Programmed ageing: decline of stem cell renewal,immunosenescence, and Alzheimer's disease

The characteristic maximum lifespan varies enormously across animal species from a few hours to hundreds of years. This argues that maximum lifespan, and the ageing process that itself dictates lifespan, are to a large extent genetically determined. Although controversial, this is supported by firm evidence that semelparous species display evolutionarily programmed ageing in response to reproductive and environmental cues. Parabiosis experiments reveal that ageing is orchestrated systemically through the circulation, accompanied by programmed changes in hormone levels across a lifetime. This implies that, like the circadian and circannual clocks, there is a master ‘clock of age’ (circavital clock) located in the limbic brain of mammals that modulates systemic changes in growth factor and hormone secretion over the lifespan, as well as systemic alterations in gene expression as revealed by genomic methylation analysis. Studies on accelerated ageing in mice, as well as human longevity genes, converge on evolutionarily conserved fibroblast growth factors (FGFs) and their receptors, including KLOTHO, as well as insulin-like growth factors (IGFs) and steroid hormones, as key players mediating the systemic effects of ageing. Age-related changes in these and multiple other factors are inferred to cause a progressive decline in tissue maintenance through failure of stem cell replenishment. This most severely affects the immune system, which requires constant renewal from bone marrow stem cells. Age-related immune decline increases risk of infection whereas lifespan can be extended in germfree animals. This and other evidence suggests that infection is the major cause of death in higher organisms. Immune decline is also associated with age-related diseases. Taking the example of Alzheimer's disease (AD), we assess the evidence that AD is caused by immunosenescence and infection. The signature protein of AD brain, Aβ, is now known to be an antimicrobial peptide, and Aβ deposits in AD brain may be a response to infection rather than a cause of disease. Because some cognitively normal elderly individuals show extensive neuropathology, we argue that the location of the pathology is crucial – specifically, lesions to limbic brain are likely to accentuate immunosenescence, and could thus underlie a vicious cycle of accelerated immune decline and microbial proliferation that culminates in AD. This general model may extend to other age-related diseases, and we propose a general paradigm of organismal senescence in which declining stem cell proliferation leads to programmed immunosenescence and mortality.     

Senescence‐associated β‐galactosidase reveals the abundance of senescent CD8+ T cells in aging humans

Aging leads to a progressive functional decline of the immune system, rendering the elderly increasingly susceptible to disease and infection. The degree to which immune cell senescence contributes to this decline remains unclear, however, since markers that label immune cells with classical features of cellular senescence accurately and comprehensively have not been identified. Using a second‐generation fluorogenic substrate for β‐galactosidase and multi‐parameter flow cytometry, we demonstrate here that peripheral blood mononuclear cells (PBMCs) isolated from healthy humans increasingly display cells with high senescence‐associated β‐galactosidase (SA‐βGal) activity with advancing donor age. The greatest age‐associated increases were observed in CD8+ T‐cell populations, in which the fraction of cells with high SA‐βGal activity reached average levels of 64% in donors in their 60s. CD8+ T cells with high SA‐βGal activity, but not those with low SA‐βGal activity, were found to exhibit features of telomere dysfunction‐induced senescence and p16‐mediated senescence, were impaired in their ability to proliferate, developed in various T‐cell differentiation states, and had a gene expression signature consistent with the senescence state previously observed in human fibroblasts. Based on these results, we propose that senescent CD8+ T cells with classical features of cellular senescence accumulate to levels that are significantly higher than previously reported and additionally provide a simple yet robust method for the isolation and characterization of senescent CD8+ T cells with predictive potential for biological age.     

Regulation of autophagy as a therapy for immunosenescence-driven cancer and neurodegenerative diseases: The role of exercise

Aging is one of the risk factors for the development of low-grade inflammation morbidities, such as several types of cancer and neurodegenerative diseases, due to changes in the metabolism, hormonal secretion, and immunosenescence. The senescence of the immune system leads to improper control of infections and tissue damage increasing age-related diseases. One of the mechanisms that maintain cellular homeostasis is autophagy, a cell-survival mechanism, and it has been proposed as one of the most powerful antiaging therapies. Regular exercise can reestablish autophagy, probably through AMP-activated protein kinase activation, and help in reducing the age-related senescence diseases. Therefore, in this study, we discuss the effects of exercise training in immunosenescence and autophagy, preventing the two main age-related disease, cancer and neurodegeneration.     

