-soluble and humans have low storage capacity, its regular intake is up to 100-fold higher than that for many other vitamins (116, 117).”

What the sources say

• Not checked yetcites [116] Huijskens, 2015, Ascorbic acid promotes proliferation of natural killer cell populations in culture systems applicable for natural killer cell therapy, Cytotherapy. source
• Not checked yetcites [117] 2000

In the paper

“However, the complexity of randomized controlled trials and lack of specific biomarkers in humans make difficult the reproducibility of the data (124).”

What the sources say

• Not checked yetcites [124] Suez, 2019, The pros, cons, and many unknowns of probiotics, Nat Med source

In the paper

“Contrarily to caloric restriction, undernutrition, which is common in older people, is associated with an immunocompromised state, linked to altered T cell numbers, a reduced response to antigens, impaired release ofmediators, such as cytokines, and decreased phagocytosis and NK cell activity.”

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

“The active form of thymulin induces the expression of markers of T lymphocyte activation, promoting T-mediated functions, acting both on the early and on the late phases of lymphocyte differentiation (109, 110).”

What the sources say

• Not checked yetcites [109] Consolini, 2000, Distribution of age-related thymulin titres in normal subjects through the course of life, Clin Exp Immunol source
• Not checked yetcites [110] Savino, 2000, Neuroendocrine control of thymus physiology, Endocr Rev source

In the paper

“They are needed in trace quantities, because the homeodynamic range is small, but the maintenance of a correct amount and balance is very rare in older people (often even in adults and young), both for scarcity and for excess due to unnecessary supplementation (78, 103).”

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

“They provide evidence that increasing intake of some of them above the habitual and recommended dose levels can enhance some aspects of immune function, and reduce the level of inflammatory status, increasing cellular resistance to aging (131–133).”

What the sources say

• Not checked yetcites [131] López-Varela, 2002, Functional foods and the immune system: a review, Eur J Clin Nutr source
• Not checked yetcites [132] Molfino, 2014, The role for dietary omega-3 fatty acids supplementation in older adults, Nutrients source
• Not checked yetcites [133] Pae, 2017, Nutritional modulation of age-related changes in the immune system and risk of infection, Nutr Res source

In the paper

“They primarily exert antioxidant, hence anti-inflammatory, effects, but individual carotenoids may also act through other mechanisms, including immune-enhancing activities (134, 135).”

What the sources say

• Not checked yetcites [134] Davinelli, 2018, Astaxanthin in skin health, repair, and disease: a comprehensive review, Nutrients source
• Not checked yetcites [135] Wood, 2000, Beta-carotene and selenium supplementation enhances immune response in aged humans, Integr Med. source

In the paper

“Metformin can trigger AMPK, a pathway activated by energy depletion, i.e., by low levels of intracellular adenosine triphosphate (ATP), leading to the extension of healthy lifespan in model organisms (95).”

What the sources say

• Not checked yetcites [95] Martin-Montalvo, 2013, Metformin improves healthspan and lifespan in mice, Nat Commun source

In the paper

“In fact, the profound structural remodeling that characterizes the thymic involution also affects thymic epithelial cells with a consequent reduction in the intrathymic production of IL-7 (155, 156).”

What the sources say

• Not checked yetcites [155] Masters, 2017, Immune senescence: significance of the stromal microenvironment, Clin Exp Immunol source
• 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

“accordingly, the therapy is less efficient in patients ≥75 years (see below), probably due to a greater degree of immunosenescence.”

In the paper

“They are in fruits, vegetables, grains, and other plant foods, the consumption of which has been linked to reduction in risk of major age-related diseases (141, 142).”

What the sources say

• Not checked yetcites [141] Tsao, 2010, Chemistry and biochemistry of dietary polyphenols, Nutrients source
• Not checked yetcites [142] Davinelli, 2016, Polyphenols: a promising nutritional approach to prevent or reduce the progression of prehypertension, High Blood Press Cardiovasc Prev source

In the paper

“IL-7 produced by thymic epithelial cells provides survival and proliferative signals to immature double negative CD4−CD8− thymocytes and promotes V(D)J recombination of the T cell receptor (TCR) γ-c locus (157).”

