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Nepakankama mityba iki nėštumo ir per nėštumą gali lemti palikuonio svorio pokyčius, vėlesnę brandą ar lėtines neinfekcines ligas suaugus. Darbo tikslas: Įvertinti mitybos iki nėštumo ir per nėštumą įtaką žiurkių palikuonių fizinei būklei. Uždaviniai: 1. Nustatyti ir palyginti žiurkių palikuonių svorio kitimo tendencijas tarp pirmos ir antros palikuonių kartų. 2. Įvertinti morfologinius pirmos ir antros kartos palikuonių išvaizdos ir elgsenos pokyčius. Tyrime naudotos 12 motininių žiurkių patelių ir 121 palikuonis. Žiurkių maitinimas vyko nustatytomis eksperimento sąlygomis: I eksperimentinės grupės (N=5) žiurkės buvo 50 proc. ribotos maisto 1 mėnesį iki nėštumo ir per visą nėštumo laikotarpį, II eksperimentinės grupės (N=5) žiurkės buvo ribotos 50 proc. maisto 1 mėnesį iki nėštumo, III eksperimentinė grupė (N=2) – kontrolinė, buvo maitinama ad libitum (apie 20 g/p). Vėliau visų grupių žiurkės šertos ad libitum. Palikuonys sverti kartą per savaitę, vertinta metabolinį stresą patyrusių ir nepatyrusių žiurkių palikuonių išvaizda, elgsena ir kiti metabolinio streso požymiai: domėjimasis aplinka, bailumas, agresyvumas, nervingumas. Rezultatai: 1. ▪ Suaugę pirmos kartos iki nėštumo ir per nėštumą maisto medžiagų ribojimą patyrusių žiurkių vyriškos lyties palikuonys sveria reikšmingai daugiau už kitas grupes; ▪ Suaugę antros kartos tik iki nėštumo maisto medžiagų ribojimą patyrusių žiurkių vyriškos lyties palikuonys sveria reikšmingai daugiau nei kitų grupių palikuonys... [toliau žr. visą tekstą] / Unsufficient diet before pregnancy or in time of pregnancy can lead to inadequate weight of offspring, delayed maturation as well as obesity and greater risk of noncommunicable diseases in adulthood. The main objective of this study was to explore if there is a change in rat offspring’s body weight that can be attributed to maternal nutrition. Materials and methods. The animals were housed under standard conditions in the vivarium of the Institute of Biochemistry. All animal procedures are in accordance with the The State Food and Veterinary Service. The cohort of 12 mature female Wistar rats was divided into 3 groups with respect to nutritional restriction. The rats were fed either a control (1 group) or restricted diet (2 groups): one experimental group was food-restricted prior to pregnancy and the other - one month prior and through the pregnancy period. Both food-restricted rat groups received 50 percent less of the feed eaten in the control group. After 1 month maternal rats were mated. After weaning all pups were fed with control diet ad libitum. Pups were weighted weekly with the same, calibrated scales. After 4 months female offspring were mated following a standard above mentioned procedure. 2nd offspring generation was kept and weighted under the same standardized conditions. We also observed and evaluated offspring appearance, behavior and other signs of metabolic stress: interest in the environment, fear, aggressiveness, nervousness. Results show that 1... [to full text]

Le vieillissement et les maladies associées constituent une préoccupation croissante des sociétés modernes. En effet, l'espérance de vie augmente rapidement et ceci n'est pas accompagné par une fécondité accrue. Par conséquent, la proportion de personnes âgées augmente et la science doit fournir des solutions pour traiter les maladies liées à l'âge. Dans ce travail, nous avons étudié une partie du réseau génétique qui a un impact sur la durée de vie par le biais du régime alimentaire. Nous nous sommes concentrés en particulier sur le rôle d'un gène conservé qui code pour la sphingosine kinase (SPHK), et