Case 9-1 Young Again Pharmaceuticals Quizlet
J Clin Invest. 2013 Mar 1; 123(3): 958–965.
Causes, consequences, and reversal of immune organization aging
Abstract
The effects of aging on the immune system are manifest at multiple levels that include reduced production of B and T cells in os marrow and thymus and diminished part of mature lymphocytes in secondary lymphoid tissues. Equally a result, elderly individuals practise not respond to immune claiming as robustly as the young. An important goal of aging research is to define the cellular changes that occur in the immune system and the molecular events that underlie them. Considerable progress has been made in this regard, and this information has provided the rationale for clinical trials to rejuvenate the aging immune system.
Introduction
One of the most recognized consequences of aging is a decline in allowed function. While elderly individuals are by no ways immunodeficient, they frequently exercise non answer efficiently to novel or previously encountered antigens. This is illustrated by increased vulnerability of individuals 70 years of age and older to flu (one), a situation that is exacerbated by their poor response to vaccination (two–4).
The effects of aging on the allowed system are widespread and affect the charge per unit at which naive B and T cells are produced too as the limerick and quality of the mature lymphocyte pool. The goal of this commodity is to review recent advances, with a focus on adaptive immunity, in the understanding of the cellular and molecular events underlying these age-induced alterations and discuss their implications for the design of strategies to rejuvenate the allowed system in the elderly.
Effects of crumbling on immune arrangement development
Following their production in the os marrow and thymus, naive B and T cells migrate to secondary lymphoid tissues such as the spleen (5–seven). This procedure is particularly robust in the young in society to generate a various allowed repertoire and to fill peripheral lymphoid compartments. In contrast, primary lymphopoiesis in the elderly is significantly diminished, equally exemplified past involution of the thymus (8–10). The causes of this historic period-related reduction in lymphocyte development are multifactorial and include changes in HSCs and progenitor cells (eleven, 12) as well as the local tissue and systemic environments (13, 14).
HSCs showroom multiple age-related changes that include impaired adherence to stromal cells and, in some strains of mice (15, xvi) and elderly humans (17), an increment in number. From an immunologic perspective, the nearly profound issue of stalk cell crumbling in both mice (eleven, 18) and humans (17) is a decreased capacity to produce lymphocytes and an increase in myeloid potential. This shift has been correlated with increased expression of myeloid lineage genes and downregulation of those specifying a lymphoid lineage fate (eleven, 17).
The ability to identify, at least in mice, distinct HSC subsets that are lymphoid biased or myeloid biased, or that exhibit balanced lympho-myeloid potential has provided new insights into how crumbling affects the stem jail cell pool (Effigy 1 and refs. 19, xx). Because each of these lineage-negative (Lin–) CD117+ (c-kit+) Sca-1+ populations tin be divers based on their relative expression of CD150, a signaling lymphocytic activation molecule family unit fellow member (Figure one and refs. 21–23), information technology is now appreciated that the number of lymphoid-biased stalk cells declines with age concomitant with an increase in myeloid-biased HSCs (19). The historic period-related increase in expression of myeloid lineage genes in the studies noted higher up (xi, 17) likely resulted from the accumulation of myeloid-biased HSCs, as these analyses were performed on unseparated pools of HSCs. Despite the increase in their number, myeloid-biased stem cells are not as robust as their young counterparts (24), which in plough could underlie the numerous age-related deficiencies observed in mature myeloid cells such every bit neutrophils and macrophages (25, 26).
Effects of aging on HSCs and lymphocyte progenitors.
Lymphopoiesis in the young (left) is characterized by robust B and T prison cell product in the bone marrow and thymus. The puddle of HSCs includes a relatively loftier number of lymphoid-biased stalk cells that efficiently generate lymphoid progenitors with high proliferative potential. Nevertheless, with increasing historic period (right), the number of lymphoid-biased HSCs declines and myeloid-biased stalk cells predominate, contributing to the reduced numbers of lymphoid progenitors. In addition, B prison cell progenitors in the bone marrow and T cell progenitors in the thymus showroom reduced rates of proliferation and higher levels of apoptosis compared with their young counterparts. The increased expression of Ink4a and Arf in pro-B cells and Ink4a in ETPs contribute to this decreased proliferation/increased apoptosis. The decline in primary lymphopoiesis in turn results in a reduced number of naive cells that migrate to secondary lymphoid tissues such as the spleen.
