Biology subjects

Piper, M. D.

Publications and source records attributed to Piper, M. D..

8 recordsLinked to original sources

bioRxiv2026

Genetic Variation in Organ System Decline Across the Drosophila Genetics Reference Panel

Genetic background has a significant impact on an organism's lifespan. Underlying this metric, ageing is characterised by a sequence of physiological systems decline that leads to death. Despite this, much of the ageing research performed on model organisms in the lab uses lifespan, rather than physiological decline, as a metric to measure ageing. Here, we sought to establish if differing genotype alters age-related organ system decline by repeatedly measuring the function of five organ systems throughout the lifespan of 19 lines from the Drosophila Genetic Reference Panel. We found that the magnitude of each organ system's decline differs across genotypes, and that different organ systems decline at different rates within a genotype. We also uncovered that while declines in activity rate and reproduction were associated with length of life, overall patterns of phenotypic organ system decline differed significantly across genotypes. Overall, these data suggest that individuals with different genetic backgrounds have distinct patterns of physiological decline, implying that the mechanisms driving ageing vary between individuals. These data underscore the importance of studying organ systems decline in addition to lifespan to gain a full understanding of ageing.

genetics↗

bioRxiv2026

A flexible diet platform for the nutrigenomic screening of Drosophila disease models

Nutrient-gene interactions shape metabolic disease phenotypes, but systematic testing is limited by the effort required to produce defined diets. We developed a flexible protocol that assembles precisely defined synthetic diets for Drosophila melanogaster from individual stock solutions. Using this approach, we generated a rational array of 51 single-nutrient-varied diets and demonstrated that flexible and standard preparation methods produce comparable developmental timing, survival, adult body weight, and starvation resistance in wildtype flies. Applying the dietary array to a Drosophila model of isolated sulfite oxidase deficiency, a severe condition caused by impaired sulfur amino acid catabolism, revealed nutrient-specific effects on pupal survival and pupariation timing, including rescue by cysteine depletion and other amino acid modified diets. This platform provides a scalable in vivo framework for mapping genotype-specific nutritional responses across Drosophila disease models. Key pointsO_LIDeveloped a flexible platform for assembling precisely defined synthetic diets in Drosophila. C_LIO_LIGenerated a rational 51-diet array, enabling scalable nutrigenomic screening. C_LIO_LIFlexible and standard diet preparations yielded matching developmental and adult fitness outcomes. C_LIO_LIDietary array screening in a sulfite oxidase deficiency model recapitulated cysteine sensitivity and identified novel nutrient modifiers. C_LI

genetics↗

bioRxiv2025

Dietary sterol depletion is associated with gut dysfunction in Drosophila melanogaster females

Recent findings have shown that dietary restriction (DR) may extend lifespan by improving late life gut health. Given that recent work has shown that micronutrients such as sterols can mediate the effects of macronutrient ratios on longevity, we decided to examine the effects of sterol limitation on gut health. We found that mothers fed low sterol diets both suffer from increased incidence of intestinal permeability and reduced lifespans. Moreover, epithelial cells in the anterior region of the guts of flies fed low sterol diets showed signs of dysfunction prematurely when compared to flies fed adequate sterols. These findings indicate that the relationship between gut dysfunction and death in D. melanogaster females is conditional on dietary sterol limitation and may point to different paths of physiological decline with ageing that depend on the precise nutritional composition of the diet.

evolutionary biology↗

bioRxiv2024

Valine restriction extends survival in a Drosophila model of short-chain enoyl-CoA hydratase 1 (ECHS1) deficiency

Short-chain enoyl-CoA hydratase 1 deficiency (ECHS1D) is a rare genetic disorder caused by biallelic pathogenic variants in the ECHS1 gene. ECHS1D is characterised by severe neurological and physical impairment that often leads to childhood mortality. Therapies such as protein and single nutrient-restricted diets show poor efficacy, whereas development of new treatments is hindered by the low prevalence of the disorder and a lack of model systems for treatment testing. Here we report on the establishment of a Drosophila model of ECHS1D. Flies carrying mutations in Echs1 (CG6543) were characterised for their physical and metabolic phenotypes, and dietary intervention to improve fly model health was explored. The Echs1 null larvae recapitulated human ECHS1D phenotypes including elevated biomarkers (S-(2-carboxypropyl)cysteamine and 2,3-dihydroxy-2-methylbutyric acid), poor motor behaviour and early mortality, and could be rescued by expression of a human ECHS1 transgene. We observed that both restriction of valine in isolation, or all branched-chain amino acids (BCAAs - leucine, isoleucine, and valine) together, extended larval survival, supporting the idea that reducing BCAA pathway catabolic flux is beneficial in this disorder. Further, metabolic profiling revealed substantial changes to carbohydrate metabolism, suggesting that Echs1 loss causes widespread metabolic dysregulation beyond valine metabolism. The similarities between Drosophila and human ECHS1D suggest that the fly model is a valuable animal system in which to explore mechanisms of pathogenesis and novel treatment options for this disorder.