nous décrivons ici pour la première fois son rôle dans la longévité induite par la restriction alimentaire. Cette thèse se compose de deux parties. Dans la première partie, C. elegans a été utilisé pour comprendre le rôle que la sphingosine kinase (sphk-1) joue dans le vieillissement. Nous rapportons que les vers porteur d'une mutation dans le gène sphk-1 vivent plus longtemps que des vers sauvages et ne répondent pas à une restriction alimentaire (RA) et ressemblent à des animaux sauvages soumis à RA. De plus, nos données suggèrent que la longévité causée par une mutation du gène sphk-1 nécessite la présence du facteur de transcription SKN-1b, connue pour son rôle dans la RA. De plus, sphk-1 et skn-1b sont tout deux exprimés dans les neurones de la tête. Nos travaux suggèrent également que la voie TOR/autophagie est impliquée dans la longévité de sphk-1 mutants. Nous avons également montré que d'autres gènes dans la voie de synthèse des céramides ont un effet similaire sur la longévité suggérant que cette voie toute entière est capable d’affecter la longévité.La deuxième partie de ce travail a été réalisée sur un modèle de souris de la maladie d’Alzheimer (MA) pour tester le rôle des gènes SPHK dans la MA et la dégénérescence neuronale. Nous avons constaté que le niveau d'expression de SPHK était significativement augmenté dans nos modèles de souris par rapport à leurs contrôles de la même portée dès l’âge de 6 mois. Un inhibiteur de la SPHK (SKI-II) a été administré à ces souris et ce traitement a permis une amélioration des performances des souris dans des tests de marche sur balancier et une augmentation du poids de cerveau, mais pas d'amélioration de la mémoire dépendante de l'hippocampe. Un autre traitement de SKI-II sur des souris de type sauvage n'a pas montré d’amélioration significative, mais la restriction calorique (RC) a réduit les niveaux de SPHK chez les souris sauvage, ce qui suggère que la sphingosine kinase a des fonctions conservées dans les voie de signalisation liés au sensing des nutriments. / Advances in medical technology and hygiene standards have increased human life expectancy at unprecedented rates worldwide. Nevertheless, one of the consequences of a growing elderly population is an increased prevalence of age-related disease. A scientific understanding of the underlying biological mechanisms of aging is essential to develop effective treatments for age-related diseases and to provide adequate health care to the elderly. In this study, we investigated part of the genetic network that mediates lifespan extension resulting from dietary restriction. We focused on the contribution of a conserved gene encoding the enzyme sphingosine kinase, and describe for the first time its role in diet-mediated longevity.This thesis is composed of two parts. In the first part, we used the nematode Caenorhabditis elegans as a model organism to investigate the role of the sphingosine kinase gene (sphk-1) in aging. We found that worms carrying a sphk-1 null mutation (sphk-1(ok1097)) are long-lived and do not benefit from further lifespan extension upon dietary restriction (DR), a regimen that extends the lives of wild-type worms. sphk-1(ok1097) animals exhibit many phenotypes displayed by animals subjected to DR, suggesting that sphk-1(ok1097) acts through the DR longevity pathway. In support of this, sphk-1(ok1097)-mediated lifespan extension requires the essential DR regulator, SKN-1b, and, similar to SKN-1b, sphk-1 is expressed in head neurons. A search for possible sphk-1(ok1097)-associated longevity determinants suggested the involvement of the TOR/autophagy pathway. Moreover, we found that mutations in ceramide