Lactate dehydrogenase expression modulates longevity and neurodegeneration in .

Lactate dehydrogenase (LDH) catalyzes the conversion of glycolysis-derived pyruvate to lactate. Lactate has been shown to play key roles in brain energetics and memory formation. However, lactate levels are elevated in aging and Alzheimer's disease patients, and it is not clear whether lactate plays protective or detrimental roles in these contexts. Here we show that transcript levels are elevated and cycle with diurnal rhythm in the heads of aged flies and this is associated with increased LDH protein, enzyme activity, and lactate concentrations. To understand the biological significance of increased gene expression, we genetically manipulated levels in adult neurons or glia. Overexpression of in both cell types caused a significant reduction in lifespan whereas down-regulation resulted in lifespan extension. Moreover, pan-neuronal overexpression of disrupted circadian locomotor activity rhythms and significantly increased brain neurodegeneration. In contrast, reduction of in neurons delayed age-dependent neurodegeneration. Thus, our unbiased genetic approach identified and lactate as potential modulators of aging and longevity in flies.