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.

Immunosenescence Does Not Abrogate Engraftment of Murine Allogeneic Bone Marrow

“…(Young BMT groups presented comparable deletion [data not shown].) as cellular aging or T-cell receptor skewing (3,26). In the old chimeric mice, the Treg pool was significantly increased, suggesting an age advantage in the maintenance of chimerism and tolerance through regulation.…”

Resolution of inflammation: a new therapeutic frontier

“…Both of these trigger a robust innate immune response that spontaneously resolves and may better facilitate exploration of post-resolution processes, offering a more 'physiological' system. Akbar and colleagues have additionally characterized the adaptive immune responses to recall antigensincluding tuberculin purified protein, which was administered by intradermal injection and subsequent suction blister -as a means of understanding immunosenescence in aged human volunteers 188,189 .…”

CD58/CD2 Is the Primary Costimulatory Pathway in Human CD28−CD8+ T Cells

“…The most widely used model for investigating immune aging is the mouse model, and there are many characteristics of aging of human T cells that are well represented by mouse models (51,52). However, there are also profound disparities regarding the immune aging in these species that have to be taken into consideration (52,53).…”

“…However, there are also profound disparities regarding the immune aging in these species that have to be taken into consideration (52,53). One striking difference between humans and mice is that in mice, CD28-deficient T cells are rare even in old animals (54)(55)(56)(57).…”