What the sources say

• Not checked yetcites [157] Peschon, 1994, Early lymphocyte expansion is severely impaired in interleukin 7 receptor-deficient mice, J Exp Med source

In the paper

“Interestingly, the expression of PD-1 increases on T cells of older adults and its blockade partially restores T cells to functional competence (166–168).”

What the sources say

• Not checked yetcites [166] McDermott, 2013, PD-1 as a potential target in cancer therapy, Cancer Med. source
• Not checked yetcites [167] Chen, 2013, Molecular mechanisms of T cell co-stimulation and co-inhibition, Nat Rev Immunol source
• Not checked yetcites [168] Viganò, 2012, Positive and negative regulation of cellular immune responses in physiologic conditions and diseases, Clin Dev Immunol source

In the paper

“TSLP provides normally a co-mitogenic activity that is less potent than that of IL-7 (161).”

What the sources say

• Not checked yetcites [161] Sims, 2000, Molecular cloning and biological characterization of a novel murine lymphoid growth factor, J Exp Med source

In the paper

“However, because dose, timing of administration, and participant age are important modulating factors of the effect of these molecules, contrasting results exist and only few studies focus on their use in older adults (149–154).”

What the sources say

• Not checked yetcites [149] Thies, 2001, Influence of dietary supplementation with long-chain n-3 or n-6 polyunsaturated fatty acids on blood inflammatory cell populations and functions and on plasma soluble adhesion molecules in healthy adults, Lipids source
• Not checked yetcites [150] Thies, 2001, Dietary supplementation with eicosapentaenoic acid, but not with other long-chain n-3 or n-6 polyunsaturated fatty acids, decreases natural killer cell activity in healthy subjects aged >55 y, Am J Clin Nutr source
• Not checked yetcites [151] Thies, 2001, Dietary supplementation with gamma-linolenic acid or fish oil decreases T lymphocyte proliferation in healthy older humans, J Nutr source
• Not checked yetcites [152] Rees, 2006, Dose-related effects of eicosapentaenoic acid oninnate immune function in healthy humans: a comparison ofyoung and older men, Am J Clin Nutr source
• Not checked yetcites [153] Bechoua, 2003, Influence of very low dietary intake of marine oil on some functional aspects of immune cells in healthy elderly people, Br J Nutr source
• Not checked yetcites [154] Meydani, 1991, Oral (n-3) fatty acid supplementation suppresses cytokine production and lymphocyte proliferation: comparison between young and older women, J Nutr source

In the paper

“For example, resveratrol, a polyphenol typically found in red wine, grape skins, and berries, induces a significant increase in T helper cells and in the delayed-type hypersensitivity response of aged rats (147).”

What the sources say

• Not checked yetcites [147] Yuan, 2012, Dietary intake of resveratrol enhances the adaptive immunity of aged rats, Rejuv Res source

In the paper

“The rescuing effect did not involve inhibition of apoptosis, as the percentage of apoptotic cells was not influenced by spermidine.”

What the sources say

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

In the paper

“Therefore, these data, which imply selective proliferation of CD28+ cells by PD-1 therapy, highlight one mechanistic explanation why cancer patients older than 75 years may not respond as well to immunotherapy as younger patients.”

In the paper

“The p38-MAPK pathway is critical for the production of inflammatory cytokines, positively regulating the production of IFN-γ in CD4 and CD8 cells (187, 188).”

What the sources say

• Not checked yetcites [187] Merritt, 2000, Activation of p38 mitogen-activated protein kinase in vivo selectively induces apoptosis of CD8+ but not CD4+ T cells, Mol Cel Biol source
• Not checked yetcites [188] Zhang, 2000, The p38 mitogen-activated protein kinase is required for IL-12-induced IFN-gamma expression, J Immunol source

In the paper

“However, IFN-α signal can activate p38, triggering cellular senescence, and leading to inhibition of proliferation and telomerase activity in non-senescent T cells (189).”

What the sources say

• Not checked yetcites [189] Lanna, 2013, IFN-α inhibits telomerase in human CD8+ T cells by both hTERT downregulation and induction of p38 MAPK signaling, J Immunol source

In the paper

“In spite of several controversial points, some clinical trials suggest a significant benefit of immunotherapy in older patients, with the exception of patients ≥75 years that obtain less benefit from these treatments.”

