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Global efforts towards decarbonization, environmental sustainability, and a growing impetus for exploiting renewable resources such as biomass have spurred the growth and usage of bio-based chemicals and fuels. In light of such developments, the biodiesel industry will likely flourish, as the transport sector is taking several initiatives to attain carbon-neutral mobility. However, this industry would inevitably generate glycerol as an abundant waste by-product. Despite being a renewable organic carbon source and assimilated by several prokaryotes, presently realizing glycerol-based biorefinery is a distant reality. Among several platform chemicals such as ethanol, lactic acid, succinic acid, 2, 3-butanediol etc., 1, 3-propanediol (1, 3-PDO) is the only chemical naturally produced by fermentation, with glycerol as a native substrate. The recent commercialization of glycerol-based 1, 3-PDO by Metabolic Explorer, France, has revived research interests in developing alternate cost-competitive, scalable and marketable bioprocesses. The current review outlines natural glycerol assimilating and 1, 3-PDO-producing microbes, their metabolic pathways, and associated genes. Later, technical barriers are carefully examined, such as the direct use of industrial glycerol as input material and genetic and metabolic issues related to microbes alleviating their industrial use. Biotechnological interventions exploited in the past five years, which can substantially circumvent these challenges, such as microbial bioprospecting, mutagenesis, metabolic, evolutionary and bioprocess engineering, including their combinations, are discussed in detail. The concluding section sheds light on some of the emerging and most promising breakthroughs which have resulted in evolving new, efficient, and robust microbial cell factories and/or bioprocesses for glycerol-based 1, 3-PDO production.

This research paper explores the question—whether it is morally permissible for an auditory impaired parent to create an auditory impaired offspring? It makes an epistemological inquiry into the experiences of persons with auditory impairments to make an informed decision on the question at stake. There is a general attitudinal bias against the disability. On the contrary, arguments have been raised that a parent with auditory impairment may have a moral right and a liberty to have a specially designed deaf baby. It is argued that a deaf parent’s desire to have a deaf child, stems from their need to relate linguistically and culturally with the child. It is also in the best interest of the child and the parent. Such arguments seem grossly misguided and are often countered with arguments of ‘open future,’ and the costs of disability. This research paper seeks to inquire into the epistemic challenges in examining the validity and the soundness of these arguments. It engages into the arguments and counter arguments with respect to whether auditory impairment is a disadvantageous condition to find that deafness does involve an element of harm though it is not only and only harm. It argues against the proposition that laws permitting abortion in case of foetal anomaly are eugenic. It uses Kantian theory to delve into the moral permissibility of the use of genetic engineering for the creation of impairment and enhancement. In the light of moral, ethical and jurisprudential considerations it finds that it is morally impermissible to use genetic interventions to create impairments or enhancements, as it strikes at the humanity in the ‘designer babies’ and uses them as a means for the satisfaction of desires.

Genetic manipulations can ameliorate the aging process and extend the lifespan of model organisms. The aim of this research was to identify novel genetic interventions that promote both lifespan and healthspan, by combining the effects of multiple longevity-associated gene inactivations in C. elegans. For this, the individual and combined effects of the odr-3 mutation and of ife-2 and cku-70 knock-downs were studied, both in the wild type and daf-16 mutant backgrounds. We found that besides increasing the lifespan of wild type animals, the knock-down of ife-2 (starting at L4) also extends the lifespan and healthspan of long-lived odr-3 mutants. In the daf-16 background, ife-2 and odr-3 impairment exert opposing effects individually, while the daf-16; odr-3; ife-2 deficient animals show a similar lifespan and healthspan as daf-16, suggesting that the odr-3 and ife-2 effector outcomes converge downstream of DAF-16. By contrast, cku-70 knock-down did not extend the lifespan of single or double odr-3; ife-2 inactivated animals, and was slightly deleterious to healthspan. In conclusion, we report that impairment of odr-3 and ife-2 increases lifespan and healthspan in an additive and synergistic manner, respectively, and that this result is not improved by further knocking-down cku-70.

Because every species has unique attributes relevant to understanding specific aspects of aging, using a diversity of study systems and a comparative biology approach for aging research has the potential to lead to novel discoveries applicable to human health. Monogonont rotifers, a standard model for studies of aquatic ecology, evolutionary biology, and ecotoxicology, have also been used to study lifespan and healthspan for nearly a century. However, because much of this work has been published in the ecology and evolutionary biology literature, it may not be known to the biomedical research community. In this review, we provide an overview of Brachionus rotifers as a model to investigate nutritional and metabolic regulators of aging, with a focus on recent studies of dietary and metabolic pathway manipulation. Rotifers are microscopic, aquatic invertebrates with many advantages as a system for studying aging, including a two-week lifespan, easy laboratory culture, direct development without a larval stage, sexual and asexual reproduction, easy delivery of pharmaceuticals in liquid culture, and transparency allowing imaging of cellular morphology and processes. Rotifers have greater gene homology with humans than do established invertebrate models for aging, and thus rotifers may be used to investigate novel genetic mechanisms relevant to human lifespan and healthspan. The research on caloric restriction; dietary, pharmaceutical, and genetic interventions; and transcriptomics of aging using rotifers provide insights into the metabolic regulators of lifespan and health and suggest future directions for aging research. Capitalizing on the unique biology of Brachionus rotifers, referencing the vast existing literature about the influence of diet and drugs on rotifer lifespan and health, continuing the development of genetic tools for rotifers, and growing the rotifer research community will lead to new discoveries a better understanding of the biology of aging.