Lymphoid-biased HSCs in old mice likewise announced to accumulate deficiencies that, as discussed beneath, may compromise their self-renewal potential and contribute to the decline of this population (27). In view of this, it is not surprising that the number of B jail cell (28–31) and T jail cell (32, 33) progenitors in bone marrow and thymus is markedly reduced with age. In addition, the poor quality of the lymphoid progenitors that are generated in the aged further exacerbates the decline in lymphopoiesis (29, 32, 34). For instance, common lymphoid progenitors, pre–pro-B cells, and pro-B cells from sometime mice do not proliferate equally extensively as do immature cells, and they exhibit significantly higher rates of apoptosis. The most immature intrathymic progenitors, which have been termed early T lineage progenitors (ETPs), generate CD4–CD8– double-negative (DN) progeny that ultimately become mature CD4+ Th cells and CD8+ cytotoxic T cells (35). Similar to B prison cell progenitors, ETPs and DN cells from old mice also exhibit age-related defects in proliferation and loftier rates of apoptosis (ref. 32 and Figure 1).
Why aging results in a decline in the number of lymphoid-biased HSCs and reduced quality of lymphoid progenitors is not fully understood. On the i hand, intrinsically programmed events in stem and progenitor cells may exist operative, which would presume that these cells have some sort of internal clock that regulates their function and longevity. However, accumulating evidence suggests that declines in lymphopoiesis are influenced by age-related changes in the environment. The precise, age-related environmental factors that event in depletion of lymphoid-biased HSCs have not been identified, although changes in levels of transforming growth factor β-i might be involved (21). Declines in the bone marrow microenvironment, possibly as a result of decreased IL-7 secretion by stromal cells, take been implicated in B cell lineage aging (36, 37). Historic period-related microenvironmental changes also have a major bear on in the thymus, where T prison cell development is dependent upon an intact thymic milieu composed of fibroblasts, macrophages, dendritic cells, and thymic epithelial cells. It is articulate that the number of thymic epithelial cells declines over fourth dimension and that they are not replaced, as a result of impaired proliferation (38). In addition, the product of inflammatory mediators that may exist thymocytotoxic too increases with age (39). The thymus, specially in humans, is increasingly infiltrated with adipocytes, the byproducts of which may exist toxic to developing thymocytes and to the remaining stromal prison cell populations (xl). A similar fatty deterioration of the bone marrow microenvironment occurs (41), but the role of adipocyte-derived factors in suppression of B lymphopoiesis is not well understood.
Systemic changes that occur during crumbling may too affect lymphocyte production (14) and thymopoiesis in particular. For case, numerous reports have demonstrated that growth hormone (GH) and IGF-i tin stimulate thymopoiesis (xiii, 42). Considering the production of these hormones declines with historic period (43), this has led to the conclusion that age-related changes in the endocrine system contribute to declines in lymphopoiesis. This view has formed the rationale for clinical trials using GH, which we discuss below.
Aging and the decline of immune part
Although the number of naive B and T cells that drift from chief to secondary lymphoid organs is reduced by crumbling, B and T prison cell development does non cease entirely. Indeed, some functional thymic tissue remains even in elderly humans (44). The continued production of lymphocytes, albeit limited, and the presence of relatively normal numbers of lymphocytes in organs such every bit the spleen raises the question of why functional immunity declines in the elderly. The respond is that the composition and quality of the mature lymphocyte pool is profoundly altered by aging.
For example, an increment in the number of memory T cells is at present a well-recognized feature of aging. These cells, which are generated post-obit the initial encounter with antigen, persist long after the initial challenge has cleared and provide a source of effectors that can respond quickly upon antigen re-exposure. Exposure to multiple pathogens over fourth dimension results in a diverse immune repertoire that includes an increased puddle of protective memory cells. Withal, chronic stimulation with persistent viral infections such as CMV can exhaust the naive pool of cells and effect in an oligoclonal memory cell expansion. This miracle is thought to be a major factor contributing to the aggregating of CD8+ retentivity cells in the elderly (45), although antigen-independent expansion of CD8+ T cells may also occur (46). These oligoclonal expanded CD8+ retentiveness T cells are further distinguished in humans by loss of expression of the CD28 co-stimulatory molecule (47, 48) and impaired immune function. The aggregating of CD8+CD28– T cells and CMV seropositivity are components of the immune run a risk contour, which has been proposed as a predictor of mortality in individuals 65 and older (49), but precisely how the combination of these events results in increased death is not clear (fifty).