pathway genes other than sphk-1 have similar effects on longevity. Finally, we discovered that sphk-1 mutants fail to reduce germ cell numbers in response to DR. Because such a reduction appears to be an essential feature of DR-mediated lifespan extension, we propose that this failure to reduce germ cell numbers may explain why sphk-1(ok1097) mutant longevity is not extended when nutrient levels are low.The second part of this study investigated the role of sphingosine kinase in brain function during normal and pathologic aging. We examined the expression of sphingosine kinase genes in wild-type mice and in a mouse model of Alzheimer’s disease (AD)-like neurodegeneration. Expression of both mouse SphK genes was increased in the brains of AD-like mice as early as 6 months of age. Chronic administration of an SphK inhibitor elevated the brain weight of AD-like mice and improved their performance in the beam walking test, but not in hippocampus-dependent memory tasks. Treatment of wild-type mice with SKI-II had little effect, but calorie restriction reduced the expression of SphK mRNA in the brain, suggesting that sphingosine kinase may play some conserved roles in nutrient sensing pathways. / 在工业化水平越来越高的当今社会，人口的老龄化正逐渐成为一个严重的社会问题。医疗手段的发展、生活水平的提高使得人们的寿命在不断增加，而与此同时生育率并没有同步增加，这就导致老年人口在整个社会人口中的比重快速增长，因此，衰老以及一些相关的疾病就得到了人们越来越多的关注，也正在成为一个越来越热门的科研领域。从科研工作者的角度，我们希望能够通过实验手段破解衰老及其相关疾病的机制从而寻找延缓衰老或治疗相关疾病的方法。在本论文中，我们研究了一个通过限制饮食来调控寿命的基因网络的一部分。我们的主要研究对象是编码鞘氨醇激酶的基因（SphK），我们第一次发现了它在饮食介导的寿命调控中的作用。本论文由两个章节组成。在第一章中，我们使用秀丽隐杆线虫作为模式动物来研究鞘氨醇激酶基因（sphk-1）在其衰老调控过程中的作用。在研究中，我们发现，携带一种sphk-1 删除突变（sphk-1(ok1097)）的突变体线虫的平均寿命显著延长，而饮食限制（DR）并不能进一步延长它的寿命。另外，这种突变体还表现出一系列与受饮食限制调控的动物相类似的表型，尽管并不是全部。这些结果都表明sphk-1 基因通过饮食介导的途径参与线虫的寿命调控。我们随后的研究显示，由sphk-1 突变引起的寿命延长依赖于DR 的一个调控因子：SKN-1b；并且，与skn-1b 类似，sphk-1 表达的位置也在线虫头部的神经元。对于其它DR 相关因子的研究还发现线虫sphk-1(ok1097)突变引起的寿命延长可能与TOR 及自噬通路的作用有关。此外，我们还发现，不仅是sphk-1，神经酰胺通路中的其它基因对于寿命调控也有类似的效果。最后，我们的研究结果显示，DR 未能减少sphk-1(ok1097)突变体线虫的生殖细胞数量，这一发现或许能够解释为什么DR不能够进一步延长sphk-1(ok1097)突变体线虫的寿命。在第二章中，我们使用了一种模拟阿尔茨海默症（AD）的小鼠模型来测试哺乳类SphK 基因在神经退行性病变中的作用。我们发现，在模型小鼠脑组织中，两种哺乳类SphK 基因的表达水平与它们的同窝对照相比显著增加，而这一显著差异早在6 月龄的小鼠脑中就能发现。在后续的实验中，我们给这些小鼠喂食了一种SphK 的抑制剂——SKI-II。这种抑制剂显著改善了模型小鼠在平衡木实验中的表现，并且显著增加了它们的脑重量，但对于海马依赖性的记忆并没有改善。在另一个实验中，给野生型小鼠注射SKI-II 并没有表现出明显的差异，但热量限制（CR）降低了野生小鼠脑中两种SphK基因的表达量，这一与线虫中类似的结果提示，鞘氨醇激酶在营养通路中可能有一些进化保守的功能。

ARAÚJO, Thiago Luís Alves Campos de. Características de carcaça e qualidade da carne de borregos Morada Nova de diferentes classes sexuais submetidos a restrições alimentares. 2016. 52 f. : Dissertação (Mestrado) - Universidade Federal do Ceará, Centro de Ciências, Departamento de Zootecnia, Programa de Pós-Graduação em Zootecnia. Fortaleza-CE, 2016. / Submitted by Eric Santiago (erichhcl@gmail.com) on 2016-08-03T13:27:36Z No. of bitstreams: 1 2016_dis_tlacaraujo.pdf: 1596910 bytes, checksum: b1de97e7ab9a7f5cf7b8b99c5a551071 (MD5) / Approved for entry into archive by Nádja Goes (nmoraissoares@gmail.com) on 2016-08-03T13:28:18Z (GMT) No. of bitstreams: 1 2016_dis_tlacaraujo.pdf: 1596910 bytes, checksum: b1de97e7ab9a7f5cf7b8b99c5a551071 (MD5) / Made available in DSpace on 2016-08-03T13:28:18Z (GMT). No. of bitstreams: 1 2016_dis_tlacaraujo.pdf: 1596910 bytes, checksum: b1de97e7ab9a7f5cf7b8b99c5a551071 (MD5) Previous issue date: 2016 / The present study has a goal of evaluating the sexual classes and feeding restriction levels on the quantitative and qualitative characteristics of Morada Nova’s lamb carcasses. Thirty-five animals with initial body weight of 14,5 ± 0,89 kg were used in a completely casualized experimental delineation, in a 3x3 factorial scheme, being three sexual classes (11 whole males, 12 castrated males and 12 females) and