DO-SRS imaging of diet regulated metabolic activities in Drosophila during aging processes (original) (raw)
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Disease Models & Mechanisms, 2014
Over the past decade, numerous reports have underscored the similarities between the metabolism of Drosophila and vertebrates, with the identification of evolutionarily conserved enzymes and analogous organs that regulate carbohydrate and lipid metabolism. It is now well established that the major metabolic, energy-sensing and endocrine signaling networks of vertebrate systems are also conserved in flies. Accordingly, studies in Drosophila are beginning to unravel how perturbed energy balance impinges on lifespan and on the ensuing diseases when energy homeostasis goes awry. Here, we highlight several emerging concepts that are at the nexus between obesity, nutrient sensing, metabolic homeostasis and aging. Specifically, we summarize the endocrine mechanisms that regulate carbohydrate and lipid metabolism, and provide an overview of the neuropeptides that regulate feeding behavior. We further describe the various efforts at modeling the effects of high-fat or -sugar diets in Drosoph...
Aging is associated with progressive declines in physiological integrity and functions alongside increases in vulnerability to develop a number of diseases. The brain regulates sensory and motor functions as well as endocrine functions, and age-associated changes in brain are likely prerequisite for the organismal aging. Lipid metabolism has been associated with brain aging, which could be easily intervened by diets and lifestyles. However, the underlying mechanism through which brain lipid metabolism is regulated by diet during aging is elusive. Using stimulated Raman scattering (SRS) imaging combined with deuterium water (D2O) labeling, we visualized that lipid metabolic activities were changed by diet manipulation in aging Drosophila brain. Furthermore, we illuminated that insulin/IGF-1 signaling (IIS) pathway mediates the transformation of brain lipid metabolic changes in both an aging-and a diet-dependent manner. The lipid droplets (LDs) in the brain gradually became inert in both activities of lipid synthesis and mobilization with aging. High sugar diets enhanced the metabolic activity through promoting lipogenesis while dietary restriction increased the metabolic activity in both lipogenesis and lipolysis in brain LDs. However, these effects were impaired in both chico 1/+ and dfoxo Drosophila mutants. We also observed that old chico 1/+ brains maintained high metabolic activities, whilst the aged dfoxo brains acted exactly the opposite. More interestingly, the sexual dimorphism in brain lipid metabolism was impaired under diet regulation in both chico 1/+ and dfoxo mutants. Locally reduced IIS activity in glial cells can mimic the systemic changes in systematic IIS mutants to maintain lipogenesis and lipolysis in aged brains, providing mechanistic insight into the anti-aging effects of IIS pathway. Our results highlight the manipulation of glia-specific IIS activity as a promising strategy in anti-aging treatments.
Optical Metabolic Imaging Uncovers Sex-and Diet-dependent Lipid Changes in Aging Drosophila Brain
Aging is associated with progressive declines in physiological integrity and functions alongside increases in vulnerability to develop a number of diseases. The brain regulates sensory and motor functions as well as endocrine functions, and age-associated changes in brain are likely prerequisite for the organismal aging. Lipid metabolism has been associated with brain aging, which could be easily intervened by diets and lifestyles. However, the underlying mechanism through which brain lipid metabolism is regulated by diet during aging is elusive. Using stimulated Raman scattering (SRS) imaging combined with deuterium water (D2O) labeling, we visualized that lipid metabolic activities were changed by diet manipulation in aging Drosophila brain. Furthermore, we illuminated that insulin/IGF-1 signaling (IIS) pathway mediates the transformation of brain lipid metabolic changes in both an aging-and a diet-dependent manner. The lipid droplets (LDs) in the brain gradually became inert in both activities of lipid synthesis and mobilization with aging. High sugar diets enhanced the metabolic activity through promoting lipogenesis while dietary restriction increased the metabolic activity in both lipogenesis and lipolysis in brain LDs. However, these effects were impaired in both chico 1/+ and dfoxo Drosophila mutants. We also observed that old chico 1/+ brains maintained high metabolic activities, whilst the aged dfoxo brains acted exactly the opposite. More interestingly, the sexual dimorphism in brain lipid metabolism was impaired under diet regulation in both chico 1/+ and dfoxo mutants. Locally reduced IIS activity in glial cells can mimic the systemic changes in systematic IIS mutants to maintain lipogenesis and lipolysis in aged brains, providing mechanistic insight into the anti-aging effects of IIS pathway. Our results highlight the manipulation of glia-specific IIS activity as a promising strategy in anti-aging treatments.
