Antagonistic pleiotropy and the stress theory of aging

The ecological stress theory of aging incorporates the normally harsh environments of natural populations and hence restricted resources. Especially towards lethal extremes, positive associations are expected among fitness traits underlain by selection for energetic efficiency favoring genotypes for stress resistance. Positive pleiotropy is therefore expected for fitness traits across varying ages under these conditions. Furthermore, hormetic zones are regions of maximum energetic efficiency, also implying positive pleiotropy. Negative pleiotropy may therefore be mainly a phenomenon of benign environments.     

Telomeres, immune aging and autoimmunity

Telomere length is important in constraining the replicative potential of cells; cellular systems that are dependent on cell replenishment for renewal or on cell proliferation for functionality are highly sensitive to telomeric erosion. Cell replication invariably leads to telomere loss, which, in some cellular systems, is partially compensated for by telomerase activity. In addition to this typical telomere loss, several mechanisms of sporadic telomere loss exist. Heterogeneity in age-dependent telomere loss can be a consequence of increased cellular turnover during a lifetime, accelerated telomeric DNA damage, or defects in telomere repair. The immune system is a prime example of a highly dynamic cellular system, for which telomere maintenance is pivotal. Immune competence is strictly dependent on rapid expansions of clonal T- and B-cell populations, and telomere loss may contribute to defective immune responses in the elderly. Equally interestingly, accelerated T-cell aging combined with telomeric shortening may predispose for autoimmune responses and thereby explain the increased susceptibility for chronic inflammatory diseases in the elderly.     

Neuroendocrine–immune interactions in healthy aging

Aim: The nervous, endocrine and immune systems are connected by shared neurotransmitters, hormones and cytokines. The function of these systems shows patterns of circadian rhythmicity and a number of age‐related changes in the 24‐h hormonal and non‐hormonal rhythms have been found in older human beings. The aim of this study was to evaluate integration among the nervous, endocrine and immune systems in the elderly. Methods: Cortisol and melatonin serum levels were measured and lymphocyte subpopulation analyses were performed on blood samples collected every 4 h for 24 h from 15 healthy young‐middle‐aged subjects (range 36–55 years, mean age ± standard error [SE] 44.08 ± 1.76) and 15 healthy old‐aged subjects (range 67–79 years, mean age ± SE 68.52 ± 1.27). Results: There was a statistically significant difference between the groups in the observed values of CD20 (total B cells higher in young‐middle‐aged subjects, P = 0.02), CD25 (activated T cells with expression of the α‐chain of interleukin‐2 receptor, higher in elderly subjects, P = 0.04) and DR⁺ T cells (activated T cells higher in elderly subjects, P = 0.01). There were different correlations among lymphocyte subpopulations and hormone serum levels in young and middle‐aged subjects in compared to old‐aged subjects. In the group of young‐middle‐aged subjects, a clear circadian rhythm was validated for the time‐qualified changes of all the factors studied. In the group of elderly subjects, a clear circadian rhythm was validated for the nyctohemeral changes of CD3 (with a phase delay of 3 h), CD8, CD4/CD8 ratio, CD16, CD25 (in opposite phase), cortisol (with a phase delay of 1 h) and melatonin. Conclusion: The results of the current study show that aging is associated with enhanced responsiveness of the T‐cell compartment, impairment of B‐cell compartment and alterations in temporal architecture and correlations of neuroendocrine–immune parameters. Geriatr Gerontol Int 2011; 11: 98–106.     