three levels of feeding restriction (0% or ad libitum, 30% e 60%). The dry matter intake and the average daily gain were higher in whole males (P<0,05) followed by castrated males and females. The characteristics of the carcasses were influenced (P<0,05) by sexual classes and feeding restriction. Whole males presented greater hot and cold carcass weights, followed by castrated males and females. However, the yield of the hot carcass was higher in females (45,25%) and castrated males (44,06%) compared to whole males (42,09%). Concerning meat quality, the luminosity values were influenced (P<0,05) by the sexual classes, with whole males presenting higher value (39,74) compared to castrated males (38,19 and females (37,47). The profile of fatty acids of the meat was not affected (P>0,05) by the sexual classes. The concentrations of palmitic acids (C16:0), palmitoleic acids (C16:1c9), stearic acids (C18:0) and oleic acids (C18:1c9) were higher (P<0,05) in the meat of the lambs submitted to 0 to 30% of feeding restriction in relation to the meat of those restricted to 60%. The concentration of desirable fatty acids was greater in the meat of animals fed ad libitum (2827,41 mg/g of meat) and submitted to 30% feeding restriction (2770,69 mg/g of meat) compared to those submitted to 60% (1697,89 mg/g of meat). Animals of distinct sexual classes produce carcasses with different quantitative characteristics without having total influence on meat quality. The lipid profile of the meat is less favorable to consumer’s health when the animals are submitted to 60% feeding restriction. / Objetivou-se no presente estudo avaliar o efeito de classes sexuais e níveis de restrição alimentar sobre as características quantitativas e qualitativas das carcaças de borregos Morada Nova. Trinta e cinco animais com peso corporal inicial de 14,5 ± 0,89 kg foram utilizados em delineamento experimental inteiramente casualizado, em esquema fatorial 3x3, sendo três classes sexuais (11 machos inteiros, 12 machos castrados e 12 fêmeas) e três níveis de restrição alimentar (0% ou ad libitum, 30% e 60%). O consumo de matéria seca e o ganho médio diário foram maiores em machos inteiros (P<0,05) seguidos por machos castrados e fêmeas. As características das carcaças foram influenciadas (P<0,05) pelas classes sexuais e pela restrição alimentar. Machos inteiros apresentaram pesos de carcaça quente e fria superiores, seguidos por machos castrados e fêmeas. No entanto, o rendimento de carcaça quente foi maior em fêmeas (45,25%) e machos castrados (44,06%) em relação aos machos inteiros (42,09%). Quanto à qualidade da carne, os valores de luminosidade (L*) foram influenciados (P<0,05) pelas classes sexuais, sendo que machos inteiros apresentaram valor superior (39,74) em relação a machos castrados (38,19) e fêmeas (37,47). O perfil de ácidos graxos da carne não foi influenciado (P>0,05) pelas classes sexuais. As concentrações dos ácidos palmítico (C16:0), palmitoleico (C16:1c9), esteárico (C18:0) e oleico (C18:1c9) foram superiores (P<0,05) na carne de borregos submetidos a 0 e 30% de restrição alimentar em relação à carne daqueles restritos a 60%. A concentração de ácidos graxos desejáveis foi maior na carne dos animais alimentados ad libitum (2827,41 mg/g de carne) e submetidos a 30% de restrição alimentar (2770,69 mg/g de carne) em relação aos submetidos a 60% (1697,89 mg/g de carne). Animais de classes sexuais distintas produzem carcaças com características quantitativas diferentes sem exercer total influência sobre a qualidade da carne. O perfil lipídico da carne é menos favorável a saúde do consumidor quando os animais são submetidos à restrição alimentar de 60%.