The immune risk contour likewise includes B cells with impaired function. B jail cell number in mice is unchanged by crumbling, but in human peripheral blood their absolute number is reduced (51). This decline is likely due to decreased numbers of IgM+ memory and switched retentiveness B cells, because the full number of naive B cells remains unchanged past aging (51, 52). Human and murine B cells too exhibit dumb grade switch recombination, which has been attributed to decreased induction of activation-induced cytidine deaminase (AID) enzyme (53). In view of the disquisitional part played past 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 flu vaccination (55) and the product of poor-quality antibodies to sugar antigens (56–58), may occur secondary to T cell deficiencies.
Multiple B prison cell subpopulations have been defined, and additional written report is required to determine how aging affects them. Thus, humoral amnesty to influenza virus occurs in T cell–independent and T prison cell–dependent waves that may involve B1, marginal zone, and follicular B cells (59). It was recently reported that marginal zone B cell number is reduced in old mice (60), merely whether and how this affects product of antibodies to specific antigens is unknown. Although present at a low frequency (61), B1 B cells play a critical role in the response to Due south. pneumoniae in mice by the secretion of anti-saccharide antibodies (62). However, very little is known near the effects of crumbling on their function. A population of CD20+CD27+CD43+CD70– human B1 cells was recently described (63), simply again, nothing is known about how aging affects their development or function.
Inflammaging (64), a condition in which there is an aggregating of inflammatory mediators in tissues, has been associated with aging. The source of these inflammatory factors has been proposed to be cells that have acquired a senescence-associated secretory phenotype (SASP) (65). The SASP could exist acquired by cells once they have aged, or it may occur gradually in various populations over fourth dimension every bit they acquire Dna lesions that in turn trigger the increased production of inflammatory mediators such as IL-six (66, 67). Regardless of how the shift occurs from a salutary to an inflammatory milieu, the cease result may be a negative consequence on the power of naive lymphocytes from the bone marrow or thymus to lodge in an organ such as the spleen as well as the function of mature lymphocytes already resident in that tissue. In the latter case, for example, CD8+ T cells that accrue in aged individuals proliferate poorly (68, 69), and, equally discussed in more detail in the post-obit department, CD4+ T cells showroom reduced T jail cell receptor signaling intensity and altered product of various cytokines post-obit antigen binding (lxx, 71).
The precise source of the various inflammatory mediators may vary betwixt individuals. In one scenario, age-related changes in microenvironmental elements such as stromal cells or dendritic cells (72) would upshot in a shift from a salutary to an inflammatory environment. However, information technology is equally plausible that changes occurring in aging B and T cells or innate effectors (26) may change microenvironmental elements. For example, with increased age, naive CD4+ T cells exhibit biased differentiation into Th17 instead of Th1 and Th2 cells, and the inflammatory mediators secreted past the latter cells could in turn affect stromal cells or other environmental populations (73). The development of Th17 cells is dependent on the basic leucine zipper transcription factor ATF-similar (BATF) transcription gene (74), but why its expression might increase with historic period is not clear. Similarly, the CD8+CD28– memory T cells that accumulate in aged humans may besides be a source of inflammatory cytokines (68, 69) that affect the function of stromal elements. The specific cells and the club in which age-related changes occur in them may vary between individuals every bit a issue of differences in genetic background and environmental exposure. Still, in one case the furnishings of aging are manifest in one or more than target populations, a vicious cycle may initiate that leads to a downward screw of increasingly compromised immune function (Figure 2).
The strength of the allowed response declines with age.
Multiple age-related changes can affect the composition and function of lymphocytes in secondary lymphoid tissues. CD4+ Th cells exhibit activation defects and increased differentiation into Th17 cells. CD8+ T cells undergo an oligoclonal expansion and loss of CD28 in humans and showroom impaired role. The number of B cells that answer to flu is reduced, and antibody avidity in response to carbohydrate antigens is diminished. In addition, the tissue surroundings includes an increased concentration of inflammatory cytokines, which may be produced by stromal elements, dendritic cells, or aging B and T cells. The increased number of memory cells that occupy tissue niches and the inflammatory milieu in turn may compromise the power of naive B and T cells migrating from the bone marrow and thymus to gild in the tissue. Together, these changes result in macerated immune role in the elderly.
