Regulation of disease tolerance defenses by the aging process - PROJECT SUMMARY/ABSTRACT Advancing age is characterized by declines in physiological function that increase susceptibility to infectious diseases, such as influenza. Organisms have evolved two defense strategies to survive infection: resistance and disease tolerance. Resistance mechanisms reduce pathogen burdens, largely via immune- mediated mechanisms. Disease tolerance mechanisms instead protect against the physiological damage (i.e., disease course) that occurs during infection, without reducing pathogen burdens. Immune function and resistance to infection are impaired in older adults. However, if and how disease courses and consequent disease tolerance mechanisms are changed with aging is not well understood. The overall purpose of this F32 fellowship project is to determine if disease courses and health trajectories are altered with aging during influenza infection and determine how expression signatures that correlate with survival and death change with age (Aim 1), and to investigate the role of the nuclear receptor Rev-erbα for promoting disease tolerance to influenza infection with aging (Aims 2 & 3). A murine influenza infection model will be used to induce divergent health and disease courses (surviving vs. dying) in organisms across the lifespan. A detailed characterization of age-related changes in disease courses and survival courses will be performed (Aim 1.1), and the transcriptional signatures in vital organs that correlate with survival and death during influenza infection across the lifespan will be identified (Aim 1.2). In pilot experiments, the transcription factor Rev-erbα was induced in multiple organs of aged mice that survived influenza infection, whereas it was down-regulated in dying mice. The cellular origins and gene targets of Rev- erbα during influenza infection will be determined in mice across the lifespan using single-nucleus sequencing and chromatin immunoprecipitation sequencing (Aim 2). Finally, the role of Rev-erbα in host defense during influenza infection with aging will be directly investigated using complementary genetic and pharmacological approaches (Aim 3). Current aging research primarily aims to eliminate harmful factors, rather than enhancing the body’s ability to function in their presence. The proposed research will address important NIA Strategic Directions for research. It will provide insight into the dynamics of the aging process by investigating the impact of aging on the progression and amelioration of disease. Further, identifying novel disease tolerance mechanisms in aged organisms could lead to the development of novel approaches for improving the health and well-being of adults as they age.