The characteristic changes of immune function with aging

It is well-known that the most prominent age-related immunological abnormalities were reduced immune response against foreign antigens and increased auto-antibody production against intrinsic antigens. To explain these immunological abnormalities, we examined the various functions of human lymphocytes from aged and young groups at cellular, molecular and genetic levels. The results indicate: The first, T cells from the aged showed significantly reduced proliferative response not only to specific antigen TAP but also to mitogen PHA or combined stimulation of PMA and ionomycin. The second, the number of IL-2 receptor, particularly high affinity ones, on aged T cells were significantly reduced in the aged after TAP and PHA stimulation. The third, the ability to express Tac (p55) and p70/75 of IL-2R and to internalize the rIL-2 bound to the receptor were reduced in aged T cells. The fourth, although the ability to proliferate in response to SAC stimulation was two folds less in the aged B cells than that in the young ones, the capacity to differentiate into IgG and IgA class ISC after the combined stimulation with SAC and partially purified BCDF were rather increased on the basis of the number of viable cells recovered. The fifth, the amount of IL-2 activity produced by aged T cells was ten fold less than that by young ones, but the amount of BCDF activity produced by aged T cells was three folds higher than that by young ones after PHA stimulation. An inverse correlation between IL-2 activity and BCDF activity was found when the both activities were determined in the same sample. The sixth, the combined stimulation with PMA and ionomycin could induce proliferative response to highly purified T cells, T cell subsets and B cells. The degree of age-related decline of the proliferative response of CD-8 positive T cells was most significant, that of CD-4 positive ones was next and that of B cells was least. The seventh, although the maximum of c-myc mRNA level was attained at 2 hr after the stimulation and similar amount between the both age groups, the amount of mRNA at 8 or 24 hr was rather higher in the aged T cells than in the young ones. The reduction of the degradation rate of c-myc mRNA seemed to be the cause. We found no difference of the maximum amount and kinetics of c-myb mRNA between both age groups in T cells.(ABSTRACT TRUNCATED AT 400 WORDS)     

Accelerated aging versus rejuvenation of the immune system in heterochronic parabiosis

The emergence of immune disorders in aging is explained by many factors, including thymus dysfunction, decrease in the proportion and function of na?ve T cells, and so forth. There are several approaches to preventing these changes, such as thymus rejuvenation, stem cells recovery, modulation of hormone production, and others. Our investigations of heterochronic parabiosis have shown that benefits of a young immune system, e.g., actively working thymus and regular migration of young hematopoietic stem cells between parabiotic partners, appeared unable to restore the immune system of the old partner. At the same time, we have established a progressive immune impairment in the young heterochronic partners. The mechanism of age changes in the immune system in this model, which may lead to reduced life expectancy, has not been fully understood. The first age-related manifestation in the young partners observed 3 weeks after the surgery was a dramatic increase of CD8(+)44(+) cells population in the spleen. A detailed analysis of further changes revealed a progressive decline of most immunological functions observable for up to 3 months after the surgery. This article reviews possible mechanisms of induction of age-related changes in the immune system of young heterochronic partners. The data obtained suggest the existence of certain factors in the old organisms that trigger aging, thus preventing the rejuvenation process.     

Premature aging of the immune system in children with juvenile idiopathic arthritis

OBJECTIVE: Juvenile idiopathic arthritis (JIA) is an autoimmune disease of the young. The pathogenesis is not completely understood. Premature aging, associated thymic involution, and compensatory autoproliferation could play important roles in the pathogenesis of autoimmunity. We undertook this study to determine whether patients with JIA demonstrate premature immunosenescence. METHODS: To test this hypothesis, we measured 3 indicators of aging: the percentages and total counts of peripheral blood naive T cells, the frequency of T cell receptor excision circles (TRECs) in naive T cells, and telomeric erosion and Ki-67 expression as estimates of the replicative history of homeostatic proliferation. RESULTS: JIA patients showed an accelerated loss of CD4+,CD45RA+,CD62L+ naive T cells with advancing age and a compensatory increase in the number of CD4+,CD45RO+ memory T cells. JIA patients demonstrated a significantly decreased frequency of TRECs in CD4+,CD45RA+ naive T cells compared with age-matched healthy donors (P = 0.002). TREC numbers correlated with age only in healthy donors (P = 0.0001). Telomeric erosion in CD4+,CD45RA+ naive T cells was increased in JIA patients (P = 0.01). The percentages of Ki-67-positive CD4+,CD45RA+ naive T cells were increased in JIA patients (P = 0.001) and correlated with disease duration (P = 0.003), which was also an independent factor contributing to telomeric erosion (P = 0.04). CONCLUSION: Our findings suggest that age-inappropriate T cell senescence and disturbed T cell homeostasis may contribute to the development of JIA. In patients with JIA, dysfunction in the ability to reconstitute the T cell compartment should be considered when exploring new therapeutic strategies.     

