Lactate dehydrogenase expression modulates longevity and neurodegeneration in Drosophila melanogaster

Dani M. Long, Ariel Frame, Patrick N. Reardon, Robert C. Cumming, David A. Hendrix, Doris Kretzschmar, Jadwiga M. Giebultowicz

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)10041-10058
Number of pages18
JournalAging
Volume12
Issue number11
DOIs
StatePublished - Jun 15 2020

Keywords

  • Aging
  • Circadian rhythms
  • Lactate dehydrogenase
  • Neurodegeneration
  • lactate
  • lifespan

ASJC Scopus subject areas

  • Aging
  • Cell Biology

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