Subtle changes in the aging human brain, such as neuronal sprouting and restructuring, are thought to underlie cognitive decline and may promote neuronal dysfunction in Alzheimer's disease. We study fundamental processes relevant to neuronal function and neurodegeneration in the 959-celled nematode C. elegans. In this transparent roundworm, we can directly observe individual fluorescently labeled neurons, as well as synapses and mitochondria, in the living animal. Recently we carefully documented how some C. elegans neurons change as animals grow old. We find that like human brain aging, there is little neuron loss as C. elegans ages. However, some types of neurons exhibit dramatic novel branching and outgrowth with age. We can score new growth using a high magnification dissecting microscope, which facilitates relatively rapid analysis within live, aging animals. We propose to characterize morphological neuronal aging in C. elegans to establish a facile model for analysis of genetic and environmental factors that influence neuronal aging.
Aim 1 is to extend our initial cell-specific analysis to diverse neuronal classes to better define what neuronal types are susceptible to age-associated morphological changes. This tractable work will document the basic neurobiology of C. elegans aging, definitively establishing an overview of differential susceptibility of specific neurons to age-associated morphological change.
Aim 2 is to survey four mechanisms hypothesized to contribute to age-associated neuronal regrowth (neuronal function, synaptic function, disrupted proteostasis, and mitochondrial changes) to identify which contributes to morphological aging. In this aim we might also identify fluorescent synaptic and mitochondrial indicators of neuronal aging. These experiments may suggest the most potent factors in age-associated neuronal restructuring.
Aim 3 is to test whether dietary restriction, a conserved mechanism for lifespan extension that has been found to improve human neuronal aging, can protect against neuronal morphological aging phenotypes. We will also test DR-mimetic drugs for efficacy in the nematode model. This work may identify a conserved mechanism for neuroprotection and establish proof-of-principle for the suitability of this new model to be used in for anti-neuronal aging drug discovery. Our work will define the first model for high throughput genetic and drug studies of age-associated neuronal morphological abnormalities that may inform on mechanisms and interventions that can better maintain the aging human nervous system.
Neuronal aging in the human brain, a major risk factor for Alzheimer's disease also proposed to influence cognitive decline in healthy aging, is associated with synaptic changes and aberrant sprouting. Recently, we discovered that some neurons in aging C. elegans exhibit aberrant branching and outgrowth and we have documented a global decline of synaptic structure with age, suggesting that fundamental neuronal aging mechanisms may be conserved from simple animals to humans. We plan to develop the C. elegans model of neuronal aging to describe susceptible neurons and identify process that can promote or protect against neuronal decline. Documentation of this model should lead to advanced mechanistic understanding that might ultimately suggest novel and efficacious therapies to combat human brain aging.
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