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The pioneering Swedish OCTO/NONA-Immune longitudinal studies led by Anders Wikby in Jönköping in the 1990s established a cluster of simple baseline immune parameters associated with excess mortality in 85 year-old non-institutionalized individuals over 2, 4 and 6-year follow-up. We dubbed this cluster the "Immune Risk Profile" (IRP) consisting of poor proliferative responses of peripheral blood mononuclear cells to T cell mitogens, accumulations of CD8+ CD28- T-cells resulting in an inverted CD4:8 ratio, decreased amounts of B-cells, and seropositivity for Cytomegalovirus (CMV). The concept of the IRP has since been applied by others to many different populations in different circumstances and at different ages, but in general without specifically establishing whether the same risk factors were relevant in the tested subjects. However, our own later studies showed that risk factors in aged populations from The Netherlands and Belgium were markedly different, indicating that the IRP cannot simply be transferred between populations. Moreover, there was a striking sex difference in the Belgian study, which was the only one large enough to include sufficient numbers of old men. The reasons for these marked differences between populations which one might have assumed a priori to be quite similar to one another are not clear, and many candidates can be speculated upon, but the important lesson is that there is a marked context-dependency of immune biomarkers of ageing, suggesting that IRPs cannot be assumed to be identical in different populations.

Aging is accompanied by many physiological changes including those in the immune system. These changes are designated as immunosenescence indicating that age induces a decrease in immune functions. However, since many years we know that some aspects are not decreasing but instead are increasing like the pro-inflammatory activity by the innate immune cells, especially by monocytes/macrophages. Recently it became evident that these cells may possess a sort of memory called trained memory sustained by epigenetic changes occurring long after even in the absence of the initiator aggressor. In this review we are reviewing evidences that such changes may occur in aging and describe the relationship between inflamm-aging and immunosenescence as an adaptation/remodelling process leading on one hand to increased inflammation and on the other to decreased immune response (immune-paralysis) mastered by the innate immune system. These changes may collectively induce a state of alertness which assure an immune response even if ultimately resulting in age-related deleterious inflammatory diseases.

The concept of frailty as a medically distinct syndrome has evolved based on the clinical experience of geriatricians and is clinically well recognizable. Frailty is a nonspecific state of vulnerability, which reflects multisystem physiological change. These changes underlying frailty do not always achieve disease status, so some people, usually very elderly, are frail without a specific life threatening illness. Current thinking is that not only physical but also psychological, cognitive and social factors contribute to this syndrome and need to be taken into account in its definition and treatment. Together, these signs and symptoms seem to reflect a reduced functional reserve and consequent decrease in adaptation (resilience) to any sort of stressor and perhaps even in the absence of extrinsic stressors. The overall consequence is that frail elderly are at higher risk for accelerated physical and cognitive decline, disability and death. All these characteristics associated with frailty can easily be applied to the definition and characterization of the aging process per se and there is little consensus in the literature concerning the physiological/biological pathways associated with or determining frailty. It is probably true to say that a consensus view would implicate heightened chronic systemic inflammation as a major contributor to frailty. This review will focus on the relationship between aging, frailty and age-related diseases, and will highlight possible interventions to reduce the occurrence and effects of frailty in elderly people.

Scientific and clinical advances in the last century have led to increased numbers of individuals living to older ages. Thus a major concern is how to live these years with a high quality of life. The ageing immune system is less well able to cope with infectious diseases than the youthful immune system probably as a consequence of altered immune response to pathogens. Thus, both innate and adaptive immune responses show age-related changes that could be decisive for healthy ageing and survival. Longitudinal studies in healthy elderly have allowed the definition of the ''immune risk phenotype" (IRP) a predictor of mortality in elderly individuals that is based on several parameters of the adaptive immune response. Here, we hypothesize that failures in innate immunity observed in frail elderly are related to those alterations described in adaptive immunity defined as the IRP. It will be important to include assays of NK cell markers and functions in future longitudinal studies in order to investigate this point in detail as well as to consider the trace element zinc as an essential co-factor for optimal NK cell activity.

Cell lineages survive as long as their descendants replicate. In human diploid fibroblasts (HDF) there is a telomere-driven clock that determines the limited replicative life span of their cell branches. Werner's syndrome fibroblasts (WF) prematurely limit their replicative life span compared to HDF on account of a defective RecQ helicase, WRNp. Here, we introduce the concept of telomeric non-reciprocal recombination (TENOR) and suggest that its dysregulation in WF is responsible for their premature senescence. We postulate that TENOR functions at the level of four-strand replisomes which are specific for and initiated at fused chromosome ends. Consequently, healthy replicatively senescent fibroblasts can undergo one further division mediated by a TENOR event. Thereby, one of the two daughter cells re-acquires proliferation capacity that initiates a new proliferating cell branch from the formerly replicatively senescent cell. We argue that the unique mechanisms of action of WRNp support this concept, and we apply it to WF. If it is stipulated that WF are defective for TENOR because of their defective WRNp, a simple model emerges as to how they become prematurely senescent.

Humans are almost certainly the longest-living of all mammals. What explains their longevity? Are there evolutionary pressures favouring longer life and if so what are they? If longevity is a positively selected trait, are many or few genes responsible for this characteristic? It is proposed here that human longevity was selected for at the level of relatively few genes and that many of these are involved in regulating the immune system.