Protecting the aging immune system to prolong quality of life

As researchers delve into the aging process, an associated breakdown of the immune system has become apparent. In turn, this understanding has led to the possibility of maintaining immunocompetence and good quality of life well into old age.     

Lineage-specific selection and the evolution of virulence in the Candida clade

Candida albicans is the most common cause of systemic fungal infections in humans and is considerably more virulent than its closest known relative, Candida dubliniensis. To investigate this difference, we constructed interspecies hybrids and quantified mRNA levels produced from each genome in the hybrid. This approach systematically identified expression differences in orthologous genes arising from cis-regulatory sequence changes that accumulated since the two species last shared a common ancestor, some 10 million y ago. We documented many orthologous gene-expression differences between the two species, and we pursued one striking observation: All 15 genes coding for the enzymes of glycolysis showed higher expression from the C. albicans genome than the C. dubliniensis genome in the interspecies hybrid. This pattern requires evolutionary changes to have occurred at each gene; the fact that they all act in the same direction strongly indicates lineage-specific natural selection as the underlying cause. To test whether these expression differences contribute to virulence, we created a C. dubliniensis strain in which all 15 glycolysis genes were produced at modestly elevated levels and found that this strain had significantly increased virulence in the standard mouse model of systemic infection. These results indicate that small expression differences across a deeply conserved set of metabolism enzymes can play a significant role in the evolution of virulence in fungal pathogens.