CoordenaÃÃo de AperfeÃoamento de Pessoal de NÃvel Superior / Objetivou-se no presente estudo avaliar o efeito de classes sexuais e nÃveis de restriÃÃo alimentar sobre as caracterÃsticas quantitativas e qualitativas das carcaÃas de borregos Morada Nova. Trinta e cinco animais com peso corporal inicial de 14,5  0,89 kg foram utilizados em delineamento experimental inteiramente casualizado, em esquema fatorial 3x3, sendo trÃs classes sexuais (11 machos inteiros, 12 machos castrados e 12 fÃmeas) e trÃs nÃveis de restriÃÃo alimentar (0% ou ad libitum, 30% e 60%). O consumo de matÃria seca e o ganho mÃdio diÃrio foram maiores em machos inteiros (P<0,05) seguidos por machos castrados e fÃmeas. As caracterÃsticas das carcaÃas foram influenciadas (P<0,05) pelas classes sexuais e pela restriÃÃo alimentar. Machos inteiros apresentaram pesos de carcaÃa quente e fria superiores, seguidos por machos castrados e fÃmeas. No entanto, o rendimento de carcaÃa quente foi maior em fÃmeas (45,25%) e machos castrados (44,06%) em relaÃÃo aos machos inteiros (42,09%). Quanto à qualidade da carne, os valores de luminosidade (L*) foram influenciados (P<0,05) pelas classes sexuais, sendo que machos inteiros apresentaram valor superior (39,74) em relaÃÃo a machos castrados (38,19) e fÃmeas (37,47). O perfil de Ãcidos graxos da carne nÃo foi influenciado (P>0,05) pelas classes sexuais. As concentraÃÃes dos Ãcidos palmÃtico (C16:0), palmitoleico (C16:1c9), esteÃrico (C18:0) e oleico (C18:1c9) foram superiores (P<0,05) na carne de borregos submetidos a 0 e 30% de restriÃÃo alimentar em relaÃÃo à carne daqueles restritos a 60%. A concentraÃÃo de Ãcidos graxos desejÃveis foi maior na carne dos animais alimentados ad libitum (2827,41 mg/g de carne) e submetidos a 30% de restriÃÃo alimentar (2770,69 mg/g de carne) em relaÃÃo aos submetidos a 60% (1697,89 mg/g de carne). Animais de classes sexuais distintas produzem carcaÃas com caracterÃsticas quantitativas diferentes sem exercer total influÃncia sobre a qualidade da carne. O perfil lipÃdico da carne à menos favorÃvel a saÃde do consumidor quando os animais sÃo submetidos à restriÃÃo alimentar de 60%. / The present study has a goal of evaluating the sexual classes and feeding restriction levels on the quantitative and qualitative characteristics of Morada Novaâs lamb carcasses. Thirty-five animals with initial body weight of 14,5  0,89 kg were used in a completely casualized experimental delineation, in a 3x3 factorial scheme, being three sexual classes (11 whole males, 12 castrated males and 12 females) and three levels of feeding restriction (0% or ad libitum, 30% e 60%). The dry matter intake and the average daily gain were higher in whole males (P<0,05) followed by castrated males and females. The characteristics of the carcasses were influenced (P<0,05) by sexual classes and feeding restriction. Whole males presented greater hot and cold carcass weights, followed by castrated males and females. However, the yield of the hot carcass was higher in females (45,25%) and castrated males (44,06%) compared to whole males (42,09%). Concerning meat quality, the luminosity values were influenced (P<0,05) by the sexual classes, with whole males presenting higher value (39,74) compared to castrated males (38,19 and females (37,47). The profile of fatty acids of the meat was not affected (P>0,05) by the sexual classes. The concentrations of palmitic acids (C16:0), palmitoleic acids (C16:1c9), stearic acids (C18:0) and oleic acids (C18:1c9) were higher (P<0,05) in the meat of the lambs submitted to 0 to 30% of feeding restriction in relation to the meat of those restricted to 60%. The concentration of desirable fatty acids was greater in the meat of animals fed ad libitum (2827,41 mg/g of meat) and submitted to 30% feeding restriction (2770,69 mg/g of meat) compared to those submitted to 60% (1697,89 mg/g of meat). Animals of distinct sexual classes produce carcasses with different quantitative characteristics without having total influence on meat quality. The lipid profile of the meat is less favorable to consumerâs health when the animals are submitted to 60% feeding restriction.