This paper discusses one area of the interface between science and ethics: the genetic manipulation and design of human beings. Genetic interventions are an increasingly powerful eugenic resource, but they raise ethical suspicions. Critics condemn them, alleging severe negative consequences for society and the manipulated individuals involved. I analyze some influential general arguments (consequentialist and non-consequentialist) proposed against artificially selecting the next generation and conclude that the arguments are insufficient to cast blanket prohibitions against genetic interventions. Eugenic projects are compatible in principle with the pursuit of dignity, freedom, and tolerance at the individual and social levels. The ethical challenges raised by genetic interventions are real and vital. Still, it seems more ethically beneficial to approach them piecemeal through public-level arguments informed by science and specific to the cases encountered.

Micronutrient deficiencies, particularly iron (Fe) and zinc (Zn), in human diets are affecting over three billion people globally, especially in developing nations where diet is cereal-based. Wheat is one of several important cereal crops that provide food calories to nearly one-third of the population of the world. However, the bioavailability of Zn and Fe in wheat is inherently low, especially under Zn deficient soils. Although various fortification approaches are available, biofortification, i.e., development of mineral-enriched cultivars, is an efficient and sustainable approach to alleviate malnutrition. There is enormous variability in Fe and Zn in wheat germplasm, especially in wild relatives, but this is not utilized to the full extent. Grain Fe and Zn are quantitatively inherited, but high-heritability and genetic correlation at multiple locations indicate the high stability of Fe and Zn in wheat. In the last decade, pre-breeding activities have explored the potential of wild relatives to develop Fe and Zn rich wheat varieties. Furthermore, recent advances in molecular biology have improved the understanding of the uptake, storage, and bioavailability of Fe and Zn. Various transportation proteins encoding genes like YSL 2, IRT 1, OsNAS 3, VIT 1, and VIT 2 have been identified for Fe and Zn uptake, transfer, and accumulation at different developing stages. Hence, the availability of major genomic regions for Fe and Zn content and genome editing technologies are likely to result in high-yielding Fe and Zn biofortified wheat varieties. This review covers the importance of wheat wild relatives for Fe and Zn biofortification, progress in genomics-assisted breeding, and transgenic breeding for improving Fe and Zn content in wheat.

Ένα κεντρικό ζήτημα στον δημόσιο διάλογο για τις γενετικές ενισχυτικές παρεμβάσεις αφορά τις ανισότητες μεταξύ πλουσίων και φτωχών στις ικανότητες, στις ευκαιρίες και στην ευημερία. Πολλοί ισχυρίζονται πως, εάν οι εν λόγω παρεμβάσεις είναι προσβάσιμες μόνο στα εύπορα κοινωνικά στρώματα, λόγω της δυνατότητας των τελευταίων να τις χρηματοδοτήσουν, οι υπάρχουσες ανισότητες θα παγιωθούν, ενώ νέες και εντονότερες θα δημιουργηθούν στο μέλλον. Ως εκ τούτου, θεωρούν ότι το κράτος πρέπει να παίξει έναν ρόλο ενάντια στην επιδείνωση των υφιστάμενων ανισοτήτων και στην εμφάνιση μελλοντικών, καθώς και να καθορίσει μια γενετική πολιτική με την οποία θα ρυθμίζει μια δίκαιη διανομή των γενετικών πόρων κάτω από συγκεκριμένες αρχές δικαιοσύνης. Το άρθρο αυτό έχει δύο κύρια τμήματα. Στο πρώτο και πιο σύντομο, εξετάζω την περίπτωση που η πρόσβαση στην ενίσχυση είναι απεριόριστη για όλους. Στο δεύτερο και εκτενέστερο, εξετάζω ποιες αρχές πρέπει ένα κράτος να υιοθετήσει προκειμένου να αντιμετωπίσει αποτελεσματικά τις άδικες ανισότητες που θα προκαλούνταν από την περιορισμένη πρόσβαση στις ενισχύσεις. Τέλος, σκιαγραφώ από την δική μου προσωπική σκοπιά ένα μέρος μιας δίκαιης κρατικής γενετικής πολιτικής., A central issue in the ethical public debate on genetic enhancement concerns the inequalities in skills, opportunities and welfare that might be created and established between rich and poor. Many argue that if only the wealthy can have access to enhancements, then existing unjust inequalities will be consolidated and new ones will emerge in the future. Therefore, they argue, state has a role to play against the exacerbating of existing inequalities and the emergence of future ones and determine a genetic policy that will regulate a fair distribution of genetic means under specific principles of justice. This article has two main sections. In the first and shorter section, I examine a case where access to enhancement would be unlimited for everyone. In the second and longer section, I examine the principles that a state should adopt in order to treat the unjust inequalities that could result from limited access to enhancement. Finally, I outline part of my own approach to a just genetic state policy.

