ReviewAging and immunity – Impact of behavioral intervention
Introduction
The process of aging mostly reflects the biological consequences of unrepaired damage over time, and has a complex phenotype associated with progressive changes in many key physiological systems (Fig. 1). Aging influences an organism’s entire physiology, impacting on functions at the molecular, cellular and systemic levels and increasing susceptibility to many major chronic diseases. Many age-related diseases have multifactorial aetiology and aging is hypothesed to alter the highly coordinated interactions on the systemic level, leading to loss of homeostasis and to decreased ability to respond to extrinsic and intrinsic challenges, resulting in senescence. For this reason, a comprehensive explanation of how and why we age requires an understanding of events at the different levels of this decline. Further complexity is introduced particularly in studies on people due to the great diversity among individuals, which results from the dynamic interaction of genetics, environment, life style, nutrition and other factors (including those still not identified). One obvious example relates to differences between male and female gender, which influence life span for reasons that remain unclear (Nussinovitch and Shoenfeld, 2012, Tower and Arbeitman, 2009). Gender-specific differences in sex hormone secretion patterns and their changes over the lifespan are clearly candidates intimately involved in controlling aging trajectories, but their exact contributions to longevity in humans are not well-established. The modulating and reciprocal influence of sex hormones on major physiological responses to environmental and cellular stressors, and to oxidative damage, may play a role in longevity. Additional factors which are proposed to have an influence in this context include telomere and telomerase-related differences, as well as changes in mitochondrial DNA (Pan and Chang, 2012). Although the role of gender differences in the regulation of inflammatory and regulatory pathways (such as insulin/IGF signalling and Target of Rapamycin (TOR) signalling) is not entirely elucidated, these pathways or factors clearly do play a role in longevity and aging-related diseases.
Particularly chronic oxidative stress is known to affect those cells constituting central regulatory systems (such as the nervous, endocrine and immune systems) and lead to disturbed communication between them. This affects their functional capacity, deregulates homeostasis and thus may influence longevity (Fuente Mde et al., 2011). In some way associated with these events, low-level inflammatory status is commonly found to be elevated in the elderly, and is implicated in frailty and mortality. Numerous attempts to define the role of chronic inflammation in aging have implicated redox stress, mitochondrial damage, immunosenescence, endocrinosenescence, epigenetic modifications and other phenomena. No single mechanism or theory is likely to be able to explain all aspects of aging – it is more likely that multiple processes contribute to this process; nonetheless, nearly all of them may be associated with inflammatory responses in some way (Jenny, 2012).
Age-related inflammatory processes are intimately intertwined with changes in immune function. At the same time, they are regulated by neuroendocrine hormones, including glucocorticoids, dehydroepiandrosterone, and the catecholamines, epinephrine, and norepinephrine. During the life course, age-related changes in endocrine function can potentially lead to the disturbance of this regulation. Social, occupational and psychological stressors are a part of our daily life and the source of life-changing events. Chronic stress of this type is also known to cause harmful effects on both neuroendocrine and immune functions and may contribute (in combination with age) to further increases in morbidity and mortality among elderly individuals (Heffner, 2011, Hawkley and Cacioppo, 2004).
Thus, accumulating evidence shows incontrovertibly that immune function changes with normal aging and independently with increased stress; and that chronic stress deregulates multiple components of innate and adaptive immunity, leading to what might be construed as premature aging of the immune system (Gouin et al., 2008). At the same time it is likely that the immune system impacts on the rate of organismal aging (Fuente Mde et al., 2011). Consistent with a central role of the immune system in this process, several lifestyle strategies such as intervening to provide an adequate diet, physical exercise, physical and mental activity, also result in improved immune functions, decreasing oxidative stress, and potentially increasing individual longevity.
Finally, human beings may be considered as ‘metaorganisms’ as a result of a close symbiotic relationship with the intestinal microbiota (and indeed also systemic microbiota, such as persistent viruses). This assumption enforces an even more holistic view of the aging process where dynamics of the interaction between environment, intestinal microbiota and all physiological processes of the host must be taken into consideration (Biagi et al., 2012).
