The protective role of exercise against age-related neurodegeneration.

Endurance exercise is a widely accessible, low-cost intervention with a variety of benefits to multiple organ systems. Exercise improves multiple indices of physical performance and stimulates pronounced health benefits reducing a range of pathologies including metabolic, cardiovascular, and neurodegenerative disorders. Endurance exercise delays brain aging, preserves memory and cognition, and improves symptoms of neurodegenerative pathologies like Amyotrophic Lateral Sclerosis, Alzheimer's disease, Parkinson's disease, Huntington's disease, and various ataxias. Potential mechanisms underlying the beneficial effects of exercise include neuronal survival and plasticity, neurogenesis, epigenetic modifications, angiogenesis, autophagy, and the synthesis and release of neurotrophins and cytokines. In this review, we discuss shared benefits and molecular pathways driving the protective effects of endurance exercise on various neurodegenerative diseases in animal models and in humans.

Dietary composition regulates Drosophila mobility and cardiac physiology.

The impact of dietary composition on exercise capacity is a subject of intense study in both humans and model organisms. Interactions between diet and genetics are a crucial component of optimized dietary design. However, the genetic factors governing exercise response are still not well understood. The recent development of invertebrate models for endurance exercise is likely to facilitate study designs examining the conserved interactions between diet, exercise and genetics. As a first step, we used the Drosophila model to describe the effects of varying dietary composition on several physiological indices, including fatigue tolerance and climbing speed, cardiac performance, lipid storage and autophagy. We found that flies of two divergent genetic backgrounds optimize endurance and cardiac performance on relatively balanced low calorie diets. When flies are provided with unbalanced diets, diets higher in sugar than in yeast facilitate greater endurance at the expense of cardiac performance. Importantly, we found that dietary composition has a profound effect on various physiological indices, whereas total caloric intake per se has very little predictive value for performance. We also found that the effects of diet on endurance are completely reversible within 48 h if flies are switched to a different diet.

Drosophila models of cardiac disease.

The fruit fly Drosophila melanogaster has emerged as a useful model for cardiac diseases, both developmental abnormalities and adult functional impairment. Using the tools of both classical and molecular genetics, the study of the developing fly heart has been instrumental in identifying the major signaling events of cardiac field formation, cardiomyocyte specification, and the formation of the functioning heart tube. The larval stage of fly cardiac development has become an important model system for testing isolated preparations of living hearts for the effects of biological and pharmacological compounds on cardiac activity. Meanwhile, the recent development of effective techniques to study adult cardiac performance in the fly has opened new uses for the Drosophila model system. The fly system is now being used to study long-term alterations in adult performance caused by factors such as diet, exercise, and normal aging. The fly is a unique and valuable system for the study of such complex, long-term interactions, as it is the only invertebrate genetic model system with a working heart developmentally homologous to the vertebrate heart. Thus, the fly model combines the advantages of invertebrate genetics (such as large populations, facile molecular genetic techniques, and short lifespan) with physiological measurement techniques that allow meaningful comparisons with data from vertebrate model systems. As such, the fly model is well situated to make important contributions to the understanding of complicated interactions between environmental factors and genetics in the long-term regulation of cardiac performance.

Tissue-specific regulation of vein/EGF receptor signaling in Drosophila.

Signaling by the Drosophila EGF receptor (DER) is modulated by four known EGF-like proteins: the agonists Vein (Vn), Spitz (Spi), and Gurken (Grk) and the antagonist Argos (Aos). DER is broadly expressed and thus tissue-specific regulation of ligand expression and activity is an important mechanism for controlling signaling. Here we investigate the tissue-specific regulation of Vn signaling by examining vn transcriptional control and Vn target gene activation in the embryo and the wing. The results show a complex temporal and spatial regulation of vn transcription involving multiple signaling pathways and tissue-specific activation of Vn target genes. In the embryo, vn is a target of Spi/DER signaling mediated by the ETS transcription factor PointedP1 (PntP1). This establishes a positive feedback loop in addition to the negative feedback loop involving Aos. The simultaneous production of Vn provides a mechanism for dampening Aos inhibition and thus fine-tunes signaling. In the larval wing pouch, vn is not a target of Spi/DER signaling but is expressed along the anterior-posterior boundary in response to Hedgehog (Hh) signaling. Repression by Wingless (Wg) signaling further refines the vn expression pattern by causing a discontinuity at the dorsal-ventral boundary. The potential for vn to activate DER target genes correlates with its roles in development: vn has a minor role in embryogenesis and does not induce DER target genes such as aos and pntP1 in the embryo. Conversely, vn has a major role in wing development and Vn/DER signaling is a potent inducer of DER target genes in the wing disc. Spi also has the potential to induce DER target genes in the wing disc. However, the ligands appear to evoke specific responses that result in different patterns of target gene expression. Finally, we show that other factors modulate the potential of Vn so that induction of Vn/DER target genes in the wing pouch is cell specific.