Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing

Nutrient sensing and signaling play pivotal roles in animal growth. However, under dietary stress, this system falters, leading to growth defects. While immune cells are increasingly recognized as key nutrient sensors, their impact on animal growth remains poorly understood. In this study, we investigate how Drosophila larval macrophages respond to excessive dietary sugar and identify a reconfiguration of their metabolic state. They undergo a glycolytic shift, intensify TCA activity, and elevate TAG synthesis. While typical of sugar-induced nutrient stress, these changes interestingly exert contrasting effects on animal growth: glycolysis and increased TCA activity inhibit growth, while the lipogenic shift promotes it. However, the lipogenic response is insufficient to counteract the metabolic events suppressing growth, resulting in an overall reduction in adult fly size under high sugar conditions. Stimulating a pro-lipogenic immune state facilitates growth recovery, suggesting a growth paradigm governed by immune-metabolic transitions. This study unveils the unexpected influence of macrophage metabolic reprogramming on organismal growth homeostasis during Drosophila development, highlighting immune cell states as central determinants of growth, particularly under dietary stress.

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Systemic extracellular acidification is a hallmark of aging

dos Santos,

Xie,

Cao

et al. 2024

Preprint

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Understanding the critical pathophysiological processes that promote age-related disease is needed to uncover effective targets for preventive medicine. Here, we investigate how extracellular pH changes with age and its impact on longevity, using fly and mouse models. We find that extracellular acidification occurs in flies during aging and correlates to mortality rate. With age, flies also become more susceptible to die from acidotic stress, which can be prevented by alkalotic treatment. Acidification is caused by insufficient acid elimination, linked to downregulation of genes in the fly excretory tract that control pH and ATP production, essential for active secretion initiation. In mice, we show that lymph-drained interstitial fluids acidify with age. Expression of genes, whose pathogenic loss-of-function variants cause tubular acidosis in humans, is decreased in the kidneys of aging mice. Overall, this study sheds light on dysregulated systemic acid-base balance as a conserved pathophysiological mechanism of aging.

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Functional-metabolic coupling in distinct renal cell types coordinates organ-wide physiology and delays premature ageing

Cited by 5 publications

References 93 publications

Renal L-2-hydroxyglutarate dehydrogenase activity promotes hypoxia tolerance and mitochondrial metabolism in Drosophila melanogaster

Renal L-2-hydroxyglutarate dehydrogenase activity promotes hypoxia tolerance and mitochondrial metabolism in Drosophila melanogaster

Dietary stress induced macrophage metabolic reprogramming, a determinant of animal growth

Systemic extracellular acidification is a hallmark of aging

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