Hierarchy and intersection of hallmarks of aging using genetic, pharmacologic, and dietary life span extending interventions in flies and mice.

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Project Summary/Abstract: (30 lines maximum) The overall goal of this proposal is to develop genetic, pharmacologic and dietary interventions that will delay the onset and progression of age-related diseases, preserving health and function until late in life. We will test the hypothesis that hallmarks of aging possess interconnectedness and hierarchical structure — some hallmarks are initiators in a cascade of events, and some hallmarks are downstream effectors. This knowledge will be utilized to develop rational therapeutic interventions to improve healthy longevity. Loss of genomic integrity and consequent loss of transcriptional silencing are initiator hallmarks that induce damage-associated molecular patterns (DAMPs) including retrotransposons (RTEs), that in turn activate innate immunity through mitochondrial mechanisms and metabolic rewiring. This cascade results in defective energy balance in central metabolism and the accumulation of and dysregulation of lipid droplets (LDs) that in turn are associated with a number of age- related ailments including obesity, diabetes, liver and neurodegenerative diseases. We postulate that accumulation of LDs ultimately comprises a critical downstream and proximal physiological insult leading to aging and age-related disease. We will directly test our hypothesis that there is an interconnectedness and hierarchy to the hallmarks of aging and that the accumulation of LDs is an essential proximal element in aging using genetic, pharmacologic and dietary interventions that selectively affect specific hallmarks of aging in the fly and mouse. The goal of these studies is to shed light on mechanisms of healthy aging and identify new and novel genetic, pharmacological and dietary interventions for translation into interventions that increase healthy human life span. We will use genetic and pharmacological life span extending interventions directed specifically at reversing initiator hallmarks of loss of genomic integrity and loss of transcriptional silencing (RTE activation) in flies to examine whether these lead to ameliorating the activation of downstream hallmarks such as activation of innate immunity and LD accumulation in aging in the fly and mouse. We will also test genetic, pharmacological and dietary interventions for their potential to reduce a downstream effector hallmark, LD accumulation in flies and mice, for their effects on LD formation, improvement in health span, and assess their ability to reverse upstream activator events such as RTE and innate immunity activation. We will test the hypotheses that these interventions act through improved downstream metabolism in the aging animals and: (1) extend life span in flies; (2) delay the onset and progression of age-related phenotypes in fly and mouse models (life span, motility (fly), frailty (mouse) and neurobehavioral tests (flies and mice) (3) reduce the accumulation of LDs (tissue staining; LipiTOX and Oil-Red) and (4) normalize or stabilize RTE activation and innate immunity (qPCR in flies and mice; reporter genes in flies; antibodies to immune cytokines and activators in mice).