Cellular and molecular mechanisms of motor aging in Drosophila

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A prerequisite toward developing future strategies for healthy aging in the light of globally increasing human life expectancy is to understand the biology of normal aging. Although numerous reports have identified molecular causes and neural correlates of functional brain decline with aging, both in humans and in invertebrate model systems, precise mapping of the molecular and neural causes of age-related performance defects into the brain remains a challenge in the field. We utilize experimental advantages of the Drosophila model system to identify molecular players and neural substrates that underlie age related decline of motor performance. First, we have started mapping the aging related loss of a specific motor behavior, the visually induced escape response, into the nervous system. When a fly detects an approaching threat in its visual field, it responds with escape jumping followed by flight. The underlying neural circuit is known and all component neurons are genetically and physiologically accessible. We have found that this behavior is lost during late life due to differential circuit vulnerability. Neither photoreceptor function and synaptic transmission to first order visual interneurons, nor motoneurons and information transmission to muscles are affected by aging, but we have mapped the cause of age-related behavioral loss to few identified brain interneurons and synapses. The first aim of this project is to precisely pinpoint the neural causes of functional circuit decline during normal aging. The second aim is to identify molecular causes of brain aging. We have identified climbing speed as a biomarker that predicts long versus short life expectancy already in healthy, mid aged flies. Based on this we have conducted transcriptomics to identify molecular causes of brain aging. We will now validate expressional changes of selected top candidate factors and map these globally into the brain and specifically onto the escape circuit. In the third aim, we will then manipulate these factors. Global manipulation in all neurons will be tested for potential positive effects on lifespan and on late life quality. Targeted manipulation in specific neurons of the escape circuit will be tested for the potential to postpone or ameliorate late-life motor performance deficits. Due to a high degree of conservation of basic molecular and cell biological principles in most animals we expect novel insights into the molecular and cellular mechanisms that underlie normal brain aging.