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...

VDJdb: a curated database of T-cell receptor sequences with known antigen specificity

“…Across the cohort, a general decrease in the number of naive T-cells ( 17 ) was compensated by clonal expansions specific for common persistent viruses such as CMV and EBV ( 18 ), while the overall T-cell pool was depleted of clonotypes specific for rarer persistent viruses such as HCV and HIV (Figure 5 ). This result supports the notion that aging is associated with a progressive loss of clonal diversity that negatively impacts the ability to mount de novo immune responses ( 19 ).…”

VDJdb: a curated database of T-cell receptor sequences with known antigen specificity

“…Across the cohort, a general decrease in the number of naive T-cells ( 17 ) was compensated by clonal expansions specific for common persistent viruses such as CMV and EBV ( 18 ), while the overall T-cell pool was depleted of clonotypes specific for rarer persistent viruses such as HCV and HIV (Figure 5 ). This result supports the notion that aging is associated with a progressive loss of clonal diversity that negatively impacts the ability to mount de novo immune responses ( 19 ).…”

Proinflammatory profile of in vitro monocytes in the ageing is affected by lymphocytes presence

“…Taken together, these results about spontaneous production of cytokines, obtained from elderly subjects corroborate the state of inflamm-aging reported in others works [55-57], which appears to predispose elderly persons to diseases such as Alzheimer's, angina and osteoporosis [58-60]. Besides, it could alter the defense mechanisms against microorganisms [57,61] and reduce the ability to provide the immediate response to pathogens, as well as integrate and influence the acquired immune response [61].…”

Lifewide profile of cytokine production by innate and adaptive immune cells from Brazilian individuals

“…Interestingly, in all analyses performed, the elderly group presented a balanced profile between regulatory and proinflammatory cytokines, with a prominent contribution of innate immune cells to this balance. Our results support the hypothesis that healthy immunosenescence involves remodeling and adaptation to the changes started in adulthood and aggravated by ageing [32, 33]. …”

VDJdb: a curated database of T-cell receptor sequences with known antigen specificity

“…Across the cohort, a general decrease in the number of naive T-cells ( 17 ) was compensated by clonal expansions specific for common persistent viruses such as CMV and EBV ( 18 ), while the overall T-cell pool was depleted of clonotypes specific for rarer persistent viruses such as HCV and HIV (Figure 5 ). This result supports the notion that aging is associated with a progressive loss of clonal diversity that negatively impacts the ability to mount de novo immune responses ( 19 ).…”

Proinflammatory profile of in vitro monocytes in the ageing is affected by lymphocytes presence

“…Taken together, these results about spontaneous production of cytokines, obtained from elderly subjects corroborate the state of inflamm-aging reported in others works [55-57], which appears to predispose elderly persons to diseases such as Alzheimer's, angina and osteoporosis [58-60]. Besides, it could alter the defense mechanisms against microorganisms [57,61] and reduce the ability to provide the immediate response to pathogens, as well as integrate and influence the acquired immune response [61].…”

Lifewide profile of cytokine production by innate and adaptive immune cells from Brazilian individuals

“…Interestingly, in all analyses performed, the elderly group presented a balanced profile between regulatory and proinflammatory cytokines, with a prominent contribution of innate immune cells to this balance. Our results support the hypothesis that healthy immunosenescence involves remodeling and adaptation to the changes started in adulthood and aggravated by ageing [32, 33]. …”

VDJdb: a curated database of T-cell receptor sequences with known antigen specificity

“…Across the cohort, a general decrease in the number of naive T-cells ( 17 ) was compensated by clonal expansions specific for common persistent viruses such as CMV and EBV ( 18 ), while the overall T-cell pool was depleted of clonotypes specific for rarer persistent viruses such as HCV and HIV (Figure 5 ). This result supports the notion that aging is associated with a progressive loss of clonal diversity that negatively impacts the ability to mount de novo immune responses ( 19 ).…”

Proinflammatory profile of in vitro monocytes in the ageing is affected by lymphocytes presence

“…Taken together, these results about spontaneous production of cytokines, obtained from elderly subjects corroborate the state of inflamm-aging reported in others works [55-57], which appears to predispose elderly persons to diseases such as Alzheimer's, angina and osteoporosis [58-60]. Besides, it could alter the defense mechanisms against microorganisms [57,61] and reduce the ability to provide the immediate response to pathogens, as well as integrate and influence the acquired immune response [61].…”

Lifewide profile of cytokine production by innate and adaptive immune cells from Brazilian individuals

“…Interestingly, in all analyses performed, the elderly group presented a balanced profile between regulatory and proinflammatory cytokines, with a prominent contribution of innate immune cells to this balance. Our results support the hypothesis that healthy immunosenescence involves remodeling and adaptation to the changes started in adulthood and aggravated by ageing [32, 33]. …”