Age-associated cardiovascular and neurodegenerative diseases lead to high morbidity and mortality around the world. Sirtuins are vital enzymes for metabolic adaptation and provide protective effects against a wide spectrum of pathologies. Among sirtuins, mitochondrial sirtuin 3 (SIRT3) is an essential player in preserving the habitual metabolic profile. SIRT3 activity declines as a result of aging-induced changes in cellular metabolism, leading to increased susceptibility to endothelial dysfunction, hypertension, heart failure and neurodegenerative diseases. Stimulating SIRT3 activity via lifestyle, pharmacological or genetic interventions could protect against a plethora of pathologies and could improve health and lifespan. Thus, understanding how SIRT3 operates and how its protective effects could be amplified, will aid in treating age-associated diseases and ultimately, in enhancing the quality of life in elders.

Cwik (2020) has written an excellent paper. His proposal that we analyze human germline genetic interventions in terms of their targets, goals, possible outcomes, and mechanisms seems sensible and ...

Although aging is a conserved phenomenon across evolutionary distant species, aspects of the aging process have been found to differ between males and females of the same species. Indeed, observations across mammalian studies have revealed the existence of longevity and health disparities between sexes, including in humans (i.e. with a female or male advantage). However, the underlying mechanisms for these sex differences in health and lifespan remain poorly understood, and it is unclear which aspects of this dimorphism stem from hormonal differences (i.e. predominance of estrogens vs. androgens) or from karyotypic differences (i.e. XX vs. XY sex chromosome complement). In this review, we discuss the state of the knowledge in terms of sex-dimorphism in various aspects of aging, and in human age-related diseases. Where the interplay between sex differences and age-related differences has not been explored fully, we present the state of the field, to highlight important future research directions. We also discuss various dietary, drug or genetic interventions that were shown to improve longevity in a sex-dimorphic fashion. Finally, emerging tools and models that can be leveraged to decipher the mechanisms underlying sex differences in aging are also briefly discussed.

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading monogenic cause of autism. The condition stems from loss of fragile X mental retardation protein (FMRP), which regulates a wide range of ion channels via translational control, protein–protein interactions and second messenger pathways. Rapidly increasing evidence demonstrates that loss of FMRP leads to numerous ion channel dysfunctions (that is, channelopathies), which in turn contribute significantly to FXS pathophysiology. Consistent with this, pharmacological or genetic interventions that target dysregulated ion channels effectively restore neuronal excitability, synaptic function and behavioural phenotypes in FXS animal models. Recent studies further support a role for direct and rapid FMRP–channel interactions in regulating ion channel function. This Review lays out the current state of knowledge in the field regarding channelopathies and the pathogenesis of FXS, including promising therapeutic implications. Ion channel dysfunctions contribute significantly to fragile X pathophysiology. In this Review, Deng and Klyachko discuss the mechanisms underlying the effects of these channelopathies in fragile X syndrome, and the therapeutic potential of pharmacological interventions that target ion channels.

Graphical abstract, Microbes propagate and thrive in complex communities, and there are many benefits to studying and engineering microbial communities instead of single strains. Microbial communities are being increasingly leveraged in biotechnological applications, as they present significant advantages such as the division of labour and improved substrate utilisation. Nevertheless, they also present some interesting challenges to surmount for the design of efficient biotechnological processes. In this review, we discuss key principles of microbial interactions, followed by a deep dive into genome-scale metabolic models, focussing on a vast repertoire of constraint-based modelling methods that enable us to characterise and understand the metabolic capabilities of microbial communities. Complementary approaches to model microbial communities, such as those based on graph theory, are also briefly discussed. Taken together, these methods provide rich insights into the interactions between microbes and how they influence microbial community productivity. We finally overview approaches that allow us to generate and test numerous synthetic community compositions, followed by tools and methodologies that can predict effective genetic interventions to further improve the productivity of communities. With impending advancements in high-throughput omics of microbial communities, the stage is set for the rapid expansion of microbial community engineering, with a significant impact on biotechnological processes.

