7. PROJECT SUMMARY/ABSTRACT Advanced maternal age decreases offspring lifespan and health in a range of species, including humans, but the mechanism controlling these “maternal age effects” are unknown. Mitochondria are maternally inherited and are prone to high levels of damage with aging, suggesting they may play a role in maternal age effects on offspring health and aging. Mitochondrial dysfunction may have an especially large impact on nervous system function, since nerve cells have high oxygen and energy demand, high mitochondrial content, and limited re- pair capacity. Human epidemiological studies and our preliminary data suggest that old-mother offspring are prone to earlier neurodegeneration than are young-mother offspring. Though studied in the context of female fertility and in vitro fertilization, the role of mitochondrial dynamics and function in maternal age effects on long- term offspring health, nervous system function, and lifespan are not known. The central hypothesis is that advanced maternal age causes accumulation of dysfunctional mitochondria in offspring through compensatory biogenesis and decreased autophagy during development. This disrupts mitochondrial-nuclear communication and mitochondrial efficiency, leading to cellular damage that accelerates offspring aging and nervous system dysfunction. The goal of the proposed research is to reveal the mitochondrial dynamics, function, and signal- ing changes that cause decreased health and lifespan in old-mother offspring. In this project we will identify the mechanisms leading to accumulation of high mtDNA copy number and damaged mitochondria in old-mother offspring using transcriptomics, pharmaceutical and RNAi testing of mechanism, and imaging approaches (Aim 1); determine the effect of maternal age on offspring mitochondrial efficiency using biochemical methods, respirometry, and imaging, and assess changes in mitochondrial retrograde signaling to the nucleus using RNA-Seq (Aim 2); and quantify the effect of maternal age on the levels and rates of accumulation of cellular damage in offspring, and characterize the effect of cellular damage on offspring nervous system function using biochemical, imaging, and functional assays (Aim 3). In keeping with the NIA's goal of increasing the diversity of model systems available to investigate questions of human health, this project will advance the development of the invertebrate monogonont rotifer, Brachinonus manjavacas, as a modern model system. Rotifers provide many advantages as models in aging research, including a century of aging-related and maternal effects re- search; a three-week lifespan enabling high replication and rapid experimentation; asexual (clonal) and sexual propagation; conservation of human homologs not present in established invertebrate model systems, and ge- netic resources including draft genomes, transcriptomes, and RNAi. This research will reveal fundamental mechanisms of aging and allow identification of ...