Microbial pathogens of humans typically have at least one close, nonpathogenic relative, and comparisons between the two provide a powerful entry point to identify and study disease-causing determinants. This approach has revealed numerous bacterial pathogenicity islands, clusters of genes required for a given strain or species to cause disease in humans. Because these gene clusters can be horizontally transferred, they can often be initially identified by comparing genome sequences of pathogenic and nonpathogenic strains. The situation with fungal pathogens is substantially different. Like their human hosts, these microbes are eukaryotes, and genes that work together are typically dispersed across different chromosomes rather than clustered; not surprisingly, horizontal transfer of groups of cofunctioning genes from one fungal species to another is rare. Thus, identifying and understanding how groups of genes work together to contribute to virulence remains a challenge in fungi.In this report, we consider two fungal pathogens that are closely related but differ in their virulence. Candida albicans is an opportunistic pathogen; it is a component of the normal human microbiota but is also the leading cause of systemic fungal infections in humans, which can have mortality rates as high as 40%. It is highly virulent when injected into the tail vein of mice, a standardized laboratory procedure that initiates a systemic blood stream infection. Candida dubliniensis is the closest known relative of C. albicans; it was first identified from the oral cavity of an HIV-infected patient and is typically found only as secondary infections. Although it is found throughout the world, C. dubliniensis is much less prevalent than C. albicans in the clinic; it is also less virulent in the mouse model of systemic infection, based on time-to-illness measurements (1–5).C. albicans and C. dubliniensis last shared a common ancestor nominally 10 million y ago, and their genomes are very similar in terms of gene content and synteny. A small number of individual genes are “missing” in one species compared to the other but there are also wide-scale differences in the expression of those genes conserved in both species (6–10). It has been proposed that both types of differences—in gene content and in regulation—contribute to the difference in pathogenicity, although neither idea has been directly demonstrated.In this report, we used an approach known as “allele-specific expression” to highlight patterns of gene-expression differences between C. albicans and C. dubliniensis and to identify those that bear the hallmarks of selection (11–15). Specifically, we created an interspecies hybrid between C. albicans (strain SC5314) and C. dubliniensis (strain CD36) by forcing them to mate with each other (16) (Fig. 1A). Both strains were originally isolated from human patients, and both have been studied extensively in the laboratory. In the hybrid, both parental genomes reside in the same cell, so any bias in mRNA levels must be due to cis-acting sequences specific to that genome. We show that ∼40% of orthologous gene pairs show statistically significant differences in their mRNA levels in the interspecies hybrid, although many of these differences are small in magnitude. We searched for pathways that showed a systematic up-regulation from one genome compared to the other, and were led to the genes for glycolysis, all 15 of which exhibited increased expression from the C. albicans genome compared with the C. dubliniensis genome. This pattern requires cis-acting changes to have accumulated at each of the 15 genes, all resulting in higher mRNA expression from the C. albicans alleles in the hybrid. The likelihood of this pattern emerging by chance is extremely low, and the observation strongly implies that this nonrandom pattern is the result of natural selection.Open in a separate windowFig. 1.RNA-seq of an interspecies hybrid systematically identifies gene-expression differences between C. albicans and C. dubliniensis that arose through cis-acting changes that accumulated since the two species shared a common ancestor. (A) C. albicans and C. dubliniensis (both diploid) were mated to a create tetraploid interspecies hybrid strain, using mating and auxotrophic marker complementation. We performed RNA-seq in the hybrid strain in the conditions listed, as well as the parent diploid strains in bovine plasma at 37 °C. We aligned RNA-seq reads to a concatenated C. albicans–C. dubliniensis genome and excluded reads mapping to both genomes or to multiple locations within a single genome (<5% of total reads). Systematic gene-expression differences of orthologous genes between the two species were assessed. Since both genomes were in the same trans-acting environment (that is, the hybrid strain), all measurable gene expression changes must be due to cis-acting changes. (B) Correlation between two replicate RNA-seq experiments of the interspecies hybrid grown in YPD at 30 °C. Each point represents the log₂ ratio of reads from the C. albicans genome versus reads from the C. dubliniensis genome in the interspecies hybrid, for each orthologous gene pair, with experimental replicates plotted on each axis. Points in the upper right quadrant represent genes with higher expression from the C. albicans genome than C. dubliniensis genome in the interspecies hybrid, and points in the lower left quadrant represent genes with higher expression from the C. dubliniensis genome than the C. albicans genome in that same hybrid, with Spearman correlation values shown in the lower right. We observed very high correlation between replicate experiments for all conditions tested (SI Appendix, Figs. S1 and S2).To test whether increased glycolysis gene expression could account for at least some of the virulence difference between C. albicans and C. dubliniensis, we created a C. dubliniensis strain in which the glycolysis genes were modestly overexpressed and found that this engineered strain showed enhanced virulence (compared with the parental strain) in the standard mouse model for disseminated candidiasis. This result indicates the importance of metabolic fitness in the establishment of fungal infections. More broadly, our results suggest that subtle changes in the expression of genes that are deeply conserved in all branches of life can play important roles in the evolution of specific pathogens.     

细胞免疫缺陷与认知衰老的关系研究

目的 探讨细胞免疫缺陷与认知衰老的关系及其可能的作用机制.方法 随机选取相同周龄（22～24周龄）的细胞免疫缺陷小鼠（Balb/c-nu/nu裸鼠）和正常小鼠（Balb/c）各6只,用Western blot法分析海马突触体素（Synaptophysin,Syn）表达水平和ELISA法检测海马促炎细胞因子IFN-γ、TNF-α含量.结果 细胞免疫缺陷小鼠海马Syn表达水平显著低于正常小鼠（P＜0.05）,并伴有IFN-γ水平显著增高（P＜0.01）.结论 细胞免疫缺陷加速认知衰老过程,其机制可能与其所致的海马突触数量减少和IFN-γ增高有关.     

How vaccines work on the background of the aging immune system

The elderly exhibit reduced responses to vaccinations, leaving them more susceptible to preventable infectious diseases such as influenza and pneumonia. It has been unclear as to the specific changes in the aging immune system that contribute to this decline, thus we have developed a mouse model to examine this phenomenon and determine why it occurs and how it can be overcome. Our ultimate goal is to determine how to enhance vaccine efficacy for elderly populations.     

