The immune system is the most important protective physiological system of the organism. It has many connections with other systems and is, in fact, often considered as part of the larger neuro–endocrine–immune axis. Most experimental data on immune changes with aging show a decline in many immune parameters when compared to young healthy subjects. The bulk of these changes is termed immunosenescence. Immunosenescence has been considered for some time as detrimental because it often leads to subclinical accumulation of pro-inflammatory factors and inflamm-aging. Together, immunosenescence and inflamm-aging are suggested to stand at the origin of most of the diseases of the elderly, such as infections, cancer, autoimmune disorders, and chronic inflammatory diseases. However, an increasing number of immune-gerontologists have challenged this negative interpretation of immunosenescence with respect to its significance in aging-related alterations of the immune system. If one considers these changes from an evolutionary perspective, they can be viewed preferably as adaptive or remodeling rather than solely detrimental. Whereas it is conceivable that global immune changes may lead to various diseases, it is also obvious that these changes may be needed for extended survival/longevity. Recent cumulative data suggest that, without the existence of the immunosenescence/inflamm-aging duo (representing two sides of the same phenomenon), human longevity would be greatly shortened. This review summarizes recent data on the dynamic reassessment of immune changes with aging. Accordingly, attempts to intervene on the aging immune system by targeting its rejuvenation, it may be more suitable to aim to maintain general homeostasis and function by appropriately improving immune-inflammatory-functions.

Lower brain glucose metabolism is present before the onset of clinically-measurable cognitive decline in two groups of people at risk of Alzheimer’s disease (AD) - carriers of apoE4, and in those with a maternal family history of AD. Supported by emerging evidence from in vitro and animal studies, these reports suggest that brain hypometabolism may precede and contribute to the neuropathological cascade leading cognitive decline in AD. The reason for brain hypometabolism is unclear but may include defects in glucose transport at the blood-brain barrier, glycolysis, and/or mitochondrial function. Methodological issues presently preclude knowing with certainty whether or not aging in the absence of cognitive impairment is necessarily associated with lower brain glucose metabolism. Nevertheless, aging appears to increase the risk of deteriorating systemic control of glucose utilization which, in turn, may increase the risk of declining brain glucose uptake, at least in some regions. A contributing role of deteriorating glucose availability to or metabolism by the brain in AD does not exclude the opposite effect, i.e. that neurodegenerative processes in AD further decrease brain glucose metabolism because of reduced synaptic functionality and, hence, reduced energy needs, thereby completing a vicious cycle. Strategies to reduce the risk of AD by breaking this cycle should aim to – (i) improve insulin sensitivity by improving systemic glucose utilization, or (ii) bypass deteriorating brain glucose metabolism using approaches that safely induce mild, sustainable ketonemia.

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.

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Major advances in preventing, delaying or curing individual pathologies are responsible for an increasingly long life span in the developed parts of our planet, and indeed reaching 8–9 decades of life is nowadays extremely frequent. However, medical and sanitary advances have not prevented or delayed the underlying cause of the disparate pathologies occurring in the elderly: aging itself. The identification of the basis of the aging processes that drives the multiple pathologies and loss of function typical of older individuals is a major challenge in current aging research. Among the possible causes, an impairment of the immune system plays a major role, and indeed numerous studies have described immunological changes which occur with age. Far from the intention of being exhaustive, this review will focus on recent advances and views on the role that modifications of cell signalling and remodelling of the immune response play during human aging and longevity, paying particular attention to phenomena which are linked to the so called inflammaging process, such as dysregulation of innate immunity, altered T-cell or B-cell maturation and differentiation, as well as to the implications of immune aging for vaccination strategies in the elderly.

It is well known that the immune response decreases during aging, leading to a higher susceptibility to infections, cancers and autoimmune disorders. Most widely studied have been alterations in the adaptive immune response. Recently, the role of the innate immune response as a first-line defence against bacterial invasion and as a modulator of the adaptive immune response has become more widely recognized. One of the most important cell components of the innate response is neutrophils and it is therefore important to elucidate their function during aging. With aging there is an alteration of the receptor-driven functions of human neutrophils, such as superoxide anion production, chemotaxis and apoptosis. One of the alterations underlying these functional changes is a decrease in signalling elicited by specific receptors. Alterations were also found in the neutrophil membrane lipid rafts. These alterations in neutrophil functions and signal transduction that occur during aging might contribute to the significant increase in infections in old age.

The study of T cell biology has been accelerated by substantial progress at the technological level, particularly through the continuing advancement of flow cytometry. The conventional approach of observing T cells as either T helper or T cytotoxic is overly simplistic and does not allow investigators to clearly identify immune mechanisms or alterations in physiological processes that impact on clinical outcomes. The complexity of T cell sub-populations, as we understand them today, combined with the immunological and functional diversity of these subsets represent significant complications for the study of T cell biology. In this article, we review the use of classical markers in delineating T cell sub-populations, from "truly na€ ıve" T cells (recent thymic emigrants with no proliferative history) to "exhausted senescent" T cells (poorly proliferative cells that display severe functional abnormalities) wherein the different phenotypes of these populations reflect their disparate functionalities. In addition, since persistent infections and chronological aging have been shown to be associated with significant alterations in human T cell distribution and function, we also discuss age-associated and cytomegalovirus-driven alterations in the expression of key subset markers. V C 2013 International Society for Advancement of Cytometry