Abstract
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 Ldh 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 Ldh gene expression, we genetically manipulated Ldh levels in adult neurons or glia. Overexpression of Ldh in both cell types caused a significant reduction in lifespan whereas Ldh down-regulation resulted in lifespan extension. Moreover, pan-neuronal overexpression of Ldh disrupted circadian locomotor activity rhythms and significantly increased brain neurodegeneration. In contrast, reduction of Ldh in neurons delayed age-dependent neurodegeneration. Thus, our unbiased genetic approach identified Ldh and lactate as potential modulators of aging and longevity in flies.
Highlights
Aging is associated with changes in various molecular and cellular processes that lead to physiological decline and a concomitant increased risk for developing diseases, such as cancer, inflammation, and diabetes [1]
Aging is associated with increased Ldh expression and elevated lactate levels To determine the effect of age and time of day on Ldh mRNA expression, young (5-days old) and old (55-days old) white1118 (w1118) males reared in cycles of 12 hours of light and 12 hours of darkness (LD 12:12) were collected every six hours at Zeitgeber time (ZT) 0, 6, 12, and 18
Ldh mRNA levels in the heads of old flies showed a diurnal rhythm with a peak at ZT12 (Figure 1A), in agreement with rhythmicity measured by RNA-seq [10]
Summary
Aging is associated with changes in various molecular and cellular processes that lead to physiological decline and a concomitant increased risk for developing diseases, such as cancer, inflammation, and diabetes [1]. Brain aging is associated with increased mitochondrial dysfunction and dysregulated energy metabolism, which may cause decline in neuronal function leading to neurodegeneration [2, 3]. The causes of age-related brain deterioration have been addressed using a variety of approaches including comparative analysis of gene expression in the brains of young and old organisms. These studies revealed shifts in transcriptional profiles that may underlie age-related alterations in brain function. Similar groups of genes are affected by age in multiple model organisms including Drosophila due to the conservation of molecular pathways associated with aging [5]. We sought to determine whether elevated Ldh expression affects aging phenotypes and longevity in flies
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