Translational research in immune senescence: assessing the relevance of current models

Abstract

Advancing age is accompanied by profound changes in immune function; some are induced by the loss of critical niches that support development of naïve cells (e.g. thymic involution), others by the intrinsic physiology of long-lived cells attempting to maintain homeostasis, still others by extrinsic effects such as oxidative stress or long-term exposure to antigen due to persistent viral infections. Once compensatory mechanisms can no longer maintain a youthful phenotype the end result is the immune senescent milieu - one characterized by chronic, low grade, systemic inflammation and impaired responses to immune challenge, particularly when encountering new antigens. This state is associated with progression of chronic illnesses like atherosclerosis and dementia, and an increased risk of acute illness, disability and death in older adults. The complex interaction between immune senescence and chronic illness provides an ideal landscape for translational research with the potential to greatly affect human health. However, current animal models and even human investigative strategies for immune senescence have marked limitations, and the reductionist paradigm itself may be poorly suited to meet these challenges. A new paradigm, one that embraces complexity as a core feature of research in older adults is required to address the critical health issues facing the burgeoning senior population, the group that consumes the majority of healthcare resources. In this review, we outline the major advantages and limitations of current models and offer suggestions for how to move forward.

Fig. 1

Immune response after acute (top) or persistent (bottom) viral infection. Responses after acute infection lead to viral clearance and long-term central memory. In persistent infection, chronic viral antigen exposure can lead to clonal expansion of effector memory T cells. Reproduced from [6] with permission.

Fig. 2

Relative risk of myocardial infarction (MI) or stroke up to 90 days post influenza vaccine (Flu VAx), Pneumococcal vaccine (PnVax), respiratory tract infection (RTI) or urinary tract infection (UTI). The red line shows a relative risk of 1 (i.e. no change from control group). Data from [4].

Fig. 3

In a mouse model of progeria, a condition of accelerated aging, elimination of p16 expressing cells reduces the senescence-associated secretory phenotype (SASP) and thereby secretion of inflammatory cytokines that effect bystander cells and retarding the effects of early “aging.” Reproduced from [43] with permission.

Fig. 4

(A) Mortality due to sepsis after cecal ligation and puncture in mice aged 4, 12, or 24 months. (B) Age-specific mortality due to sepsis in humans with and without co-morbidity. (A) Reproduced from [81] with permission; (B) Reproduced from [82] with permission.

Fig. 5

Proposed model for translational immune senescence research in which clinical human studies more accurately inform mechanistic animal models, and vice versa across inciting events, pathophysiologic mechanisms, and key intermediate endpoints.