Introduction. Aging is a natural time-dependent process characterized by the accumulation of damage in cellular structures that compromises cellular and tissue function leading ultimately to the death of the organism. Furthermore, aging is the most significant risk factor for chronic diseases including cancer, cardiovascular disease (CVDs) and neurodegeneration. Nine candidates have been proposed as the main features of aging. These candidates which have been regarded as "The Hallmarks of Aging" are: telomere attrition, genomic instability, epigenetic alterations, loss of proteostasis, mitochondrial dysfunction, deregulated nutrient sensing, cellular senescence, stem cell exhaustion, and altered intercellular communication. Given the great complexity of the changes that participate in the establishment of the aging phenotype, numerous theories have been proposed to explain its aetiology, but neither of them appears to be capable of fully explaining the origin of this process, and they often contradict each other. Among them, the Free Radical Theory of Aging proposes that oxidative stress and redox imbalance are factors directly related with aging. The general idea of this theory is to consider reactive oxygen species (ROS) and other reactive species, that are continuously generated in the organism, as the main cause of aging. Therefore, cellular aging is associated with chronic oxidative stress. ROS are products of normal cellular metabolism in mitochondrial respiration and can be also produced in defensive responses of cells against infectious agents, upon exposure to xenobiotics, cytokines, redox stress, and in a several of intracellular signaling pathways. Mitochondria are both the main source and a major target of ROS. Mitochondria are one of the most important organelles in aerobic organisms, as the sites where aerobic respiration takes place to produce the energy that is necessary to sustain most cellular processes. Mitochondria also participate in additional cellular processes of great relevance, including β-oxidation of fatty acids, calcium signaling, and apoptosis. However, ROS and free radicals are generated as by-products of mitochondrial metabolism that attack nucleic acids, proteins, and membrane phospholipids. Among phospholipids, those containing polyunsaturated fatty acids (PUFAs) are more susceptible to oxidation by free radicals, leading to lipid peroxidation that causes a loss of membrane fluidity and impairs many cell functions. Additionally, with age, mitochondrial enzymes, ATP production, and respiratory capacity decline and, at the same time, ROS and mitochondrial mutations increase, being these changes accompanied by alterations in morphology and abundance of these organelles. Mutations in mtDNA result in a loss of mitochondrial function and turnover. This leads to the autophagic digestion of defective mitochondria which, if not accompanied by efficient mitochondrial biogenesis, may lead to the consequent decrease in the synthesis of ATP and bioenergetic dysfunction. Mitochondria are generated by growth and division of pre-existing organelles. In addition, they are highly dynamic structures that undergo continuous changes in size, shape, number, and distribution, which is highly controlled by a balance between fusion and fission. Their dynamics is determined by mitochondrial turnover, biogenesis, and a balance between the frequency of fusion and fission events. These events are critical for the normal function of cells, allowing the replacement of old or damaged mitochondria which are continuously removed from the cell. All these mechanisms allow the maintenance and distribution of mtDNA, the quality control of the organelle, and the regulation of apoptosis. Imbalanced mitochondria dynamics contributes to the loss of mitochondrial homeostasis, leading to alterations in mitochondrial function, metabolism, and signaling. Progressive mitocondrial dysfunction is considered a hallmark of aging, and it has been involved in a wide range of pathological conditions whose incidence increases with aging, as neurodegenerative diseases, diabetes, CVDs, muscle atrophy and cancer, and it is also related with several processes of embryonic development. Mitochondria are eliminated when they are damaged or dysfunctional through a process regulated called mitophagy. Nutritional and genetic interventions are among the strategies currently followed by researchers to delay or even reverse the deleterious consequences of aging. Caloric restriction (CR) without malnutrition is the most effective nongenetic intervention that delays aging and increases lifespan in numerous organisms. Beneficial effects of CR on longevity are mainly due to an improvement in mitochondrial function. Furthermore, there is an important metabolic adaptation to CR, causing substantial changes in numerous signaling pathways that regulate growth, metabolism, repair of damage, oxidative stress, autophagy and inflammatory processes. Among these changes, CR increases the amount of monounsaturated fatty acids (MUFAs) in membranes while decreasing PUFAs without any observed changes in saturated fatty acids (SFA), which is in accordance with the Theory of Membranes in Aging that proposes that lifespan is inversely related to the level of unsaturation, particularly the level of n-3 PUFA, in membrane phospholipids. Moreover, CR modulates key molecules involved in the regulation of autophagy and increases NAD+ levels activating enzymatic activity of the sirtuins (SIRTs). Homeostasis of NAD+ is important for the maintenance of many functions and protection against aging and age-related diseases. NAD+ is a metabolic regulator and its efficacy has been reported in metabolic diseases such as insulin resistance, fatty liver or hypertension. The overexpression of enzymes capable of generating NAD+ from the oxidation of NADH, as NADH-cytochrome b5 reductase-3 (CYB5R3), is another strategy that is currently under evaluation. CYB5R3 is a flavoprotein that participates in the elongation and desaturation of fatty acids, which seems to be an excellent candidate as a novel effector for the regulation of metabolism, mainly at mitochondrial level. CYB5R3 plays an important role in the regulation of metabolic pathways associated with healthspan and aging through mechanisms that appear to be related with protection against oxidative stress, production of cellular NAD+ and alterations in fatty acids composition. Although CYB5R3 shows a constitutive basal expression in many tissues, its expression can be also induced in response to environmental stress and nutrient deprivation. Constitutive expression of the Cyb5r3 gene is controlled by SP1 transcription factor, which can be further upregulated through pathways involving forkhead box O3 (FOXO3a) and nuclear factor erythroid 2-related factor 2 (NFE2L2) transcription factors. Mice overexpressing this protein showed increased longevity and displayed greater protection against diseases associated with aging. At the metabolic level, CYB5R3 overexpression increases insulin sensitivity, decreases inflammation and oxidative stress, and protects mice against cancer induction. Therefore, this enzyme plays a fundamental role in the regulation of lipid metabolism that allows to increase lifespan, suggesting that strategies aimed at incrementing CYB5R3 expression and/or activity may constitute viable interventions to confer protection against metabolic pathologies and to improve healthspan. Dietary fats are essential components to generate energy. Fatty acids (FAs) can be categorized as saturated (SFAs), monounsaturated (MUFAs), or polyunsaturated (PUFAs) and most of them can be synthesized by the organisms excepting the socalled essential fatty acids that must be ingested through the diet. In addition, FAs are an important source of energy due to their ability to be efficiently stored as triglycerides (TGs). Several studies have reported the relationship between dietary fat and the risk of metabolic and CVDs, among other disorders. Diets rich in MUFAs and PUFAs have cardioprotective effects, while the relationship between SFA and the risk of coronary heart disease is still controversial. Fatty acids can undergo autoxidation reactions generating lipid peroxides that affect the properties of biological membranes. Additionally, the toxic products derived from peroxidation can damage proteins, DNA, and other biomolecules. Since lipids are prone to oxidation, which exerts negative effects in health, the use of antioxidants in foods has become extensive to prevent lipid oxidation. The liver and heart are closely related in health and in disease. Deregulated hepatic lipid metabolism and many metabolic diseases, such as diabetes and obesity, are ultimately detrimental to cardiac function. The liver is the main organ in the regulation of energy metabolism. It performs three essential functions: the metabolic processing of proteins, carbohydrates and lipids after their absorption in the intestine, the detoxification of toxic agents and substances, and the storage of energy in form of glycogen. In spite of some changes occurring during aging (see below), the liver ages fairly well. Although in normal conditions hepatocyte turnover rate is low, the liver shows a relatively high rate of regeneration. That is why this organ has been widely used as a model to study the effects of diets, CR and other anti-aging interventions. Aging-related changes in liver include a reduction of weight and volume, a decline in the rate of hepatic regeneration, increased size of hepatocytes, polyploid nuclei, decreased area of smooth endoplasmic reticulum, decreased clearance of free radicals, and a decrease in the number and function of mitochondria, resulting in a decline in the ATP production. Aging is also associated with redistribution of fat in the body characterized by increased fat deposition in non-adipose tissues, including liver. All these structural and functional alterations could contribute to the development of liver disease with age. The heart is the main organ of the circulatory system and one of the first organs to be formed during the embryonic development. The heart is a complex organ containing different cell types that contribute to the structural, biochemical, mechanical, and electrical properties of the organ. Among the cell types, cardiomyocytes, responsible for the contractile function of the myocardium, are well differentiated cells without regeneration capacity. The most drastic changes in heart function occurring with age are: left ventricular hypertrophy, alterations in the diastolic function, aortic valve calcification, arrhythmia and heart failure. These alterations are, at least in part, due to a decrease in the number of cardiomyocytes, as well to hypertrophy and fibrosis due to an increased collagen and alterations in the extracellular matrix. As postmitotic cells, cardiomyocytes are highly susceptible to age-related mitochondrial damage and ROS production which