Immunosenescence and Immunogenetics of Human Longevity

Abstract

At present, individuals can live up to 80–120 years, a time much longer than that of our ancestors, as a consequence of the improvements in life conditions and medical care. Thus, the human immune system has to cope with a lifelong and evolutionarily unpredicted exposure to a variety of antigens, which are at the basis of profound age-related changes globally indicated as immunosenescence, a multifaceted phenomenon that increases morbidity and mortality due to infections and age-related pathologies. The major changes occurring during immunosenescence are the result of the accumulation of cellular, molecular defects and involutive phenomena (such as thymic involution) occurring concomitantly to a hyperstimulation of both innate and adaptive immunity (accumulation of expanded clones of memory and effector T cells, shrinkage of the T cell receptor repertoire, progressive activation of macrophages), and resulting in a low-grade, chronic state of inflammation defined as inflammaging. It is unknown whether inflammaging, which represents a risk factor for most age-related pathologies, is a cause or rather an effect of the aging process. In this complex scenario, the role of genetic background likely represents a fundamental variable to attain successful aging and longevity. Accordingly, centenarians seem to be equipped with gene variants that allow them to optimize the balance between pro- and anti-inflammatory molecules, and thus to minimize the effects of the lifelong exposure to environmental insults and stressors. The remarkable features of the genetics of aging and longevity are reviewed, stressing the unexpected and unusual results obtained regarding such a postreproductive type of genetics.

Cause-specific mortality in classic Kaposi's sarcoma: a population-based study in Italy (1995–2002)

“…Our deficit for lung cancer is in contrast to the excess for the other populations. The similarities for lymphoid malignancies could reflect immunological perturbations (immunodepression in persons with HIV/AIDS and transplant recipients and immunesenescence/inflammaging (Ostan et al, 2008) in elderly persons with CKS), whereas the differences for solid cancers could reflect different lifestyles/risk factors.…”

Reversing T cell immunosenescence: why, who, and how

“…Phenotypic analyses have confirmed that the exhaustion of thymic output with advancing age was the basis of the deficient replacement of naïve T cells lost in the periphery (i.e., by death or conversion to memory/ effector cells) (Kohler et al 2005;Ostan et al 2008;Haines et al 2009;Weiskopf et al 2009). Whether this contributes to the inability of maintaining the T cell repertoire breadth in older adults, TREC values could not be immediately interpreted to reflect continuous thymic output of naïve T cells (Hazenberg et al 2003).…”

“…This results from a shift from a CD4 + T helper cells, Th1-like cytokine response to a Th2-like response, and furthermore an increase in levels of proinflammatory cytokines (i.e., IL-6, tumor necrosis factor (TNF-α), as well as IL-1β, . While a wide range of factors has been claimed to contribute to this state (i.e., increased amount of adiposity, decreased production of sex steroid, and chronic health comorbid disorders) (Ostan et al 2008;Fulop et al 2010), this altered inflammatory response has also been attributed to the continuous exposure to CMVantigen stimulation and/or reactive oxygen species (Pawelec et al 2009;Brunner et al 2011;Larbi et al 2011). However, whether these parameters could provide a robust set of criteria for the determination of an individual's immunological status in the older old adults, further studies are still required in order to identify biomarkers that are identifiable earlier in life so that intervention strategies can be administered sooner rather than later (Govind et al 2012).…”

“…With this aim, genomic may help to identify factors usable not only as a measure of biological aging but that may also be useful as a tool for predicting immune capabilities within the population (Ostan et al 2008). Studies that tracked the changes in thymic output have attempted to establish the number of naïve cells and thereby provide an assessment of immune status by using an excisional by-product of T cell receptor (TCR) genes rearrangement (Douek et al 1998;Hazenberg et al 2002;Mitchell et al 2010;Govind et al 2012).…”

“…Age-associated changes in cell-mediated immunity strongly depend on thymic function ). Thymic involution is one of the major feature of human immunosenescence because it is the single preceding event in all cases (Ostan et al 2008;Aspinall et al 2010). It is characterized by a progressive, reduction in size, due to profound changes in its anatomy with reducing the active areas of thymopoiesis related to fat accumulation throughout life.…”