Aging and immunosenescence
The hallmark of immunosenescence is immune dysregulation. Each component or effector mechanism of the immune system is affected, although T cells appear to be the most susceptible. The number of naïve T cells is vanishingly small in most elderly and the diversity of the T cell antigen receptor repertoire is reduced, contributing to the decreased ability to respond to new infections. The memory T-cell compartments are also affected: although the numbers of memory cells increase in most elderly people, their variety and functional integrity decrease. This helps to explain the reduced ability to respond adequately to re-infection and persistent infections. The number of B cells is also generally decreased and the number of natural killer (NK) cells increased, but their function on a per cell basis is decreased. The development of the “Senior Europeans” (SENIEUR) protocol to select very healthy aged individuals for immunogerontological studies showed that even in these donors, free of any overt disease, alterations in T-cell responses could still be detected, including diminished T cell proliferation and antigen recognition.
The increasing frequencies of cells previously exposed to antigen (memory cells) and decreasing frequencies of cells able to recognize and combat the source of new antigens (naïve cells) are also likely to have also major consequences for the establishment of therapeutic or prophylactic interventions. Memory cells are necessary to provide protection against recurrent pathogens, but show signs of dysfunction in the elderly, including so-called “clonal exhaustion”. Together with the retention of T cell homeostatic mechanisms, their accumulation in the elderly coupled with an age-associated diminished output of naïve T cells from the thymus, to a less diverse T-cell repertoire for new antigens and a preferential expansion of memory cells recognizing epitopes which were either circulating in the past or incorporated in previous vaccines (e.g. flu). A striking example of this was provided by the fact that SARS was rarely fatal in young people but had >50% mortality in the elderly. The same holds for pathogens rapidly evolving antigenic variation, such as the influenza virus, which is responsible for up to one quarter of deaths of people over 65. These changes contribute to morbidity and mortality, decreased quality of life and increased health care burden in later life.
The exact cause of these age-associated immune alterations is still not clear. Thus, we are facing an aging paradigm (immunosenescence) which can be only imprecisely defined by markers that correlate with clinical consequences, making cause and effect much more difficult to distinguish. Exactly which factors are the most important and what causes these changes remains unclear, but it is likely that many interacting factors are involved, rather than a single cause. Therefore, an in-depth knowledge on the underlying mechanisms of this dysfunctional status is a prerequisite to develop strategies to prevent or reverse the process. The aim of the GERONTOSHIELD consortium is to address the core of this issue.