Research Project
10303445
PROJECT SUMMARY Influenza (flu) is foremost among all infectious diseases causing death and disability in older adults, despite widespread vaccination programs. Age-related changes in the immune system contribute to declines in the ability to mount a highly protective immune response following flu infection in both humans and mouse models. With advancing age, we observe slower viral clearance and lingering lung inflammation, which could set the stage for secondary bacterial infection. Importantly, aging impacts almost every aspect of the adaptive immune response including generation of virus-specific CD4 and CD8 T cell effectors and high affinity antibody production. While flu infection is entirely localized to the lungs, functional decrements in skeletal muscle are also observed with upregulation of inflammatory and atrophy genes and downregulation of positive muscle regulators, ultimately resulting in loss of physical function. Importantly, the impact of flu infection on these molecular changes and overall functional declines is more pronounced and prolonged with aging, suggesting decreased physiologic resilience. Even though much research has been done, the ultimate cause of these age-related decrements has not been elucidated. One of the most prominent features of aging is the accumulation of senescent cells and in this project we will explore their role in the age-related changes in response to flu infection. Cellular senescence is characterized by irreversible growth arrest that occurs when cells experience a range of stresses. The number of senescent cells increases with chronological aging, resulting in many age-related pathologies and disease. Factors secreted by senescent cells can also have a direct impact on surrounding cells driving dysfunction and influencing cell subset differentiation. Interestingly, many of these factors are cytokines that are of vital importance for an effective anti-viral immune response. Senescent cells play a causal role in the progression of many age-related disorders, indicating that clearance of senescent cells might slow down the entire aging process. Importantly, we and others have started to develop drugs, which can specifically kill senescent cells (termed senolytics). Intermittent administration of senolytics can alleviate a range of age-related diseases. However, the impact of senolytics on immune system function in aged population has not yet been examined. The overall hypothesis that we will be addressing in this proposal is that senescent cells play a causal role in the age-related impaired response to flu infection. We will test this hypothesis by eliminating senescent cells in aged mice using senolytic drugs. This approach will allow us to simultaneously examine the role of cellular senescence in the compromised immune response and the associated changes in skeletal muscle and declines in physical function during flu infection in an aged mouse model.