Intracellular changes in developing and mature lymphocytes
The analysis of stem and progenitor cells from various tissues has revealed that aging often results in the dysregulation of similar molecular pathways (75). For example, alterations in the PI3K pathway are frequently exhibited by aging cells. Consistent with this ascertainment, HSCs are depleted due to build-up of ROS in mice in which FOXO, a key downstream PI3K component, is deleted (76). Levels of ROS in cells may also be regulated past clutter telangiectasia mutated (ATM) kinase, and age-related declines in expression of ATM can result in an increase in ROS in cells (77, 78). Increased expression of tumor suppressor proteins such as p16Ink4a and ARF also occurs in crumbling cells from multiple tissues (79, lxxx). Expression of p16Ink4a results in activation of retinoblastoma, leading to cell cycle inhibition, while p19Arf promotes the activity of p53, which induces jail cell cycle arrest and/or apoptosis. We accept had a particular interest in understanding why the quality of lymphoid progenitors is reduced with age, and recent studies have shown that both Ink4a and Arf expression increases in pro-B cells from old mice and that inhibiting their expression can partially opposite the effects of aging (81). We also observed increased expression of Ink4a, but not Arf, in ETPs and their DN progeny (82).
Other historic period-associated changes may be more specific to the hematopoietic system. For example, altered expression of various B lineage transcription factors has been proposed to underlie declines in B lymphopoiesis (83). Recent interest has focused on BATF, the expression of which is highest in the hematopoietic system, in the reject of lymphoid-biased HSCs during aging. Wang and colleagues demonstrated that BATF levels increased in HSCs in response to DNA damage and that this resulted in the differentiation of lymphoid-biased HSCs at the expense of their self-renewal (27). This is a specially interesting finding, because information technology provides a molecular machinery for the historic period-related decline in the number of lymphoid-biased HSCs discussed above.
Although there has been considerable focus on stalk and progenitor cells, aging also affects patterns of gene expression in mature B and T cells. As previously discussed, grade switch recombination is impaired in aging murine and man B cells due to decreased expression of enzymes such every bit Assist (53, 84). Aberrant T prison cell signaling has likewise been associated with crumbling (48, 85), and the list of dysregulated genes continues to grow, as indicated by several recent reports (86–88), two of which focused on altered expression of dual specific phosphatases (DUSPs). DUSPs deactivate target kinases, including those in the MAPK pathway whose activity is critical for T cell activation, differentiation, and cytokine production. Ane report reported the induction and sustained transcription of DUSP4 in activated CD4+ retentivity 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). 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 Thursday cells, particularly in response to low-affinity stimuli (88).
These signaling abnormalities in HSCs, lymphoid progenitors, and mature B and T cells may occur, at to the lowest degree in part, as a result of the age-related alterations in the systemic and local tissue environments discussed in a higher place. For example, over time exposure to an inflammatory milieu might induce epigenetic modifications that touch on the expression of genes required for growth, survival, or differentiation (89, 90). The observation that changes in methylation status as a result of differential expression of various Dna methyltransferases (DNMTs) tin touch on HSC behavior is consistent with this view. In this regard, loss of DNMT3a impairs differentiation of HSCs while their number increases in the bone marrow (91), and mice with hypomorphic expression of DNMT1 exhibit relatively normal myeloerythroid potential only show a meaning cake in lymphoid development (92). Nevertheless, prison cell-democratic events might too contribute to aging. Thus, repeated cell division may effect in progressive telomere shortening that in turn results in DNA damage that can no longer be repaired efficiently due to age-related defects in Dna repair mechanisms (75). It is interesting that telomere dysfunction has been associated with changes in mitochondrial metabolism (93), in view of a report linking compromised mitochondrial function and depressed thymopoiesis (94).
Rejuvenating the crumbling immune system
The ultimate goal of research in immune arrangement aging is to use the data to develop strategies to stimulate immunity in the elderly (summarized in Table 1). Equally discussed to a higher place, a number of molecules have been identified whose aberrant expression contributes to crumbling, and targeting these molecules may potentially irksome or opposite the crumbling process. For example, pharmacologic inhibition of Cdc42, a small Rho GTPase whose increased expression has been linked to murine HSC crumbling, with a selective Cdc42 action inhibitor rejuvenated HSCs (95), and other studies have shown the potential of antioxidants to improve the function of onetime HSCs (76, 96). Equally additional age-related changes in the expression of transcription factors, signaling intermediates, prison cell cycle regulators, and microRNAs (97, 98) are defined, novel pharmacologic interventions will likely emerge. 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).