Here, we will briefly survey the cells and functions of the vertebrate immune system focussing on the human immune system, and the effects of aging thereon, before considering if and how behavioral interventions might be able to restore appropriate immune function in the elderly.
Section snippets
Age-related changes in the immune system
Age-related physiological changes can be very well exemplified in the immune system, which is continuously remodelled over the life course. The most important task of the immune system is to defend the body’s integrity against external pathogens or altered internal factors, and to facilitate the maintenance of a beneficial microbiota (Pawelec, 2012). Various immune mechanisms of both the innate and adaptive arms of the immune system, including different cell populations, are available to
Cells of the innate immune system and impact of aging
Innate immune responses initially call adaptive immune responses into play and both arms act together to eliminate pathogens. Cells of the innate immune system, such as natural killer cells, macrophages, dendritic cells, and neutrophils, generate a more rapid but less finely antigen-specific immune response than the cells of the adaptive immune system.
The adaptive immune system and immunosenescence
The cells of the adaptive immune system (T- and B-lymphocytes) act in a highly antigen-specific manner and imbue the system with immunological memory (Medzhitov and Janeway, 1997) as well as regulating immune homeostasis. The receptors of these lymphocytes are generated through somatic recombination of segments of their encoding sequences (Bonilla and Oettgen, 2010) and in this way provide an extremely diverse repertoire of receptor specificities capable of recognizing components of essentially
Development of lymphocytes and impact of aging
Development of lymphocytes occurs in the specialized environments of the bone marrow and thymus. The lymphoid precursors of T- and B-cells originate from the pluripotent hematopoietic stem cells in the bone marrow.
Inflammaging
As mentioned above, chronic low-grade inflammation has been repeatedly identified in seemingly healthy individuals during aging and is characterized by increased levels of circulating pro-inflammatory cytokines, such as TNF-α, IL1Rα, IL-6 and markers of inflammation such as C-reactive protein (CRP). It was postulated that this so-called “inflammaging“ process appears to be a key phenomenon associated with different age-related diseases and their pathological features (Franceschi et al., 2007,
Humoral immunity
Humoral immunity in an aged organism is known to be both qualitatively and quantitatively different than in the young. There is a lower frequency and absolute number of pro-B lymphocytes in the bone marrow, along with a reduction in their ability to differentiate into pre-B lymphocytes (Fig. 4, left). Immunoglobulin diversity and affinity are reduced in the elderly because of impaired somatic hypermutation inside the germinal center (GC), which is the main site of B cell proliferation and
Impact of life style factors on immunosenescence
Many lifestyle factors are known or suspected to contribute to perceived deleterious age-associated changes to immunity. These include psychosocial parameters, stress responsiveness, physical inactivity, macro- and micro-nutrition, all of which may play important roles in immunosenescence.
Stress may play a crucial role in mediating inflammation and age-associated impairments of immunity. Stress may be induced by a variety of factors, including situations both physical and mental, such as
Impact of behavioral interventions on immunosenescence
It is now clear that a variety of genetic and environmental factors impact upon health in old age, including effects on immunity. However, the relative contribution of these factors to immunosenescence will have to be more accurately established. These variables clearly include nutrition (micro and macro) and obesity, as well as gender and ethnicity, genetic background, psychosocial parameters (including stress), mental wellbeing, socioeconomic status, early life events and exposures, physical
Conclusions
A current evolutionary understanding of immunosenescence as postulated in this review is based on the consensus that the constantly remodelling immune system is most dynamic in childhood as a result of responding to and generating memory for the diversity of pathogens to which the person is most exposed in early life (in order to survive childhood and still be around in later life). The individual therefore invests heavily in expensive (and potentially dangerous) adaptive immune responses to
Acknowledgments
This work was supported by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, BMBF) under grant numbers #16SV5536K, #16SV5537, #16SV5538, and #16SV5837 and the BMBF Network “GerontoShield” ((BMBF Gerontoshield 0315890F), as well as the European Commission (EUFP7 IDEAL 259679) (to G.P.). LM would like to gratefully aknowlege Dr. Frank Schmidt for his competent help during the writing of the manuscript.
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