Ex vivo apoptotic potential of peripheral blood mononuclear cells of the elderly human subject

Studies of immunosenescence have led to a detailed knowledge of immune system dysfunctions in the ageing human being. Apoptosis seems to be one of the process regulating an immune response after the antigenic stimulation. We examined whether commonly used methods of assessing apoptosis in the elderly human subject produce comparable results to young subjects. PBMC of young and elderly volunteers were isolated from the venous blood and cultured for 6 or 24 h with antigens of anti-influenza vaccine or PMA. The intensity of apoptosis was measured using the annexinV test, flow cytometric evaluation of DNA content (sub-G1 peak in DNA histograms), 'ladder' by DNA gel electrophoresis, and fluorescence microscope. Apoptosis in 6 h-lasting cultures of the elderly was more intense in annexinV test, while it was decreased assessing subG1 peak. Additionally, in the aged group, those changes were associated with cell cycle arrest. Our results suggest that the apoptosis after the stimulation with the vaccine antigens seems to be some kind of activation-induced cell death (AICD). Different patterns of apoptosis after stimulation may be associated with the cell cycle arrest of the PBMC in the elderly.     

The natural killer cell dysfunction of aged mice is due to the bone marrow stroma and is not restored by IL‐15/IL‐15Rα treatment

Immune dysfunctions in the elderly result in increased susceptibility to infectious diseases, cancer, and autoimmune diseases. Natural killer (NK) cells are bone marrow‐derived lymphocytes crucial for host defense against several infections and cancer. We have previously shown that compared to young, aged C57BL/6 mice have decreased numbers of mature NK cells in the blood, spleen, and bone marrow, resulting in susceptibility to mousepox, a lethal disease caused by ectromelia virus. Here, we describe further age‐related defects in NK cells including reduced proliferation in vivo, additional signs of immaturity, and dysregulated expression of activating and inhibitory receptors. Aging also alters the expression of collagen‐binding integrins in conventional NK cells and the frequency and phenotype of liver tissue‐resident NK cells. We additionally show that the defect in NK maturation is the consequence of deficient maturational cues provided by bone marrow stromal cells. Moreover, we demonstrate that in aged mice, treatment with complexes of the cytokine IL‐15 and IL‐15Rα induce massive expansion of the NK cells, but most of these NK cells remain immature and are unable to restore resistance to mousepox. The use of rodent model to understand immunosenescence may help the development of treatments to improve the immune fitness of the aged. Our work with NK cells should contribute toward this goal.     

Age-associated elevation in TLR5 leads to increased inflammatory responses in the elderly

Aging is accompanied by a progressive decline in immune function. Studies have shown age-related decreases in the expression and signaling efficiency of Toll-like receptors (TLRs) in monocytes and dendritic cells and dysregulation of macrophage TLR3. Using a multivariable mixed effect model, we report a highly significant increase in TLR5-induced production of IL-8 from monocytes of older individuals (P < 0.0001). Elevated IL-8 is accompanied by increased expression of TLR5, both protein and mRNA, and by increased levels of TLR5-mediated phosphorylation of MAPK p38 and ERK. We noted incomplete activation of NF-κB in response to TLR5 signaling in monocytes of elderly donors, as reflected by the absence of an associated increase in the production of TNF-α. Elevated TLR5 may provide a critical mechanism to enhance immune responsiveness in older individuals.     

Age-related variation in immunity in a wild mammal population

Age‐related changes in immunity are well documented in humans and laboratory mammals. Using blood samples collected from wild Soay sheep, we show that pronounced differences in T‐cell subsets and inflammatory markers amongst age classes are also evident under natural conditions. These shifts parallel those observed in mammals experiencing protected environments. We found progressive declines in the proportion of naïve CD4 T cells with age, a precipitous drop in γδ T cells after the second year of life and an increase in acute phase protein levels amongst geriatric sheep. Our findings suggest immune aging patterns observed in laboratory and domestic mammals may generalize to more complex, challenging environments and could have fitness costs under natural conditions.     

Pandemic Influenza H1N1 2009, Innate Immunity,and the Impact of Immunosenescence on Influenza Vaccine

Seasonal and pandemic strains of influenza have widespread implications for the global economy and global health. This has been highlighted recently as the epidemiologic characteristics for hospitalization and mortality for pandemic influenza H1N1 2009 are now emerging. While treatment with neuraminidase inhibitors are effective for seasonal and pandemic influenza, prevention of morbidity and mortality through effective vaccines requires a rigorous process of research and development. Vulnerable populations such as older adults (i.e., > age 65 years) suffer the greatest impact from seasonal influenza yet do not have a consistent seroprotective response to seasonal influenza vaccines due to a combination of factors. This short narrative review will highlight the emerging epidemiologic characteristics of pandemic H1N1 2009 and focus on immunosenescence, innate immune system responses to influenza virus infection and vaccination, and influenza vaccine responsiveness as it relates to seasonal and H1N1 pandemic influenza vaccines.