dc.description.abstract
The question of how to decelerate aging will persist as long as humankind exists. Recently, healthy aging has come into focus. The mind should remain sharp in the same way as the body should stay agile. According to the World Health Organization, dementia will rise dramatically within the following decades, and the highest risk factor is aging. The problem is how to address this fundamental topic. Here, a tiny animal named Drosophila melanogaster is one solution. Due to its short lifespan, easy genetic access, and evolutionary conserved aging mechanisms between flies and humans, it serves as a suitable model organism.
In my studies, I used a classical pavlovian conditioning assay to draw connections between aging and cognitive decline. The flies were trained with an aversive olfactory approach. In the first part, I examined a potential anti-aging supplement, the natural-occurring flavonoid 4,4‘-Dimethoxychalcone. I found this substance prolonged the lifespan of treated animals and enhanced mobility yet did not improve memory performance. Spermidine, another anti-aging supplement, promotes longevity and also prevents age-induced memory decline. I discovered that a mild attenuation of the enzyme, which catalyzes the first step of the hypusination of the eukaryotic translation initiation factor 5A and needs Spermidine as a co-factor, already impaired the memory of young animals. Further, I examined some effects of autophagy. I could show that deficient macroautophagy, where an autophagosome engulfs cargo for degradation, provoked severe memory problems at a young age already, similar to aged animals.
Analogously, an early memory decay occurred in animals lacking the neuropeptide sNPF (in mammals: NPY), which levels also decreased in macroautophagy-deficient animals or at advanced ages. However, further experiments demonstrated that a boost of either macroautophagy or sNPF could not protect from age-induced memory impairment.
Other investigations revealed no memory benefit from a downregulated insulin-signaling pathway, which promotes longevity. Thus, a prolonged lifespan is not automatically accompanied by better cognitive abilities.
Moreover, I investigated synaptic aspects of aging. The amount of scaffold proteins at the presynaptic active zone, where neurotransmitters are released, is enhanced in challenging situations like aging or sleep deprivation, seemingly leading to an operating peak of the system, followed by memory deficits. A moderate increase of one active zone component, the ELKS family member Bruchpilot, could prevent the memory issues of chronically sleep-deprived flies. Additionally, my examinations on another active zone protein, Unc13, the synaptic vesicle release factor, revealed its essential role in memory formation in the mushroom body, the learning center of the fly brain.
Taken together, my thesis sheds light on the mosaic of healthy aging, potentially supporting future preventive or therapeutic strategies for high-quality aging.
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