Hand-grip strength is strongly correlated with measures of muscle mass and can be taken to predict morbidity and mortality. The aim of this study was to investigate the relationship between hand-grip strength and other markers associated with immune ageing, such as Cytomegalovirus (CMV) infection, leukocyte telomere length and serum levels of inflammatory and anti-inflammatory markers in the elderly. We have assessed grip strength with the Smedley Dynamometer in younger (22–37 years) and older (60–85 years) men and women in a sample of people living in Berlin (the BASE-II study). Serum cytokine levels were determined by flow-cytometry, CMV serostatus via ELISA and leukocyte telomere length by quantitative PCR. IL-1β levels tended to be negatively associated with grip strength, but we did not find a significant association with IL-6 levels. CMV-seropositivity was not associated with higher levels of IL-1β, IL-6 or TNF, nor with weaker grip strength in men or women at any age. A putative general measure of organismal ageing, overall leukocyte telomere length, was also found not to be associated with lower grip strength in the elderly. Hand-grip strength remains an important biomarker independent of CMV infection or shorter telomere lengths, and poorly reflected in peripheral pro-inflammatory cytokine levels, all of which have been associated in some studies with frailty and mortality.

The effectiveness of the adaptive immune system relies upon extensive proliferation of an initially small number of antigen-specific T cells. At the end of a successful response, the majority die by apoptosis and a small minority joins the memory cell pool. Upon re-challenge with antigen, these memory cells must again undergo clonal expansion in order to mediate an effective response. Thus, T cells are subjected to marked proliferative stress which may result in clonal exhaustion due to replicative senescence. In other systems made up of rapidly proliferating cells (e.g. in the gut) individual clones are identical and are replaced at the end of their lifespan by differentiation from a stem cell reservoir. However, because of the unique clonal distribution of antigen receptors on T cells, mere replacement with other T cells is not sufficient to maintain the integrity of the system. Moreover, the very source of new T cells decreases with age (due to thymic involution). Therefore, the adaptive immune system may be uniquely susceptible to the deleterious effects of replicative senescence. Particularly in humans, in vivo studies of the behaviour of individual T-cell clones in the body is difficult. However, T-cell longevity, measured as proliferative capacity in terms of population doublings, can be usefully modelled at the clonal level in vitro. This paper discusses the surprisingly little that is known about the average longevity, variation between clones, and the maximal longevity of human T cells under clonal culture conditions in vitro. From our own studies, we show that average lifespan of human T cells is as little as 17 PD; however, established clones reach 35 PD on average, with maximum longevity generally in the region of 60-80 PD, regardless of the source of the cloned cells. Expression of surface molecules in general did not differ strikingly between young and old donors, but the frequency of clones secreting IL-10, and the amount secreted per clone was higher in the elderly than in the young. Conversely, the frequency of clones secreting IL-6 and the amount secreted per clone was higher in the young.

The incidence of cancer increases with age in humans and in laboratory animals alike. There are different patterns of age-related distribution of tumors in different organs and tissues. Aging may increase or decrease the susceptibility of various tissues to initiation of carcinogenesis and usually facilitates promotion and progression of carcinogenesis. Aging may predispose to cancer in two ways: tissue accumulation of cells in late stages of carcinogenesis and alterations in internal homeostasis, in particular, alterations in immune and endocrine systems. Increased susceptibility to the effects of tumor promoters is found both in aged animals and aged humans, as predicted by the multistage model of carcinogenesis. Aging is associated with a number of events at the molecular, cellular and physiological levels that influence carcinogenesis and subsequent cancer growth. An improved understanding of age-associated variables impacting on the tumor microenvironment, as well as the cancer cells themselves, will result in improved treatment modalities in geriatric oncology.

T-cell functions are critical for the efficiency of the adaptive immune response. It is now clear that aging is associated with changes in the T-cell response to antigenic stimulation, one of the many changes collectively resulting in immune senescence. Several hypotheses have been proposed to explain such changes. We believe that chronic stimulation of T-cells enhances the appearance of apoptosis-resistant anergic dysfunctional cells; in humans in vivo these are predominantly specific for antigens of persistent viruses, especially CMV. Concomitantly, age-associated zinc deficiency is common and one hypothesis is that lack of zinc bioavailability contributes to impaired T-cell function. This could further compromise the integrity of T-cells under chronic antigenic stress, which can be modelled in long-term clonal cultures in vitro. Newly synthesized heat-shock proteins (HSPs) protect the cellular proteins from degradation under such conditions. In this short review we will briefly outline the role of heat-shock proteins and zinc deficiency in aging in order to finally discuss our own results in the context of a link between HSPs, aging and zinc.

Clusterin/Apolipoprotein J (CLU) is a cellular senescence biomarker implicated in several physiological processes. In this work we have investigated CLU expression and function in human haematopoietic cells. We found that early passage human T cell clones (TCC) express minimal endogenous amounts of CLU, which are significantly elevated in late passage cells. Moreover, exposure of TCC to increased levels of the essential micronutrient zinc in culture resulted in intense induction of CLU. Because haematopoietic cells cease proliferation following induction of terminal differentiation, we also studied the expression profile of CLU in the leukemic progenitor cell lines K562 and HL-60. We found that, like TCC, both cell lines express minimal endogenous levels of CLU in their actively proliferating state. However, when induced to differentiate into their distinct cell types, CLU was found to be up-regulated specifically in those cells expressing the main differentiation markers. Enforced stable over-expression of CLU in K562 cells inhibited the expression of the CD14 differentiation marker and blocked differentiation to either monocytes/megacaryoblasts or to erythrocytes. Overall, our results suggest that CLU is actively involved in both replicative senescence and terminal differentiation in different types of human haematopoietic cells.

Humans are almost certainly the longest-living of all mammals. What explains their longevity? Are there evolutionary pressures favouring longer life and if so what are they? If longevity is a positively selected trait, are many or few genes responsible for this characteristic? It is proposed here that human longevity was selected for at the level of relatively few genes and that many of these are involved in regulating the immune system.