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.

The consolidation of newly formed memories and their retrieval are energetically demanding processes. Aerobic glycolysis (AG), also known as the Warburg effect, consists of the production of lactate from glucose in the presence of oxygen. The astrocyte neuron lactate shuttle hypothesis posits that astrocytes process glucose by AG to generate lactate, which is used as a fuel source within neurons to maintain synaptic activity. Studies in mice have demonstrated that lactate transport between astrocytes and neurons is required for long-term memory formation, yet the role of lactate production in memory acquisition and retrieval has not previously been explored. Here, we examined the effect of dichloroacetate (DCA), a chemical inhibitor of lactate production, on spatial learning and memory in mice using the Morris water maze (MWM). In vivo hyperpolarized 13 C-pyruvate magnetic resonance spectroscopy revealed decreased conversion of pyruvate to lactate in the mouse brain following DCA administration, concomitant with a reduction in the phosphorylation of pyruvate dehydrogenase. DCA exposure before each training session in the MWM impaired learning, which subsequently resulted in impaired memory during the probe trial. In contrast, mice that underwent training without DCA exposure, but received a single DCA injection before the probe trial exhibited normal memory. Our findings indicate that AG plays a key role during memory acquisition but is less important for the retrieval of established memories. Thus, the activation of AG may be important for learning-dependent synaptic plasticity rather than the activation of signaling cascades required for memory retrieval.

The field of behavioral genetics has recently begun to explore the effect of age on social behaviors. Such studies are particularly important, as certain neuropsychiatric disorders with abnormal social interactions, like autism and schizophrenia, have been linked to older parents. Appropriate social interaction can also have a positive impact on longevity, and is associated with successful aging in humans. Currently, there are few genetic models for understanding the effect of aging on social behavior and its potential transgenerational inheritance. The fly is emerging as a powerful model for identifying the basic molecular mechanisms underlying neurological and neuropsychiatric disorders. In this review, we discuss these recent advancements, with a focus on how studies in Drosophila melanogaster have provided insight into the effect of aging on aspects of social behavior, including across generations.

Background Although lactate has traditionally been considered a waste product, recent discoveries show lactate plays many beneficial roles in the brain. Astrocyte generated lactate can function as a fuel for neurons to enable long‐term memory. However, elevated lactate has been detected within the brain and cerebrospinal fluid of Alzheimer’s disease patients; a finding associated with hastened memory impairment. Whether perturbed lactate levels contribute to age‐related memory impairment is unknown. This study uses the fruit fly Drosophila melanogaster to elucidate the role of lactate metabolism in cognition during aging. Method The enzyme lactate dehydrogenase (dLdh), which facilitates the interconversion between lactate and pyruvate, was genetically manipulated in glia and neurons of Drosophila melanogaster. Transgenic flies were tested for changes in lifespan, memory, climbing ability, neurodegeneration as well as dLdh and lactate levels in the brain. Tests in transgenic flies were performed at ages ranging from young (7 days) to old (28 days). Memory was assessed using the courtship conditioning paradigm, of which only male flies can be tested. Results Lactate and dLdh protein levels were correspondingly elevated or lowered in transgenic flies with increased or decreased dLdh expression respectively. Transgenic flies with either increased or decreased dLdh expression exhibited reduction in lifespan and neurodegeneration at old age. These detrimental effects were present whether dLdh expression was altered in either neurons or glia, yet only neuronal dLdh upregulation caused deficits in climbing ability. Young transgenic flies with altered dLdh expression in either neurons or glia all exhibited memory similar to control. Interestingly, only flies with increased glial‐derived dLdh expression had an impact; memory was impaired at middle age then recovered at old age. Conclusion Prolonged perturbation of lactate metabolism results in neurodegeneration and increased rate of health decline in flies. The impact of altered lactate levels on memory appears to be cell type specific and dynamic. Excess glial‐derived lactate only appears detrimental to memory during middle age. However, excess or diminished production of lactate, within neurons or glia, hastens aging and neurodegeneration. Future studies of age‐related diseases, such as Alzheimer’s, should focus on lactate metabolism and metabolic interplay between neurons and glia.

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The astrocyte-neuron lactate shuttle hypothesis posits that glial-generated lactate is transported to neurons to fuel metabolic processes required for long-term memory. Although studies in vertebrates have revealed that lactate shuttling is important for cognitive function, it is uncertain if this form of metabolic coupling is conserved in invertebrates or is influenced by age. Lactate dehydrogenase (Ldh) is a rate limiting enzyme that interconverts lactate and pyruvate. Here we genetically manipulated expression of Drosophila melanogaster lactate dehydrogenase (dLdh) in neurons or glia to assess the impact of altered lactate metabolism on invertebrate aging and long-term courtship memory at different ages. We also assessed survival, negative geotaxis, brain neutral lipids (the core component of lipid droplets) and brain metabolites. Both upregulation and downregulation of dLdh in neurons resulted in decreased survival and memory impairment with age. Glial downregulation of dLdh expression caused age-related memory impairment without altering survival, while upregulated glial dLdh expression lowered survival without disrupting memory. Both neuronal and glial dLdh upregulation increased neutral lipid accumulation. We provide evidence that altered lactate metabolism with age affects the tricarboxylic acid (TCA) cycle, 2-hydroxyglutarate (2HG), and neutral lipid accumulation. Collectively, our findings indicate that the direct alteration of lactate metabolism in either glia or neurons affects memory and survival but only in an age-dependent manner.