In the paper

“Moreover, the use of spermidine dramatically improved the CD8+ T cell response to vaccination and infection in aged mice in an autophagy-dependent manner, contributing to the increased numbers of antigen-specific CD8+ T cells (191).”

What the sources say

• Not checked yetcites [191] Puleston, 2014, Autophagy is a critical regulator of memory CD8(+) T cell formation, Elife source

In the paper

“Moreover, fecal microbiota composition of 26 patients with metastatic melanoma, using 16S rRNA, at time 0 and before each Ipilimumab treatment, was clustered on microbiota patterns.”

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

In the paper

“However, the telomerase activity in CD8+/CD45RA+ T cells is improved by blocking only the p38 pathway but not the PD-1 signaling, indicating that non-overlapping signaling pathways are involved (193, 194).”

What the sources say

• Not checked yetcites [193] Henson, 2012, Reversal of functional defects in highly differentiated young and old CD8 T cells by PDL blockade, Immunology source
• Not checked yetcites [194] Wherry, 2007, Molecular signature of CD8+ T cell exhaustion during chronic viral infection, Immunity source

In the paper

“Autophagy, by inhibiting cell senescence, is a critical regulator of memory CD8+ formation, and age-related autophagy defect is one of the explanations why CD8+ T memory formation becomes defective in old age (38, 185).”

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
• 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 particular, the blockade with Ipilimumab can establish an anti-leukemic effect after allogeneic hematopoietic stem cell transplantation and can restore anti-tumor reactivity for patients with relapse (174).”

What the sources say

• Not checked yetcites [174] Knaus, 2017, Immunomodulatory drugs: immune checkpoint agents in acute leukemia, Curr Drug Targets source

In the paper

“They are also involved in the production of pro-inflammatory cytokines, as well as in the intracellular signaling cascades initiated when a cytokine binds to its corresponding receptor (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

“These findings conflict with earlier studies showing the central importance of mTOR in innate immunity, specifically in the production of anti-inflammatory IL-10 and the suppression of pro-inflammatory cytokines IL-21 and IL-1β (209).”

What the sources say

• Not checked yetcites [209] Weichhart, 2009, The multiple facets of mTOR in immunity, Trends Immunol source

In the paper

“Moreover, in senescent CD8+ T cells, p38-MAPK induces an increase in autophagy through interactions between a p38 interacting protein and autophagy protein 9, in a mTOR-independent manner, suggesting that p38-MAPK blockade reverses senescence via mTOR-independent pathway (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

“The knockout of sMAC restored T cell activity (antigen-specific proliferation and cytokine production) from older humans, and enhanced responsiveness to influenza vaccination in the aged mice (196).”

What the sources say

• Not checked yetcites [196] Lanna, 2017, A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging, Nat Immunol source

In the paper

“In particular, sestrins stimulate the activation of AMPK (by an unknown mechanism), inhibiting mTORC1 signaling.”

What the sources say

• Not checked yetcites [200] Wang, 2017, Recent insights into the biological functions of sestrins in health and disease, Cell Physiol Biochem source

In the paper

“The two low-dose everolimus regimens improved immune function without causing serious side effects.”

What the sources say

• Not checked yetcites [206] Mannick, 2018, TORC1 inhibition enhances immune function and reduces infections in the elderly, Sci Transl Med source

In the paper

“Sestrins, the mammalian products of the Sesn1, Sesn2, and Sesn3 genes, are a family of stress sensing proteins (196).”

What the sources say

• Not checked yetcites [196] Lanna, 2017, A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging, Nat Immunol source

In the paper

“This pathway can inhibit telomerase activity, T cell proliferation, and expression of key components of the TCR signalosome.”

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

“These findings highlight the efficient effect of adjuvants in the stimulation of cytokine production and point toward the potential use of appropriately selected combination of TLR agonists in future vaccination approaches for older adults to overcome the CD4 inability to respond.”

In the paper

“In fact, immunization with two or more TLR agonists, an activator anti-CD40 antibody, IFN-γ, and surfactants were sufficient to drive unprecedented levels of CD8 responses to peptides or protein antigens and highly polarized Th1 CD4 responses.”

What the sources say

• Not checked yetcites [213] Wells, 2008, Combined triggering of dendritic cell receptors results in synergistic activation and potent cytotoxic immunity, J Immunol source