One of the greatest risk factors for disease is advanced age. As the human lifespan has increased, so too have the burdens of caring for an increasingly older population suffering from rising rates of cardiovascular disease, kidney disease, diabetes, and dementia. The need for improving medical technology and developing new therapies for age-related diseases is manifest. Yet our understanding of the processes of aging and how to attenuate the effects of aging remains incomplete. Various studies have established calorie restriction as a robust method for extending lifespan in laboratory organisms; however the mechanism is a topic of much debate. Advancing our understanding of calorie restriction holds promise for illuminating biochemical processes involved in the aging process. One of the best explanations for the lifespan extension benefits of calorie restriction is that it improves cellular protein homeostasis (proteostasis), but because proteostasis is dynamic, it can be difficult to measure. We developed a novel combined omics methodology integrating kinetic proteomics, and applied it to a mouse model placed on calorie restriction. Our unbiased approach integrating just three measurements (kinetic proteomics, quantitative proteomics, and transcriptomics) enabled us to characterize the synthesis and degradation of thousands of proteins, and determine that calorie restriction largely alters proteostasis by slowing global protein synthesis post-transcriptionally. Validating our omics approach, we were able to replicate many previous results found in the literature, demonstrating the differential regulation of various protein ontologies in response to the nutrient stress of calorie restriction. Moreover, we were able to detect differential degradation of the large and small ribosomal subunits under calorie restriction, and proposed a model in which the rate of protein synthesis could be attenuated by the depletion of the large ribosomal subunit relative to the small subunit. The flexibility of our dynamic combined omics approach was demonstrated by the expansion of measurements to include nucleic acids and lipids. Flux measurements of DNA, ribosomal RNA, and lipids yielded cellular division rates, ribosome turnover, and lipid metabolism insights, respectively. We also adapted this approach to two-dimensional tissue imaging by DESI-MS in a proof-of-concept study to demonstrate its utility for studying regional differences in metabolism. The future integration of metabolomics and lipidomics into our combined omics approach would be facile, and add unprecedented depth to systems-wide studies involving cellular metabolism. Applied to the regulation of cellular homeostasis in humans, this has the potential to open new avenues for elucidating the etiology of aging, understanding the pathology of age-related diseases, and identifying novel targets for therapeutics.

O diabetes mellitus (DM) é uma síndrome metabólica crônica, cuja característica principal é a hiperglicemia. O diabetes do tipo 2 (DM2) é a forma mais prevalente da doença, podendo ser iniciado com o desenvolvimento de resistência à insulina em tecidos periféricos e produção insuficiente desta frente à demanda do corpo. Os níveis elevados de glicose no sangue podem levar a uma série de alterações celulares e moleculares nas vias de sinalização da insulina, de inflamação, respostas ao estresse oxidativo e nos processos de reparo do DNA que podem levar ao ciclo vicioso de disfunção das células ? pancreáticas, à resistência insulínica e declínio metabólico. Visto o impacto que o sobrepeso e a obesidade têm em pacientes com DM2, intervenções nutricionais são sempre recomendadas nesses indivíduos. Além disso, foi relatado que restrições nutricionais têm efeitos positivos quanto à extensão da longevidade e redução da incidência de doenças associadas ao envelhecimento. Nesse contexto, os objetivos do presente estudo consistiram em avaliar os efeitos da hiperglicemia crônica em vias de sinalização molecular ligadas ao estresse oxidativo, reparo do DNA, resistência à insulina e inflamação, bem como análise do quadro de estresse oxidativo ao nível celular, mitocondrial e no pool de nucleotídeos, em pacientes com DM2 avaliados antes e após uma intervenção sob restrição proteica, e em pacientes DM2 portadores de hiperglicemia crônica comparados a um grupo de indivíduos sadios. Foi observado que em apenas 4 semanas a dieta com restrição proteica foi eficiente em reduzir significativamente os danos no DNA dos pacientes com DM2. Quanto aos genes avaliados, não foram observadas diferenças significativas nos níveis de expressão após a intervenção, sendo apenas observada uma leve tendência de indução dos genes PI3K, PRKAA1 e ATM. No entanto, foi possível observar em alguns pacientes a indução de genes (OGG1, MUTYH, SOD1, FOXO3, NUDT1) relacionados a reparo do DNA e resposta a danos. Adicionalmente, em relação aos níveis de bases oxidadas no pool de nucleotídeos, o período de intervenção não foi suficiente para demonstrar efeitos nesse sentido. Porém, foi observado que indivíduos com DM2 possuem níveis