Transition to Aging Research for Predoctoral Students (F99/K00 Clinical Trial Not Allowed)

Project Summary The ability of the organism to mount responses against stress sources declines with age. External threats such as pathogens activate the innate immune response and generate an inflammatory state. In addition, aberrant activation of proinflammatory conditions as organisms age is known as inflammaging. Inflammation is a hallmark of age-related diseases and increases mortality among the elderly. There is an urgent need to elucidate the molecular mechanisms that affect the across-tissue effects of innate immune activation with protein homeostasis to develop new strategies to improve healthspan. This proposal aims to determine the contribution of innate immune activation to the integration of stress responses to restore protein homeostasis and aging. In the F99 phase of the award, the researcher demonstrated the link between innate immune-ordered protein aggregation with the activation of proinflammatory and cell death programs. The proposed aims for the K00 phase will address: 1) the cross-tissue relationship of innate immune activation with proteostasis decay during aging, and 2) the impact of innate immune protein activation during developmental stages on stress resilience. To develop such goals, the researcher will employ the model organism C.elegans, which has a conserved innate immune response and is an excellent organism to study longevity and across tissue communications. First, using genetic reporters for proteostasis, the researcher will evaluate the effect of innate immune activation on proteostasis signaling in distal tissues and its impact on longevity. Second, optogenetic tools will enable interrogation at the spatiotemporal resolution of the activation of innate immune proteins. These experiments aim to demonstrate the sufficiency of innate immune activation in developing a resilient state that impacts protein homeostasis in the organism. Such tools will also allow dissecting the interplay of the intestine and nervous system in sensing and integrating stress responses to increasing fitness. Completing these aims will identify molecular substrates of stress response and reveal an unexplored role of ordered innate immune protein self-assemblies in regulating aging. The proposed work is innovative and brings emerging biophysical concepts to the aging and immune senescence fields.