Table one
Potential interventions to rejuvenate the aging allowed system
Because of the key role played by T lymphocytes in the immune response and the clear issue of aging on mature CD4+ and CD8+ cells, rejuvenation of the involuted thymus to replenish the peripheral T jail cell pool has been of considerable involvement. A complete discussion of the various hormones and growth factors involved has been reviewed elsewhere (99, 100), only at that place has been considerable involvement in using classical endocrine hormones such every bit GH and IGF-one as well as other agents such equally IL-7 and FGF7 to stimulate thymopoiesis (Figure iii).
Selected strategies to rejuvenate the involuted thymus.
The potential of several hormones and growth factors to rejuvenate the involuted thymus has been tested in diverse preclinical and clinical trials. Many of these factors can be grouped into three categories. Those in the first (i), such as IL-seven, demark to progenitors in the bone marrow and thymus and have only modest effects on thymopoiesis. There is little evidence that IL-vii has effects on thymic stromal cells. Instead, the benefit of IL-7 may lie in its power to stimulate peripheral T jail cell survival/expansion. The second category (ii) includes hormones such as GH that have been demonstrated in preclinical and clinical trials to stimulate thymopoiesis and increase thymic size. Many GH effects are mediated through induction of IGF-ane. IGF-1 can bind to receptors on thymic stroma and thymocytes, although its actions are primarily mediated through effects on the former cells. Stromal jail cell–derived factors presumably then human action on thymocytes (curved arrow). A third category of factors (iii), typified by FGF7, demark to stromal cells but not thymocytes. Stromal cell–induced factors and then act on thymocytes (curved arrow), and we take recently demonstrated that furnishings include downregulation of Ink4a in ETPs (82). The thymopoietic furnishings of several additional factors accept been evaluated, and recent detailed reviews should exist consulted for more data (99, 100).
GH and IGF-1 bind to receptors expressed on thymocytes (101) and thymic epithelial cells (102), and numerous studies (42) take shown that thymus size is increased in old mice administered either hormone (101, 103). These preclinical data were the ground for a man clinical trial to determine whether one year of daily GH administration could rejuvenate the thymus of HIV-infected adults. Despite depression viral loads, those enrolled in this trial had low CD4+ T cell counts. GH treatment resulted in increased thymic mass, increased thymic output equally measured by T prison cell receptor rearrangement excision circles in circulating T cells, and increased numbers of naive CD4+ T cells. Many GH effects are mediated through induction of IGF-ane production, and the elevated levels of IGF-i in GH-treated patients were consistent with this. Administration of IGF-1 to old mice enhances thymopoiesis predominantly through effects on thymic epithelial cells and not thymocytes (104). The latter observations advise that GH in the human subjects resulted in an induction of IGF-1 that functioned in a similar style. It is important to note that the furnishings of GH were not thymus specific, as the subjects also had expanded numbers of naive peripheral CD4+ T cells (105).
In contrast to GH and IGF-1, which increment thymus cell number approximately two-fold in mice (101), FGF7 is particularly remarkable because its administration to sometime mice results in a renewal of the thymic microenvironment, increased numbers of ETPs, and a restoration of thymus cellularity to levels observed in the young (106, 107). FGF7, also known as keratinocyte growth factor and marketed as Kepivance (palifermin; Biovitrum), is approved past the FDA for treatment of oral mucositis in patients undergoing myelotoxic therapy. We hypothesized that the increased thymopoiesis in FGF7-treated old mice occurred because signals from the rejuvenated microenvironment in turn reduced Ink4a expression in ETPs. As predicted, levels of Ink4a expression in ETPs and DN cells harvested from FGF7-treated mice were downregulated, and these cells exhibited enhanced proliferation (82). These observations are consistent with a recent report showing that conditional deletion of Ink4a in DN thymocytes tin significantly delay thymic involution (108). It will thus exist of interest to identify the gene(s) released from FGF7-stimulated thymic epithelial cells that then act on aged ETPs and DN cells, as these could have therapeutic potential.
