Causes, consequences, and reversal of immune system aging

In the paper

“Despite the increase in their number, myeloid-biased stem cells are not as robust as their young counterparts (24)”

What the sources say

• Not checked yetcites [24] source

In the paper

“This is illustrated by increased vulnerability of individuals 70 years of age and older to influenza (1)”

What the sources say

• Not checked yetcites [1] source

In the paper

“As a result, elderly individuals do not respond to immune challenge as robustly as the young.”

• Also stated in: § Introduction · hedged

  “While elderly individuals are by no means immunodeficient, they often do not respond efficiently to novel or previously encountered antigens.”

• Also stated in: § Introduction · plain

  “This is illustrated by increased vulnerability of individuals 70 years of age and older to influenza (1), a situation that is exacerbated by their poor response to vaccination (2)(3)(4).”

What the sources say

• Not checked yetcites [1] source
• Not checked yetcites (2)(3)(4)

In the paper

“which in turn could underlie the numerous age-related deficiencies observed in mature myeloid cells such as neutrophils and macrophages (25,26).”

What the sources say

• Not checked yetcites [25] source
• Not checked yetcites [26] source

In the paper

“This shift has been correlated with increased expression of myeloid lineage genes and downregulation of those specifying a lymphoid lineage fate (11,17).”

What the sources say

• Not checked yetcites [11] source
• Not checked yetcites [17] source

In the paper

“primary lymphopoiesis in the elderly is significantly diminished, as exemplified by involution of the thymus (8)(9)(10).”

What the sources say

• Not checked yetcites (8)(9)(10)

In the paper

“The causes of this age-related reduction in lymphocyte development are multifactorial and include changes in HSCs and progenitor cells (11,12) as well as the local tissue and systemic environments (13,14).”

What the sources say

• Not checked yetcites [11] source
• Not checked yetcites [12] source
• Not checked yetcites [13] source
• Not checked yetcites [14] source

In the paper

“The age-related increase in expression of myeloid lineage genes in the studies noted above (11,17) likely resulted from the accumulation of myeloid-biased HSCs, as these analyses were performed on unseparated pools of HSCs.”

What the sources say

• Not checked yetcites [11] source
• Not checked yetcites [17] source

In the paper

“a situation that is exacerbated by their poor response to vaccination (2)(3)(4).”

What the sources say

• Not checked yetcites (2)(3)(4)

In the paper

“this has led to the conclusion that age-related changes in the endocrine system contribute to declines in lymphopoiesis.”

What the sources say

• Not checked yetcites [13] source
• Not checked yetcites [42] source
• Not checked yetcites [43] source

In the paper

“The answer is that the composition and quality of the mature lymphocyte pool is profoundly altered by aging.”

In the paper

“Indeed, some functional thymic tissue remains even in elderly humans (44).”

What the sources say

• Not checked yetcites [44] source

In the paper

“In view of the critical role played by CD4 + T cells in orchestrating the immune response, some of the age-related deficiencies observed in B cells (51,53,54), which include a reduction in the number of plasmablasts that develop in response to influenza vaccination (55) and the production of poor-quality antibodies to carbohydrate antigens (56)(57)(58), may occur secondary to T cell deficiencies.”

What the sources say

• Not checked yetcites [51] source
• Not checked yetcites [53] Frasca, 2008, J Immunol. source
• Not checked yetcites [54] source
• Not checked yetcites [55] source
• Not checked yetcites (56)(57)(58)

In the paper

“It was recently reported that marginal zone B cell number is reduced in old mice (60)”

What the sources say

• Not checked yetcites [60] source

In the paper

“In view of this, it is not surprising that the number of B cell (28)(29)(30)(31) and T cell (32,33) progenitors in bone marrow and thymus is markedly reduced with age.”

What the sources say

• Not checked yetcites (28)(29)(30)(31)
• Not checked yetcites [32] Min, 2004, J Immunol. source
• Not checked yetcites [33] Heng, 2005, J Immunol. source

In the paper

“Because the production of these hormones declines with age (43)”

What the sources say

• Not checked yetcites [43] source

In the paper

“A similar fatty deterioration of the bone marrow microenvironment occurs (41)”

What the sources say

• Not checked yetcites [41] source

In the paper

“The immune risk profile also includes B cells with impaired function.”

In the paper

“However, accumulating evidence suggests that declines in lymphopoiesis are influenced by age-related changes in the environment.”

In the paper

“Human and murine B cells also exhibit impaired class switch recombination, which has been attributed to decreased induction of activation-induced cytidine deaminase (AID) enzyme (53).”

• Also stated in: § Intracellular changes in developing and mature lymphocytes · plain

  “class switch recombination is impaired in aging murine and human B cells due to decreased expression of enzymes such as AID (53,84).”