results in an overall enhancement in the rate of cardiomyocyte death with age. The progressive decline of cardiomyocyte mitochondrial function is considered the major mechanism underlying heart aging, in addition to the accumulation of cholesterol and fatty acids in tissues which lead to the production of inflammatory cytokines as well as ROS that further contribute to CVDs prevalence and mortality. Starting hypothesis and objectives. Previous studies developed in our group were focused on NADH-cytochrome b5 reductase-3 (Cyb5r3) as a new pro-longevity gene. Mice overexpressing CYB5R3 contain higher levels of polyunsaturated fatty acids in hepatic membranes, which resembles, at least partially, the effects of the consumption of a diet containing fish oil or the overexpression of the Fat-1 gene of C. elegans. Unsaturated fatty acids show high susceptibility to peroxidation. However, CYB5R3 transgenic mice exhibited a significant reduction in lipid peroxidation. The specific changes in FA composition that take place in mice overexpressing CYB5R3 may be the result of a metabolic reprogramming, and could be indicative of an improvement in mitochondrial function, leading to a lower generation of ROS and the prevention of the oxidative damage accumulation, which partially mimics the effects observed in animals subjected to CR. These mice showed increased insulin sensitivity and improved regulation of glucose homeostasis, less inflammation and decreased oxidative damage, and were protected against induced cancer. However, mice over- expressing CYB5R3 fed a standard diet ad libitum were fatter than wild-type controls, and preferentially use carbohydrate to meet their energy needs. This differs from studies with CR as antiaging intervention that showed an improvement in healthspan and lifespan due to the enhancement of β-oxidation as a preferential source of energy. Thus, CYB5R3 overexpression could contribute to extend lifespan in mice by mechanisms that may be independent of those described for CR. Since CYB5R3 increase has been reported in long-term CR intervention, it has been hypothesized that the beneficial effects of CR could be mediated, at least partially, by a such increase of CYB5R3. However, it has not yet been studied how the CYB5R3 overexpression affects mitochondrial processes that are relevant to determine the aging pattern, and how the alterations in fatty acid composition and CR can interact with the changes elicited by CYB5R3 overexpression in transgenic mice. The working hypothesis of this PhD is that mitochondrial efficiency is optimized in CYB5R3 transgenic mice, which leads to an improvement in energy production and better preservation of mitochondria during aging. For this reason, our main objective has been to study several mitochondrial function markers in liver and heart tissues of CYB5R3-overexpressing mice submitted to nutritional interventions (CR and alterations in fat composition of the diet) and aging. To this end, we have pursued the following 5 specific aims: 1. To study the physiological effects of CYB5R3 overexpression, dietary fats, CR and aging on body composition and biochemical profile. 2. To characterize the CYB5R3 overexpression in liver and heart in the three proposed interventions. 3. To determine the combined effect of CYB5R3 overexpression and CR on key markers of mitochondrial function. 4. To determine dietary conditions that maximize mitochondrial preservation in mice overexpressing CYB5R3. 5. To determine the effects of aging on the mitochondria parameters studied in the previously indicated aims in CYB5R3 overexpressing mice. The results of this PhD can help identify healthy lifestyles and nutritional patterns that can modulate healthy aging and extend longevity, as well as to identify new mitochondrial targets that allow the preservation of mitochondrial physiology and aid in the prevention of metabolic diseases associated with age. Introducción. El envejecimiento se define como el declive funcional dependiente del tiempo que se caracteriza por la acumulación de daños en las estructuras celulares, comprometiendo la función celular y tisular dando lugar, en último término, a la muerte del organismo. El envejecimiento es el principal factor de riesgo de las enfermedades crónicas incluyendo cáncer, enfermedades cardiovasculares (CVDs) y neurodegenerativas. Se han propuesto nueve causas principales por las que se produce el envejecimiento: las denominadas “marcas distintivas del envejecimiento”, que son las siguientes: acortamiento telomérico, inestabilidad genómica, modificaciones epigenéticas, pérdida de la proteostasis, disfunción mitocondrial, desregulación de la detección del estado nutricional, senescencia celular, alteración de la comunicación intercelular y perdida de células madre. Para tratar de explicar los cambios celulares que dan lugar el fenotipo del envejecimiento se han propuesto numerosas teorías, pero, debido a la complejidad de este proceso, ninguna de ellas puede explicar completamente el origen del envejecimiento. De estas teorías, la llamada Teoría de los Radicales Libres propone que el estrés oxidativo y el desajuste en el estado redox del organismo dan lugar al envejecimiento. Esta teoría considera que las especies reactivas de oxígeno (ROS) y otras especies reactivas (que están continuamente generándose en el organismo) son la principal causa del envejecimiento. Por lo tanto, el envejecimiento celular estaría provocado por un estrés oxidativo crónico. Las ROS son