DO-SRS imaging of metabolic dynamics in aging Drosophila
Emerging studies have shown that lipid metabolism plays an important role in aging. High resolution in situ imaging of lipid metabolic dynamics inside cells and tissues affords a novel and potent approach for understanding many biological processes such as aging. Here we established a new optical imaging platform that combines D 2 O-probed stimulated Raman scattering (DO-SRS) imaging microscopy and a Drosophila model to directly visualize metabolic activities in situ during aging. The sub-cellular spatial distribution of de novo lipogenesis in the fat body was quantitatively imaged and examined. We discovered a dramatic decrease in lipid turnover in 35-day-old flies. Decreases in protein turnover occurred earlier than lipids (25-day vs. 35-day), and there are many proteins localized on the cell and lipid droplet membrane. This suggests that protein metabolism may act as a prerequisite for lipid metabolism during aging. This alteration of maintenance of protein turnover indicates disrupted lipid metabolism. We further found a significantly higher lipid turnover rate in large LDs, indicating more active metabolism in large LDs, suggesting that large and small LDs play different roles in metabolism to maintain cellular homeostasis. This is the first study that directly visualizes spatiotemporal alterations of lipid (and protein) metabolism in Drosophila during the aging process. Our study not only demonstrates a new imaging platform for studying lipid metabolism, but also unravels the important interconnections between lipid metabolism and aging. † Electronic supplementary information (ESI) available. See
Genes & Nutrition, 2019
Aging is a complex phenomenon caused by the time-dependent loss of cellular homeodynamics and consequently of physiological organismal functions. This process is affected by both genetic and environmental (e.g., diet) factors, as well as by their constant interaction. Consistently, deregulation of nutrient sensing and signaling pathways is considered a hallmark of aging. Nutrigenomics is an emerging scientific discipline that studies changes induced by diet on the genome and thus it considers the intersection of three topics, namely health, diet, and genomics. Model organisms, such as the fruit fly Drosophila melanogaster, have been successfully used for in vivo modeling of higher metazoans aging and for nutrigenomic studies. Drosophila is a well-studied organism with sophisticated genetics and a fully annotated sequenced genome, in which~75% of human disease-related genes have functional orthologs. Also, flies have organs/tissues that perform the equivalent functions of most mammalian organs, while discrete clusters of cells maintain insect carbohydrate homeostasis in a way similar to pancreatic cells. Herein, we discuss the mechanistic connections between nutrition and aging in Drosophila, and how this model organism can be used to study the effect of different diets (including natural products and/or their derivatives) on higher metazoans longevity.
Journal of Proteome Research, 2014
Dietary restriction (DR) is one of the most universal means of extending lifespan. Yet, whether and how DR specifically affects the metabolic changes associated with aging is essentially unknown. Here, we present a comprehensive and unbiased picture of the metabolic variations that take place with age at the whole organism level in Caenorhabditis elegans by using 1 H high-resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) analysis of intact worms. We investigate metabolic variations potentially important for lifespan regulation by comparing the metabolic fingerprint of two previously described genetic models of DR, the long-lived eat-2(ad465) and slcf-1(tm2258) worms, as single mutants or in combination with a genetic suppressor of their lifespan phenotype. Our analysis shows that significant changes in metabolite profiles precede the major physiological decline that accompanies aging and that DR protects from some of those metabolic changes. More specifically, low phosphocholine (PCho) correlates with high life expectancy. A mutation in the tumor suppressor gene PTEN/DAF-18, which suppresses the beneficial effects of DR in both C. elegans and mammals, increases both PCho level and choline kinase expression. Furthermore, we show that choline kinase function in the intestine can regulate lifespan. This study highlights the relevance of NMR metabolomic approaches for identifying potential biomarkers of aging.