What the sources say

• Not checked yetcites [53] Frasca, 2008, J Immunol. source
• Not checked yetcites [84] Frasca, 2008, J Immunol. source

In the paper

“For example, an increase in the number of memory T cells is now a well-recognized feature of aging.”

In the paper

“In addition, the poor quality of the lymphoid progenitors that are generated in the aged further exacerbates the decline in lymphopoiesis (29,32,34).”

What the sources say

• Not checked yetcites [29] Min, 2006, J Immunol. source
• Not checked yetcites [32] Min, 2004, J Immunol. source
• Not checked yetcites [34] source

In the paper

“Declines in the bone marrow microenvironment, possibly as a result of decreased IL-7 secretion by stromal cells, have been implicated in B cell lineage aging (36,37).”

What the sources say

• Not checked yetcites [36] source
• Not checked yetcites [37] Stephan, 1998, Blood. source

In the paper

“CD8 + T cells that accumulate in aged individuals proliferate poorly (68,69)”

What the sources say

• Not checked yetcites [68] source
• Not checked yetcites [69] Weng, 2009, Trends Genet.

In the paper

“Systemic changes that occur during aging may also affect lymphocyte production (14) and thymopoiesis in particular.”

What the sources say

• Not checked yetcites [14] source

In the paper

“Inflammaging (64), a condition in which there is an accumulation of inflammatory mediators in tissues, has been associated with aging.”

What the sources say

• Not checked yetcites [64] source

In the paper

“In addition, the production of inflammatory mediators that may be thymocytotoxic also increases with age (39).”

What the sources say

• Not checked yetcites [39] source

In the paper

“For example, numerous reports have demonstrated that growth hormone (GH) and IGF-1 can stimulate thymopoiesis (13,42).”

What the sources say

• Not checked yetcites [13] source
• Not checked yetcites [42] source

In the paper

“For example, with increased age, naive CD4 + T cells exhibit biased differentiation into Th17 instead of Th1 and Th2 cells”

In the paper

“other studies have shown the potential of antioxidants to improve the function of old HSCs (76,96).”

What the sources say

• Not checked yetcites [76] source
• Not checked yetcites [96] source

In the paper

“Nevertheless, cell-autonomous events might also contribute to aging.”

In the paper

“However, once the effects of aging are manifest in one or more target populations, a vicious cycle may initiate that leads to a downward spiral of increasingly compromised immune function (Figure 2).”

In the paper

“Although there has been considerable focus on stem and progenitor cells, aging also affects patterns of gene expression in mature B and T cells.”

In the paper

“A subsequent report from the same laboratory described the increased expression of DUSP6 in naive CD4 + human T cells, which resulted in activation of a lower fraction of Th cells, particularly in response to low-affinity stimuli (88).”

What the sources say

• Not checked yetcites [88] source

In the paper

“For example, alterations in the PI3K pathway are frequently exhibited by aging cells.”

In the paper

“Administration of IGF-1 to old mice enhances thymopoiesis predominantly through effects on thymic epithelial cells and not thymocytes (104).”

What the sources say

• Not checked yetcites [104] source

In the paper

“The observation that changes in methylation status as a result of differential expression of various DNA methyltransferases (DNMTs) can affect HSC behavior is consistent with this view.”

In the paper

“Increased expression of tumor suppressor proteins such as p16 Ink4a and ARF also occurs in aging cells from multiple tissues (79,80).”

What the sources say

• Not checked yetcites [79] Krishnamurthy, 2004, J Clin Invest. source
• Not checked yetcites [80] source

In the paper

“The analysis of stem and progenitor cells from various tissues has revealed that aging often results in the dysregulation of similar molecular pathways (75).”

What the sources say

• Not checked yetcites [75] source

In the paper

“In this regard, the increased expression of DUSP6 in naive CD4 + T cells described above was due to the age-related decline in miR-181a expression (88).”

What the sources say

• Not checked yetcites [88] source

In the paper

“in view of a study linking compromised mitochondrial function and depressed thymopoiesis (94).”

What the sources say

• Not checked yetcites [94] source

In the paper

“Consistent with this observation, HSCs are depleted due to build-up of ROS in mice in which FOXO, a key downstream PI3K component, is deleted (76).”

What the sources say

• Not checked yetcites [76] source

In the paper

“For example, over time exposure to an inflammatory milieu might induce epigenetic modifications that affect the expression of genes required for growth, survival, or differentiation (89,90).”

What the sources say

• Not checked yetcites [89] source
• Not checked yetcites [90] source

In the paper

“numerous studies (42) have shown that thymus size is increased in old mice administered either hormone (101, 103).”