genetics↗

bioRxiv2023

GCN2 mediates access to stored amino acids for somatic maintenance during Drosophila ageing

Many mechanistic theories of ageing argue that a progressive failure of somatic maintenance, the use of energy and resources to prevent and repair damage to the cell, underpins ageing. To sustain somatic maintenance an organism must acquire dozens of essential nutrients from the diet, including essential amino acids (EAAs), which are physiologically limiting for many animals. In Drosophila, adulthood deprivation of each individual EAA yields vastly different lifespan trajectories, and adulthood deprivation of one EAA, phenylalanine (Phe), has no associated lifespan cost; this is despite each EAA being strictly required for growth and reproduction. Moreover, survival under any EAA deprivation depends entirely on the conserved AA sensor GCN2, a component of the integrated stress response (ISR), suggesting that a novel ISR-mediated mechanism sustains lifelong somatic maintenance during EAA deprivation. Here we investigated this mechanism, finding that flies chronically deprived of dietary Phe continue to incorporate Phe into new proteins, and that challenging flies to increase the somatic requirement for Phe shortens lifespan under Phe deprivation. Further, we show that autophagy is required for full lifespan under Phe deprivation, and that activation of the ISR can partially rescue the shortened lifespan of GCN2-nulls under Phe deprivation. We therefore propose a mechanism by which GCN2, via the ISR, activates autophagy during EAA deprivation, breaking down a larvally-acquired store of EAAs to support somatic maintenance. These data refine our understanding of the strategies by which flies sustain lifelong somatic maintenance, which determines length of life in response to changes in the nutritional environment.

molecular biology↗

bioRxiv2023

A defined diet for pre-adult Drosophila melanogaster

Drosophila melanogaster is unique among animal models because it has a fully defined synthetic diet available to study nutrient-gene interactions. However, use of this diet is limited to adult studies due to impaired larval development and survival. Here, we provide an adjusted formula that improves larval growth, development rate, and rescues survival. We demonstrate its use for exploring pre-adult diet compositions of therapeutic potential in a model of an inherited metabolic disorder.

genetics↗

bioRxiv2021

Target of Rapamycin drives unequal responses to essential amino acid depletion in egg laying

Nutrition shapes a broad range of life history traits, ultimately impacting animal fitness. A key fitness-related trait, female fecundity is well known to change as a function of diet. In particular, the availability of dietary protein is one of the main drivers of egg production, and in the absence of essential amino acids egg laying declines. However, it is unclear whether all essential amino acids have the same impact on phenotypes like fecundity. Using a holidic diet, we fed adult female D. melanogaster diets that contain all necessary nutrients except one of the 10 essential amino acids and assessed the effects on egg production. For most essential amino acids, depleting a single amino acid induced as rapid a decline in egg production as when there were no amino acids in the diet. However, when either methionine or histidine were excluded from the diet, egg production declined more slowly. Next, we tested whether GCN2 and TOR were involved in this difference in response across amino acids. While mutations in GCN2 did not eliminate the differences in the rates of decline in egg laying among amino acid drop-out diets, we found that inhibiting TOR signalling caused egg laying to decline rapidly for all drop-out diets. TOR signalling does this by regulating the yolk-forming stages of egg chamber development. Our results suggest that amino acids differ in their ability to induce signalling via the TOR pathway. This is important because if phenotypes differ in sensitivity to individual amino acids, this generates the potential for mismatches between the output of a pathway and the animals true nutritional status.

developmental biology↗

bioRxiv2019

Restriction of essential amino acids dictates the systemic response to dietary protein dilution

Dietary protein dilution (DPD) promotes metabolic remodelling and health but the precise nutritional components driving this response remain elusive. Here we demonstrate that dietary amino acids (AA) are sufficient and necessary to drive the response to DPD. In particular, the restriction of dietary essential AA (EAA) supply, but not non-EAA, drives the systemic metabolic response to total AA deprivation. Furthermore, systemic deprivation of Thr and Trp, independent of total AA supply, are both adequate and necessary to confer the systemic metabolic response to both diet, and genetic AA-transport loss, driven AA restriction. Thr is also potentially limiting in low-protein diet fed humans, and dietary Thr restriction (DTR) retarded the development of obesity-associated metabolic dysfunction in mice. Liver-derived fibroblast growth factor 21 was required for the metabolic remodelling with DTR. Strikingly, hepatocyte-selective establishment of Thr biosynthetic capacity reversed the systemic response to DTR. Taken together, our studies demonstrate that the restriction of EAA are sufficient and necessary to confer the systemic metabolic effects of DPD.

physiology↗