productos del metabolismo celular producidos por la respiración mitocondrial, respuesta defensiva de las células frente a agentes infecciosos, exposición a xenobióticos, respuesta a citoquinas y estrés redox. Además, actúan como moléculas de señalización celular. Las mitocondrias son la mayor fuente de ROS y las principales afectadas por el daño oxidativo que estas moléculas pueden llegar a causar. Además, son uno de los orgánulos más importantes en los organismos aeróbicos, que se encargan de la respiración celular y producen la energía necesaria para las funciones vitales de la célula. Las mitocondrias también participan en otros procesos celulares de gran importancia como la β-oxidación de ácidos grasos, homeostasis de calcio y apoptosis. Sin embargo, las ROS y los radicales libres son productos del metabolismo mitocondrial que, debido a su alta reactividad, interaccionan con los ácidos nucleicos, proteínas y fosfolípidos de membranas, dañando sus estructuras. Los fosfolípidos de membrana que contienen ácidos grasos poliinsaturados (PUFA) son los más susceptibles de ser oxidados por los radicales libres, dando lugar a la peroxidación lipídica, que altera las características de las membranas biológicas y afecta considerablemente a la función celular. Por otro lado, con el envejecimiento, las enzimas mitocondriales, la producción de ATP y la capacidad respiratoria de la célula disminuyen, a la vez que aumenta la producción de ROS. Los daños producidos en las mitocondrias dan lugar a mutaciones y alteraciones en la morfología y abundancia de estos orgánulos. Las mutaciones en el DNA mitocondrial (mtDNA) dan lugar a una pérdida de la función mitocondrial y a una desregulación de su recambio en la célula. El recambio mitocondrial se produce mediante la eliminación de mitocondrias dañadas por el proceso de autofagia, y la síntesis de nuevas mitocondrias a través de la biogénesis mitocondrial. Alteraciones en alguno de esos procesos dan lugar a una disminución de la síntesis de ATP y disfunción bioenergética. La biogénesis mitocondrial se produce por el crecimiento y división de mitocondrias preexistentes. Además, estos orgánulos son altamente dinámicos y están constantemente cambiando de forma, tamaño, número y distribución en la célula. Esta dinámica está controlada por un balance entre los procesos fusión y fisión mitocondrial, siendo estos eventos críticos para el correcto funcionamiento de las células que, a su vez, permiten el reemplazo de las mitocondrias viejas o dañadas. Todos esos mecanismos, además, participan en la distribución del DNA mitocondrial, en el mantenimiento del orgánulo en condiciones óptimas y en la regulación de la apoptosis. Un desajuste en la dinámica mitocondrial da lugar a la perdida de la homeostasis del orgánulo, provocando alteraciones en su funcionamiento, metabolismo y señalización. La disfunción mitocondrial progresiva está considerada una marca distintiva del envejecimiento e involucra una gran variedad de condiciones patológicas que aumentan con el envejecimiento como son las enfermedades neurodegenerativas, diabetes, CVDs, atrofia muscular y cáncer. También están implicadas en numerosos procesos del desarrollo embrionario. La eliminación mitocondrial por autofagia es un proceso altamente regulado llamado mitofagia. Con el fin de retrasar o revertir los efectos deletéreos del envejecimiento, numerosas intervenciones nutricionales y genéticas están siendo estudiadas. Entre ellas, la restricción calórica (CR) sin malnutrición es la intervención no genética más efectiva que retrasa el envejecimiento e incrementa la vida máxima en numerosos organismos. Los efectos beneficiosos de la CR sobre la longevidad se deben en gran parte a una mejora en la función mitocondrial. Además, la CR produce adaptaciones metabólicas muy importantes dando lugar a cambios en numerosas rutas de señalización que participan en el crecimiento, metabolismo, mecanismos de reparación de daños, estrés oxidativo, autofagia y procesos inflamatorios. Entre esos cambios, la CR aumenta el contenido de ácidos grasos monoinsaturados (MUFA), disminuye el contenido de PUFA y no provoca cambios en la cantidad de ácidos grasos saturados (SFA) en las membranas biológicas, lo que apoya la Teoría de las Membranas en el envejecimiento que establece que la longevidad máxima esta inversamente relacionada con el nivel de insaturación de las membranas biológicas, particularmente con los niveles de PUFA n-3. Por otro lado, la CR modula moléculas clave que participan en la regulación de la autofagia e incrementa los niveles de NAD+ resultando en la activación de enzimas como las sirtuinas. La homeostasis de NAD+ es importante para el mantenimiento de muchas funciones y protección frente al envejecimiento y de las enfermedades relacionadas con éste. El NAD+ es un regulador metabólico y su eficacia ha sido probada en enfermedades metabólicas como la resistencia a insulina, hígado graso o hipertensión. La sobreexpresión de enzimas capaces de generar NAD+, como la NADH citocromo b5 reductasa 3 (CYB5R3), es una estrategia que está siendo estudiada actualmente. La CYB5R3 es una flavoproteína que participa en la elongación y desaturación de ácidos grasos, lo que la hace una excelente candidata para la regulación del metabolismo, principalmente a nivel mitocondrial. La CYB5R3 tiene un rol fundamental en la regulación de rutas metabólicas asociadas con la prolongación de la vida saludable y el envejecimiento a través de mecanismos que parecen estar relacionados