Lactate dehydrogenase expression modulates longevity and neurodegeneration in Drosophila melanogaster

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.

Daytime Dependence of the Activity of the Rat Brain Pyruvate Dehydrogenase Corresponds to the Mitochondrial Sirtuin 3 Level and Acetylation of Brain Proteins, All Regulated by Thiamine Administration Decreasing Phosphorylation of PDHA Ser293

“…Moreover, the central position of PDHC in the energy metabolism known to oscillate during the day [ 10 , 12 ], suggests dysregulation of this complex to contribute to multiple pathological states linked to perturbation of circadian rhythms [ 17 , 18 ]. In particular, diminished flux through PDHC may be responsible for the decreased longevity upon overexpression of lactate dehydrogenase (LDH) in adult neurons and glia [ 19 ]. Remarkably, pan-neuronal LDH overexpression disrupts circadian rhythms in locomotion and accelerates neurodegeneration, while the LDH downregulation has opposite effects [ 19 ].…”

“…In particular, diminished flux through PDHC may be responsible for the decreased longevity upon overexpression of lactate dehydrogenase (LDH) in adult neurons and glia [ 19 ]. Remarkably, pan-neuronal LDH overexpression disrupts circadian rhythms in locomotion and accelerates neurodegeneration, while the LDH downregulation has opposite effects [ 19 ].…”

Metabolic switch in the aging astrocyte supported via integrative approach comprising network and transcriptome analyses

“…Ldh upregulation occurs during Drosophila melanogaster aging, where loss-of-function in either neurons or astrocytes leads to an increase in lifespan, while gain-of-function reduces lifespan (Long et al . 2020).…”

“…2020). Ldh overexpression also leads to increased neurodegeneration and motor function decline, while ldh downregulation is neuroprotective (Long et al . 2020).…”

Microglial metabolic flexibility: emerging roles for lactate

“…In aging Drosophila, LDH expression/activity and lactate levels were recently shown to be increased, and were associated with increased conversion of pyruvate into lactate. Moreover, overexpression of LDH in all adult glial cells decreased Drosophila lifespan, whereas LDH inhibition was effective in promoting longevity [97]. In addition, several studies report an age-related increase in CNS lactate levels [98,99].…”