Inflamm‐ageing and lifelong antigenic load as major determinants of ageing rate and longevity

Abstract

Immunosenescence is the consequence of the continuous attrition caused by chronic antigenic stress. The most important characteristics of immunosenescence (accumulation of memory and effector T cells, reduction of naive T cells, shrinkage of T cell repertoire, reduction of the immunological space) are compatible with this assumption. Immunosenescence can be taken as proof that the beneficial effects of the immune system, devoted to the neutralization of harmful agents early in life, become detrimental late in life, in a period not foreseen by evolution. This perspective could explain the mechanisms of the ageing process as well as the pathogenesis of age-related diseases. Keywords: Antigenic load; Inflamm-ageing; Ageing rate; Immunosenescence; Age-related diseases Evolutionary-based immunosenescenceImmunosenescence is a recent phenomenon, related to the extraordinary and linear improvements in survival and lifespan that began around the 19th century and are still occurring. It is possible to speculate that the role of immunosenescence was indeed negligible in the past, when the human lifespan was 40-50 years, and that its impact on morbidity and mortality has emerged in combination with the extension of lifespan [1]. The changes associated with immunosenescence, such as inflamm-ageing, shrinkage of the T cell repertoire and filling up of the immunological space with memory/effector cells, are playing a more and more important role in the emergence of a series of age-related pathologies, conditioning the present epidemiology of old people [2].The ageing of the immune system (IS) is not a random process without rules or directions, but rather is subject to evolutionary constraints [3]. The IS has been probably selected to serve individuals living until reproduction. The trend of thymic ontogenesis and involution likely supports this hypothesis [4]. Our ancestors lived until 30-50 years of age. Nowadays, the IS must serve the soma of individuals living 80-120 years, an enormous amount of time longer than that predicted by evolutionary forces. Therefore, old people have to cope with a lifelong antigenic burden encompassing several decades of evolutionary unpredicted antigenic exposure. This chronic antigenic stress and the subsequent inflammatory burden have a major impact on survival and frailty. The quality of ageing and the peculiar remodeling of the IS in more advanced age are the results of the individual immunological history, which therefore heavily influences both longevity and successful ageing [5]. Individual immunological history derives from the interaction between genetic background and specific lifelong antigenic burden [6,7]. This latter depends on historical period where you live, on geography (poor/dirty or reach/hygienized countries) and on social/economic status and education. Indeed, since the genetic pool of humans remained almost constant in the last century, the recent spectacular improvement in survival can be largely attributed to improved life conditions and hygiene [8]. Chronic an...

Cytokine Serum Profile in a Group of Sicilian Nonagenarians

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“…Advancing age is correlated to an increase of inflammatory response, which is believed to be a direct consequence of the continuous attrition caused by antigenic load during the life-span-a condition that is commonly called by the authors ''inflamm-aging,'' [3] also sustained by the immune system remodeling, which physiologically occurs during aging (''immuno-senescence''). It is a slow but inexorable process leading to an immune system that shows peculiar features, predisposing older people to a different kind of reaction to injuries in comparison to young individuals.…”

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“…It has been well documented that ageing is associated with a decline in immune system function (De Martinis et al 2005;Franceschi et al 2000) linked to numerous infections and frequently with chronic diseases (Deleidi et al 2015). Ageing also affects innate and adaptive immune systems (Shaw et al 2013).…”

Age-related loss of CpG methylation in the tumour necrosis factor promoter

“…Many aspects of the both the adaptive and innate immune systems change with increasing age leading to a state termed 'inflammageing' [12]. In the adaptive system the ability to generate high affinity antibodies after immunization is reduced perhaps as result of reduced levels of CD8+ CD28-cells [13], in addition to the ratio of naïve to memory T cells alters [14].…”