Chronic antigenic stress, immunosenescence and human survivorship over the 3 last centuries: heuristic value of a mathematical model

Abstract

In previous investigations we pursued the hypothesis that lifelong, chronic antigenic load (CAL) is the major driving force of immunosenescence, which impacts on human lifespan by reducing the number of virgin antigen-non experienced (ANE) T cells, and filling the immunological space with expanded clones of memory and effector, antigen-experienced (AE) T cells. A model has been proposed to relate CAL with the conversion rate from ANE to AE CD8+ T cells. In addition, in order to account for individual variations of immunosenescence and lifespan, a noise term has been introduced to describe the individual fluctuations of CAL. This model was able to follow with a reasonable approximation the age-related decrease of ANE CD8+ T cells, as well as human survival curves. In this paper we extend this approach to historical survival curves, starting from 1750 until present days, and show that the quality of the fit of historical demographic data improves as we approach the recent, quantitative and qualitative decrease of CAL. Indeed, the almost linearity in the increase of lifespan and in the decrease of the noise fluctuation amplitude within this historical period suggests that the improvement of life conditions has steadily lowered the intensity of CAL and restricted the variability which results from the interaction between the individuals and their immunological environment. On the whole, this approach allows to appreciate when and how immunosenescence has started to impact on survivorship, and predicts its increasing, crucial role in explaining human mortality in hygienized, economically developed societies.

Introduction

Recent data suggest that age-associated immune remodelling, i.e. immunosenescence, may have a clinical impact, being responsible, at least in part, of some major age-related pathologies (Franceschi et al., 1995). However, until now, no reliable biomarker of immunosenescence is available. Taking into account that a major characteristic of immunosenescence is the accumulation of memory plus effector antigen-experienced (AE) T cells (Fagnoni et al., 1996, Wack et al., 1998), accompanied by a decrease of virgin antigen-non experienced (ANE) T cells (Fagnoni et al., 2000), it is reasonable to hypothesize that such parameters can be assumed bona fide as candidate biomarkers of immunosenescence (Franceschi et al., 1999, Franceschi et al., 2000a, Pawelec et al., 2002a). Indeed, the so called ‘Immunological Risk Phenotype’, capable of predicting impinging morbidity and mortality in the elderly, includes the number of CD4+ and CD8+ AE T cells, as well as other parameters related to chronic inflammation (Franceschi et al., 2000c, Bonafè et al., 2001, Pawelec et al., 2002b). A unifying approach suggests that both the accumulation and the expansion of AE T cells, and particularly of CD8+ T cells, and the increase of inflammatory markers present in old people, is a consequence of the largely inescapable, lifelong chronic antigenic load (CAL) (Franceschi et al., 2000b, Franceschi et al., 2000c).

This scenario has been conceptualized and modelled, and the results suggest that the number and the concentration of ANE CD95− CD8+ T cells (Fagnoni et al., 2000) can be assumed as a biomarker capable of predicting mortality in humans (Luciani et al., 2001a, Luciani et al., 2001b). In this model we pursued the hypothesis that CAL can be represented by an average component which quantifies the conversion rate from ANE CD95− to AE CD95+ CD8+ T cells and determines the average lifespan. In addition, in order to account for individual variations of immunosenescence and lifespan, we introduced an additional noise term for the fluctuations of CAL. This parameter was able to describe with a reasonable approximation not only the age-related decrease of AE CD8+ T cells but also the shape of human survival curves.

In the present paper we extend this model to human survival curves starting from 1750 until present days in Swedish cohorts, and show that the fitting of these demographic data improves as we approach recent, improved conditions of life, where CAL underwent a qualitative and quantitative reduction, suggesting that immunosenescence is becoming more and more important as a possible cause of mortality.