aumentados de basesoxidadas no pool de nucleotídeos quando comparados aos indivíduos sadios. Quanto às análises de estresse oxidativo a nível celular e mitocondrial, alterações significativas na quantificação de ROS, de potencial de membrana e massa mitocondrial não foram observadas quando comparados pacientes com DM2 e indivíduos sadios. Assim, foi observado que a hiperglicemia crônica promove um quadro de estresse oxidativo nos pacientes com DM2 e que a intervenção nutricional durante 4 semanas foi eficiente em reduzir significativamente os danos no DNA em pacientes com DM2, bem como melhorar o controle glicêmico desses indivíduos. Enquanto alterações na expressão transcricional de genes e nos níveis de bases oxidadas não foram observadas após o período de intervenção, é sugerido que um controle alimentar mais prolongado e um maior número amostral forneça informações relevantes acerca desta abordagem em pacientes com DM2 / Diabetes mellitus (DM) is a chronic metabolic syndrome, mainly characterized by hyperglycemia. Type 2 diabetes (T2D), the most prevalent form of diabetes, can be initiated with poor insulin secretion, lack of insulin sensitivity in target tissues or the combination of both. Elevated blood glucose levels can lead to a number of cellular and molecular changes in insulin signaling pathways, inflammation, oxidative stress responses, and DNA repair processes that can lead to pancreatic ?-cells dysfunction, insulin resistance and metabolic decline. Considering the impact of overweight and obesity on individuals with T2D, nutritional interventions are recommended for those individuals. In addition, it has been reported that dietary restrictions have a positive effect on longevity extension and reduction of age-related diseases. In this context, the purpose of the present study was to evaluate the effects of chronic hyperglycemia on molecular signaling pathways linked to oxidative stress, DNA repair, insulin resistance and inflammation, as well as analysis of oxidative stress at the mitochondrial level and nucleotide pool in T2D patients evaluated before and after an intervention under protein restriction. T2D patients with chronic hyperglycemia compared to a group of healthy individuals were also evaluated. It was observed that following a period of 4 weeks, the protein-restricted diet led to decreased levels of DNA damage in patients with T2D. Regarding the target genes, no significant differences were observed in the expression levels after the intervention. Only a slight tendency of induction was observed for PI3K, PRKAA1 and ATM genes. However, for some patients there was an induction of several genes (OGG1, MUTYH, SOD1, FOXO3, NUDT1) related to DNA repair and response to damage. In addition, in relation to the levels of oxidized bases in the nucleotide pool, the intervention period was not sufficient to exert alterations in those levels. However, it has been observed that individuals with T2D have increased levels of oxidized bases in the nucleotide pool when compared to healthy individuals. Regarding mitochondrial analysis, no significant alterations in the quantification of ROS, membrane potential and mitochondrial mass were observed when comparing T2D patients and healthy individuals. Thus, it was observed that chronichyperglycemia promotes an oxidative stress condition in T2D patients, and dietary restriction during 4 weeks was found efficient in significantly reducing DNA damage in patients with T2DM, as well as improving the glycemic control of these individuals. While changes in transcriptional gene expression and oxidized bases levels were not observed after the intervention period, thus suggesting that longer nutritional control and a larger sample number might provide relevant information about this approach in T2D patients

Une restriction alimentaire améliore la qualité du vieillissement et augmente la durée de vie chez de nombreuses espèces, y compris certains primates. Cependant, cette intervention s'accompagne souvent d'une baisse significative des capacités reproductives. Il est donc légitime de se demander si des signaux provenant du système reproductif contribuent aux effets positifs de la restriction alimentaire sur la longévité. Durant ma thèse, j'ai montré que l'expression de DAF-9/CYP27A1 et la production de l'hormone stéroïdienne D7- acide dafachronique (DA) sont augmentées chez C. elegans lorsque les vers sont soumis à une restriction alimentaire. De plus, la signalisation à l'acide dafachronique via le récepteur hormonal nucléaire NHR-8/NHR et la kinase let-363/mTOR est essentielle à l'augmentation de la durée de vie par restriction alimentaire. La signalisation stéroïde affecte également la plasticité de la lignée germinale en condition de jeûne. De plus, nous montrons que cette plasticité est nécessaire à l'augmentation de la longévité dans ce context de restriction. Les résultats présentés dans cette thèse démontrent que la signalisation des hormones stéroïdes est activée par le manque de nutriments et est requise pour l'augmentation de la longévité par la voie mTOR. En effet, chez un animal