Lineage-specific modulation of calcium pump expression during myeloid differentiation.

Calcium is accumulated from the cytosol into the endoplasmic reticulum by sarco-endoplasmic reticulum calcium transport ATPase (SERCA) enzymes. Because calcium stored in the endoplasmic reticulum is essential for cell growth, differentiation, calcium signaling, and apoptosis and because different SERCA enzymes possess distinct functional characteristics, in the present report we explored SERCA expression during in vitro differentiation of the human myeloid/promyelocytic cell lines HL-60 and NB4 and of freshly isolated acute promyelocytic leukemia cells. Two SERCA species have been found to be coexpressed in these cells: SERCA 2b and another isoform, SERCAPLIM, which is recognized by the PLIM430 monoclonal antibody. Induction of differentiation along the neutrophil granulocytic lineage by all-trans retinoic acid or cyclic AMP analogs led to an increased expression of SERCAPLIM, whereas the expression of the SERCA 2b isoform was decreased. The modulation of SERCA expression was manifest also on the mRNA level. Experiments with retinoic acid receptor isoform-specific retinoids indicated that SERCA expression is modulated by retinoic acid receptor alpha-dependent signaling. SERCA expression of retinoic acid-resistant cell variants was refractory to treatment. Differentiation along the monocyte/macrophage lineage by phorbol ester resulted in an increased expression of both SERCA isoforms. In addition, when cells were treated by phorbol ester in the presence of the glucocorticoid dexamethasone, a known inhibitor of monocyte differentiation, a selective blockage of the induction of SERCAPLIM was observed. Altered SERCA expression modified the functional characteristics of calcium transport into the endoplasmic reticulum. These observations show for the first time that the modulation of calcium pump expression is an integral component of the differentiation program of myeloid precursors and indicate that a lineage-specific remodelling of the endoplasmic reticulum occurs during cell maturation. In addition, these data show that SERCA isoforms may serve as useful markers for the study of myeloid differentiation.     

Effects exerted by prostaglandins and indomethacin on the immune response during aging

The effect of in vitro addition of indomethacin, an inhibitor of the cyclooxygenase pathway, and of prostaglandin E1 and E2 on the proliferative capacity of phytohemagglutinin- and concanavalin A-stimulated spleen lymphocytes from young and old, long-lived (C3H X C57BL/10 RIII)F1 mice was investigated. Mitogen-activated splenocytes from old mice showed a different sensitivity to these drugs than splenocytes from young animals. Additionally, our data indicate that drugs can act either as inhibitors or as stimulators of mitogenesis, depending on the mitogen used, the dose of the drug, the age of the cell donor and the length of time in culture. It is suggested that prostaglandins of the E series may play a role in the pathogenesis of age-associated immune impairment.     

Neuroimmune networks and aging of the immune system: biological and clinical significance

Over the past few years the concept of a bidirectional communication between the hypothalamus-pituitary-adrenal axis (HPAA) and the immune system has been reinforced by several experimental and clinical evidences. In this framework, recent studies have provided evidence that nerve cells and leukocytes release similar substances, e.g. cytokines, neurohormones and neuropeptides and, at the same time, these cells also bear specific receptors for the above substances. Additionally, it is well known that stressful life events, phobic disorders and migraine are characterized by profound deficits of host immune responsiveness. On these grounds, here emphasis has been placed on the aging phenomenon in which both nervous and immune cells are affected in terms of reduced percentage and functional activities. The overall data suggest that in aged people there is occurrence of several deficits of non-specific and specific immune responses, however, one has to take into consideration a possible alteration of the neuro-immune network in elderly. Therefore, life stresses or neuropsychiatric disorders could aggravate immune dysfunctions in aged individuals, this implying the need for therapeutical approaches able to improve both HPAA and immune functions.