Saturday, May 4, 2024
5/4/2024
SUMMARY The association between advanced age and impaired resistance to infections is well known, but poorly understood. The current COVID-19 pandemic is a clear example of the vulnerability of the elderly to SARS- CoV-2 infection as well as many other pathogens. Considerable research efforts have shown that components of both the innate and adaptive immune systems show signs of dysfunction as we age, with signs of both immunodeficiency, including reduced innate response and poor induction of adaptive immune memory, and immunopathology including an exaggerated “cytokine storm”. However, while aspects of age-related changes in immune cells have been explored in depth, the focus has been on defining the nature of dysfunction within cells of the immune system itself, rather than investigating the potential role of other cell populations in dominantly compromising immune homeostasis and immunological response to pathogens. Also, although the increase in immunosenescence with age, defined by cell surface markers for immune cell exhaustion, has been examined, the extent of cellular senescence in immune cell populations with age and pathogen exposure remains undefined. Our recent findings indicate that senescent cells (SnCs), including senescent immune cells, can exert a “bystander” effect on immune cells, provoking immunological dysfunction through secretion of inflammatory factors, including cytokines and chemokines, termed the “senescence-associated secretory phenotype” (SASP). We demonstrated that SASP factor production is increased when SnCs or mice containing SnCs are exposed to pathogens or microbial products that induce innate immune activation. Exposure of old mice to normal microbial experience (NME) housing resulted in 100% mortality compared to no mortality in young mice. However, reducing the senescent cell burden in aged mice before or following pathogen exposure reduced the spread of senescence, the cytokine storm and overall mortality. These results suggests that SnCs, acting at least in part through SASP factors, can increase peripheral senescence and immune dysfunction following pathogen exposure. Moreover, viral infection itself drives senescence, termed virus induced senescence, in mice and humans. Using mouse models in which cellular senescence is induced specifically in immune cells, we also demonstrated that senescent immune cells drive immunological dysfunction and secondary senescence and pathology in non-lymphoid tissues. Thus, our overarching hypothesis is that senescent cells, including senescent immune cell types, dominantly compromise innate and adaptive immune cell homeostasis in both lymphoid and non-lymphoid organs and reactivity to pathogens. Importantly, we also hypothesize that these adverse effects can be reversed by SnC elimination with senolytics, providing a new therapeutic strategy to restoring immune function in the aged. We propose to test these hypotheses in our PPG application entitled “The role of senescent cells in dysregulating immune responses and pathogen control”, consisting of three collaborative projects and three integrated cores.
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