Aging cell, 2014
Target of rapamycin (TOR) signaling is a nutrient-sensing pathway controlling metabolism and lifespan. Although TOR signaling can be activated by a metabolite of diacylglycerol (DAG), phosphatidic acid (PA), the precise genetic mechanism through which DAG metabolism influences lifespan remains unknown. DAG is metabolized to either PA via the action of DAG kinase or 2-arachidonoyl-sn-glycerol by diacylglycerol lipase (DAGL). Here, we report that in Drosophila and Caenorhabditis elegans, overexpression of diacylglycerol lipase (DAGL/inaE/dagl-1) or knockdown of diacylglycerol kinase (DGK/rdgA/dgk-5) extends lifespan and enhances response to oxidative stress. Phosphorylated S6 kinase (p-S6K) levels are reduced following these manipulations, implying the involvement of TOR signaling. Conversely, DAGL/inaE/dagl-1 mutants exhibit shortened lifespan, reduced tolerance to oxidative stress, and elevated levels of p-S6K. Additional results from genetic interaction studies are consistent with ...
Direct Imaging of Lipid Metabolic Changes in Drosophila Ovary During Aging Using DO-SRS Microscopy
Emerging studies have shown that lipids and proteins play versatile roles in various aspects of aging. High-resolution in situ optical imaging provides a powerful approach to study the metabolic dynamics of lipids and proteins during aging. Here, we integrated D 2 O probing and stimulated Raman scattering (DO-SRS) microscopy to directly visualize metabolic changes in aging Drosophila ovary. The subcellular spatial distribution of de novo protein synthesis and lipogenesis in ovary was quantitatively imaged and examined. Our Raman spectra showed that early stages follicles were protein-enriched whereas mature eggs were lipid-enriched. DO-SRS imaging showed a higher protein synthesis in the earlier developing stages and an increased lipid turned over at the late stage. Aged (35 days) flies exhibited a dramatic decrease in metabolic turnover activities of both proteins and lipids, particularly, in the germ stem cell niche of germarium. We found an accumulation of unsaturated lipids in the nurse cells and oocytes in old flies, suggesting that unsaturated lipids may play an important role in the processes of oocyte maturation. We further detected changes in mitochondrial morphology and accumulation of Cytochrome c during aging. To our knowledge, this is the first study that directly visualizes spatiotemporal changes in lipid and protein metabolism in Drosophila ovary during development and aging processes. Our study not only demonstrates the application of a new imaging platform in visualizing metabolic dynamics of lipids and proteins in situ but also unravels how the metabolic activity and lipid distribution change in Drosophila ovary during aging.
Dietary composition specifies consumption, obesity, and lifespan in Drosophila melanogaster
Aging Cell, 2008
The inability to properly balance energy intake and expenditure with nutrient supply forms the basis for some of today's most pressing health issues including diabetes and obesity. Mechanisms of nutrient homeostasis may also lie at the root of dietary restriction, a manipulation whereby reduced nutrient availability extends lifespan and ameliorates age-related deteriorations in many species. The traditional belief that the most important aspect of the diet is its energetic (i.e., caloric) content is currently under scrutiny, and hypotheses that focus on more subtle characteristics revolving around composition are beginning to emerge. Using Drosophila melanogaster, we asked whether diet composition alone, independent of its caloric content, was sufficient to impact behavior, physiology, and lifespan. We found that providing flies with a yeast-rich diet produced lean, reproductively-competent animals with reduced feeding rates. Excess dietary sugar, on the other hand, promoted obesity, which was magnified during aging. Addition of dietary yeast often limited or reversed the phenotypic changes associated with increased dietary sugar and vice versa, and dietary imbalance was associated with reduced lifespan. Our data reveal that diet composition, alone and in combination with overall caloric intake, modulates lifespan, consumption, and fat deposition in flies, and they provide a useful foundation for dissecting the underlying genetic mechanisms that link specific nutrients with important aspects of general health and longevity.