sauvage, le niveau d’expression de let-363/mTOR diminue en condition de jeûne. Ceci n’est pas observé lorsque les hormones stéroïdes sont absentes. De plus, le nombre de cellules de la lignée germinale au sein de la zone proliférative n'est plus affecté par le jeûne chez des animaux pour lesquels la synthèse d'hormones stéroïdes est inhibée. Une réduction artificielle du nombre de cellules germinales suffit à rétablir une réponse normale à la restriction alimentaire. Ceci suggère donc qu'il existe un lien étroit entre la lignée germinale et la longévité induite par une restriction alimentaire, et que ce lien repose en partie sur la signalisation des hormones stéroïdes. La kinase let-363/mTOR joue également un rôle central dans l'intégration de signaux nutritionnels et reproductifs. Nos données suggèrent également l'existence d'un signal entre lignée germinale et soma produit en condition de restriction alimentaire. L'augmentation de la durée de vie par restriction alimentaire implique donc une réponse systémique coordonnée qui implique l'appareil reproducteur. / Dietary restriction (DR) increases healthspan and longevity in many species, including primates, but it is often accompanied by impaired reproductive function. Whether signals associated with the reproductive system contribute to or are required for DR effects on lifespan has not been established. In my doctoral thesis presented here, we show that expression of DAF-9/CYP27A1 and production of the steroid hormone ∆7-dafachronic acid (DA) are increased in C. elegans subjected to DR. DA signaling through the non-canonical nuclear hormone receptor NHR-8/NHR and the nutrient-responsive kinase let-363/mTOR is essential for DR-mediated longevity. Steroid signaling also affects germline plasticity in response to nutrient deprivation and this is required to achieve lifespan extension. Results presented in my thesis demonstrate that steroid signaling is activated by nutrient scarcity and is required for DR effects on lifespan extension through TOR signaling. In the absence of proper steroid signaling, let-363/mTOR levels remain high during starvation and the number of germ cells within the proliferative zone of the germ line is no longer affected by nutrient availability. Interestingly, genetic reduction of germ cells alleviates the requirement for steroid signaling for DR-mediated lifespan extension. Genetically lowering the germ cell count mimics the response of the germ line to DR. These data demonstrate that steroid signaling links germline physiology to lifespan when nutrients are limited, and establish a central role for let-363/mTOR in integrating signals derived from nutrients and steroid hormones. We speculate that this induces a signal that is usually emitted when nutrients are scarce and the germ line becomes less active. Taken together, this thesis work suggests that, diet-induced lifespan extension is part of a coordinated response that involves reproductive phenotypes.

<p>This study was performed to better understand the physiological responses of the cricket <em>Acheta domesticus</em> to dietary restriction and nutritional geometry (relative nutritional balance). Dietary restriction in crickets decreases the growth rate, survivorship, maturation mass and delays maturation, but it has the benefit of increasing their maximum longevity. Measurements of maturation mass, maturation age and longevity were obtained and used to calculate adult duration, growth rate and survivorship. This experiment combined both dietary restriction and nutritional geometry. Treatments were dietary restricted and provided with one of three macronutrients: lipid, carbohydrate or protein. The macronutrients were predicted to modulate the effects of dietary restriction while still producing an increase in maximum longevity. The lifetime restricted males and females obtained the highest maximum longevity of all treatments. The females of the carbohydrate treatment experienced significant increases in survivorship when compared to the lifetime restricted treatment. The males of the carbohydrate treatment achieved the second highest maximum longevity as well as a significant increase in longevity when compared to the lipid and protein males. A significantly earlier maturation age was obtained by the carbohydrate males when compared to the lifetime restricted treatment. The protein females had a significantly higher maximum longevity than the control treatment. The lipid treatment had an extremely low survivorship, a decreased adult duration as well as a low maturation mass. In summary, carbohydrates decreased the maturation age and increased the survivorship of the female crickets and increased the longevity of the male crickets. The protein treatment did not obtain the expected increases in growth rates or maturation mass associated with high protein diets. Therefore, different high protein diets should be tested in conjunction with the carbohydrate diet, in order to offset the negative effects of dietary restriction.</p> / Master of Science (MSc)

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