What the sources say

• Not checked yetcites [42] source
• Not checked yetcites [101] source
• Not checked yetcites [103] Welniak, 2002, J Leuk Biol. source

In the paper

“One study reported the induction and sustained transcription of DUSP4 in activated CD4 + memory T cells from humans 65 and older, which correlated with their altered cytokine production and an impaired ability to provide help for B cells (87).”

What the sources say

• Not checked yetcites [87] source

In the paper

“Many GH effects are mediated through induction of IGF-1 production, and the elevated levels of IGF-1 in GH-treated patients were consistent with this.”

In the paper

“The latter observations suggest that GH in the human subjects resulted in an induction of IGF-1 that functioned in a similar manner.”

What the sources say

• Not checked yetcites [104] source

In the paper

“These signaling abnormalities in HSCs, lymphoid progenitors, and mature B and T cells may occur, at least in part, as a result of the age-related alterations in the systemic and local tissue environments discussed above.”

In the paper

“It is interesting that telomere dysfunction has been associated with changes in mitochondrial metabolism (93)”

What the sources say

• Not checked yetcites [93] source

In the paper

“For example, pharmacologic inhibition of Cdc42, a small Rho GTPase whose increased expression has been linked to murine HSC aging, with a selective Cdc42 activity inhibitor rejuvenated HSCs (95)”

What the sources say

• Not checked yetcites [95] source

In the paper

“This is a particularly interesting finding, because it provides a molecular mechanism for the age-related decline in the number of lymphoid-biased HSCs discussed above.”

What the sources say

• Not checked yetcites [27] source

In the paper

“We also observed increased expression of Ink4a, but not Arf, in ETPs and their DN progeny (82).”

What the sources say

• Not checked yetcites [82] source

In the paper

“Haynes and colleagues (111) found that CD4 + T cells generated from old HSCs were functional in young but not old hosts”

What the sources say

• Not checked yetcites [111] Eaton, 2008, J Immunol. source

In the paper

“However, these cells would still reside in an aged microenvironment that could eventually dampen their potential to mature or function.”

In the paper

“abrogation of mature B cells in aging mice has been reported to stimulate primary bone marrow B lymphopoiesis (109).”

What the sources say

• Not checked yetcites [109] source

In the paper

“CR may also increase GH levels (114)”

What the sources say

• Not checked yetcites [114] source

In the paper

“CR has been reported to have multiple beneficial effects on the immune system of both rodents and non-human primates that include a delay in the accumulation of senescent T cells (112) and a stimulation of thymopoiesis (113).”

What the sources say

• Not checked yetcites [112] source
• Not checked yetcites [113] source

In the paper

“CR reportedly reduces IGF-1 secretion (114)”

What the sources say

• Not checked yetcites [114] source

In the paper

“optimal interventions may need to address the effects of aging on multiple cellular targets.”

In the paper

“CR has been reported to block the age-related elevation of the thymic proadipogenic master regulator, PPARγ (113).”

What the sources say

• Not checked yetcites [113] source

In the paper

“Correcting age-related deficiencies in lymphocyte progenitors or mature T and B cells may result in significant restoration of immune function in the elderly.”

In the paper

“neoplastic cells might also express receptors resulting in tumor growth (115).”

What the sources say

• Not checked yetcites [115] source

In the paper

“These observations are consistent with a recent report showing that conditional deletion of Ink4a in DN thymocytes can significantly delay thymic involution (108).”

What the sources say

• Not checked yetcites [108] source

In the paper

“implying that the aged thymic or peripheral microenvironments critically influence the degree to which immune system rejuvenation can occur.”

In the paper

“inhibition of mTOR, a PI3K pathway intermediate, with rapamycin has been shown to stimulate CD8 + T cell responses in preclinical studies (110).”

What the sources say

• Not checked yetcites [110] Chi, 2012, Nat Rev Immunol. source

In the paper

“Many of the suggested interventions discussed herein have not been evaluated in preclinical models or clinical trials.”

In the paper

“the reduction of DUSP6 levels by increasing miR-181a expression or repressing activity with the allosteric inhibitor BCI improved the responsiveness of old naive CD4 + T cells (88).”

What the sources say

• Not checked yetcites [88] source

In the paper

“CR has been reported to have multiple beneficial effects on the immune system of both rodents and non-human primates that include a delay in the accumulation of senescent T cells (112) and a stimulation of thymopoiesis (113).”

What the sources say

• Not checked yetcites [112] source
• Not checked yetcites [113] source

In the paper

“The studies reviewed above provide proof-of-concept data that pharmacologic stimulation of immunity in the elderly is possible”