Strategies that focus on mature B and T cells may also exist of value in stimulating immunity in the elderly. For example, if naive lymphocytes are unable to lodge efficiently in the spleen because niches are occupied by retentivity cells, deletion of the latter cells might create space. The depletion of mature lymphocytes might have feedback effects on primary lymphoid organs, as abrogation of mature B cells in crumbling mice has been reported to stimulate master bone marrow B lymphopoiesis (109). It may also exist possible to target specific pathways in old lymphocytes. For example, inhibition of mTOR, a PI3K pathway intermediate, with rapamycin has been shown to stimulate CD8+ T jail cell responses in preclinical studies (110). Targeting the expression of DUSP4 (87) or DUSP6 (88) in erstwhile retentivity or naive CD4+ T cells, respectively, may too take therapeutic potential. In support of this, 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).
Correcting historic period-related deficiencies in lymphocyte progenitors or mature T and B cells may result in meaning restoration of immune function in the elderly. Yet, these cells would still reside in an anile microenvironment that could eventually dampen their potential to mature or function. Consistent with this view, Haynes and colleagues (111) found that CD4+ T cells generated from old HSCs were functional in young but not old hosts, implying that the aged thymic or peripheral microenvironments critically influence the degree to which immune system rejuvenation can occur. In view of this point, optimal interventions may need to address the furnishings of aging on multiple cellular targets.
Approaches to inhibit or reverse crumbling should be widely available and applicable to a large cohort. In addition to pharmacologic interventions, caloric restriction (CR) may as well meet these criteria. CR has been reported to have multiple beneficial effects on the immune arrangement of both rodents and not-man primates that include a filibuster in the accumulation of senescent T cells (112) and a stimulation of thymopoiesis (113). This latter effect is at showtime puzzling, because CR reportedly reduces IGF-1 secretion (114), and low levels of IGF-one have, equally discussed above, been associated with thymic involution. However, CR may also increase GH levels (114), which could exist thymopoietic, or may work through IGF-1–independent pathways. For example, CR has been reported to block the age-related acme of the thymic proadipogenic master regulator, PPARγ (113). In addition to farther studies to increase our understanding of how CR affects the immune organization, we likewise need to learn more than most when information technology should commence in view of a report that beneficial effects were observed when it commenced in adults simply were non evident when initiated in prepubertal or aged non-human being primates (112). A terminal point is that, while CR is specially attractive because it is a non-invasive approach, getting a large number of individuals to adopt this regimen might be challenging.
Caveats in immune system rejuvenation
The studies reviewed above provide proof-of-concept information that pharmacologic stimulation of immunity in the elderly is possible, and propose that such interventions could be administered to a large cohort of individuals. All the same, as the field moves forward, at that place are several points to consider. Showtime, how long do agents need to exist administered, and how much rejuvenation is necessary in order to find positive effects on immune function? These issues are relevant to the use of GH, IGF-1, and FGF7 to stimulate the thymus, because their effects are transient and the thymus reverts to its former size following the abeyance of treatment. Another caveat is that factors such as GH, IGF-1, and FGF7 accept widespread systemic effects due to the expression of their receptors on cells in multiple tissues. A business concern with the apply of some agents is that neoplastic cells might also express receptors resulting in tumor growth (115). Thus, like whatever drug, the use of these hormones to rejuvenate the thymus must be counterbalanced with potential adverse effects. It will also be crucial to ensure that the rejuvenated immune organisation functions commonly. In item, information technology will be of import to establish that the effector populations that develop accept been accordingly tolerized and are not autoreactive. The fact that many autoimmune diseases occur in late adulthood makes this a particularly important issue (116).
Conclusions and perspectives
As indicated above, a tremendous amount is now known regarding the cellular changes that occur in the crumbling allowed system and the molecular events that underlie them. Thus, it is not unreasonable to expect that this information volition continue to be translated into therapies to rejuvenate the aging immune organization.
It is likely that the effects of aging on the immune organization will not exist compatible between individuals. Thus, an ultimate goal would exist to identify primal biomarkers and establish simple laboratory tests to define each person's aging profile. Such information could and so exist used to develop a personalized arroyo in which targeted interventions could be directed to the individual'due south specific aging deficit. Notwithstanding, whatever standard of care is ultimately adopted for stimulating immunity, the emphasis should not necessarily be placed on increasing life bridge. Rather, the aim is to increase wellness bridge, divers as years of salubrious living (117).
Acknowledgments
Piece of work from the authors' laboratory was supported by NIH grant AG034875.
Footnotes
Disharmonize of interest: The authors have alleged that no disharmonize of involvement exists.
Citation for this article: J Clin Invest. 2013;123(3):958–965. doi:ten.1172/JCI64096.
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