con la protección frente a estrés oxidativo, la producción de NAD+ celular y las alteraciones en la composición de ácidos grasos. A pesar de que esta proteína tiene una expresión basal constitutiva en muchos tejidos, puede ser también inducida en respuesta a estrés ambiental y deprivación de nutrientes. La expresión constitutiva del gen Cyb5r3 está controlada por el factor de transcripción SP1, siendo además regulada por los factores de transcripción FOXO3a y NFE2L2. Los ratones que sobrexpresan CYB5R3 muestran una mayor longevidad y una mayor protección frente enfermedades asociadas con el envejecimiento. A nivel metabólico, la sobreexpresión de esta enzima aumenta la sensibilidad a insulina, disminuye la inflamación y el estrés oxidativo y protege a los ratones frente a la inducción de cáncer. Además, esta enzima tiene un papel fundamental en la regulación del metabolismo lipídico, lo que permite aumentar la esperanza de vida, sugiriendo que aquellas estrategias centradas en aumentar su expresión y/o actividad pueden constituir intervenciones viables que confieran protección frente a patologías metabólicas y prolonguen la vida saludable. Los ácidos grasos son componentes de la dieta esenciales para generar energía. Los ácidos grasos pueden ser categorizados como saturados (SFA), monoinsaturados (MUFA) y poliinsaturados (PUFA) y la mayoría de ellos pueden ser sintetizados por el organismo, a excepción de los llamados ácidos grasos esenciales, que solamente pueden ser obtenidos a través de la ingesta. Además, los ácidos grasos son fuentes importantes de energía que pueden ser almacenados en forma de triglicéridos. Numerosos estudios han informado de la relación de los ácidos grasos de la dieta con el riesgo de enfermedades metabólicas y cardiovasculares, así como con otros trastornos. Las dietas ricas en MUFA y PUFA tienen efectos cardioprotectores, mientras que la relación entre SFA y el riesgo de sufrir enfermedades cardiovasculares sigue en debate. Los ácidos grasos pueden dar lugar a reacciones de autooxidación provocando peroxidación lipídica, lo que afecta a las propiedades de las membranas biológicas. Además, los productos tóxicos derivados de la peroxidación lipídica pueden dañar proteínas, DNA y otras biomoléculas. Debido a que los lípidos son propensos a la oxidación y causar efectos negativos en la salud, se ha extendido el uso de antioxidantes en los alimentos para prevenir su oxidación. El hígado y el corazón son dos órganos estrechamente relacionados en la salud y enfermedad. La desregulación del metabolismo lipídico hepático y muchas enfermedades metabólicas como la diabetes y la obesidad son, en última instancia, perjudiciales para la función cardíaca. El hígado es el principal órgano que regula el metabolismo energético desempeñando tres funciones fundamentales: el procesamiento metabólico de proteínas, carbohidratos y lípidos tras su absorción en el intestino, la detoxificación de agentes tóxicos y fármacos, y el almacenamiento de energía en forma de glucógeno. El hígado envejece relativamente bien a pesar de algunos cambios que ocurren con el envejecimiento. En condiciones normales el hígado tiene una tasa de regeneración bastante alta, a pesar de que el recambio de sus hepatocitos es relativamente bajo. Es por ello que el hígado ha sido muy utilizado por los investigadores como modelo de estudio del efecto de las dietas, la CR y otras intervenciones antienvejecimiento. Los cambios relacionados con la edad que experimenta el hígado incluyen una reducción del peso y volumen del órgano, el aumento del tamaño de los hepatocitos, la aparición de núcleos poliploides, una disminución del área del retículo endoplásmico liso, una menor capacidad de eliminación de ROS y la disminución en el número y función de las mitocondrias, procesos que tienen como resultado un declive de la producción de ATP. El envejecimiento ha sido asociado con la redistribución de la grasa del cuerpo, caracterizado por un incremento en la deposición de grasa visceral, incluido el hígado. Todos esos cambios estructurales y funcionales pueden contribuir a desarrollar enfermedades hepáticas con la edad. El corazón es el órgano principal del sistema circulatorio y, debido a su importancia, es uno de los órganos que se forman en primer lugar durante el desarrollo embrionario. El corazón es un órgano complejo formado por diferentes tipos celulares que dan lugar a sus distintivas propiedades estructurales, bioquímicas, mecánicas y eléctricas. Los cardiomiocitos son las células responsables de la función contráctil del miocardio y son células altamente diferenciadas sin capacidad de regeneración. Los cambios más drásticos que se producen en la función cardiaca con el envejecimiento son: hipertrofia del ventrículo izquierdo, alteraciones de la función diastólica, calcificación de la válvula aórtica, arritmia y fallo cardiaco. Esas alteraciones son, en parte, debido a una disminución en el número de cardiomiocitos, así como la hipertrofia y fibrosis provocadas por un incremento en el colágeno y por las alteraciones de la matriz extracelular. Como células postmitóticas, los cardiomiocitos son altamente susceptibles a los daños mitocondriales relacionados con el envejecimiento y producción de ROS, lo que potencia su muerte con la edad. El declive progresivo de la función mitocondrial de los cardiomiocitos es considerado la señal más clara de envejecimiento en el corazón. Por otra parte, la acumulación de colesterol y ácidos grasos en los tejidos da lugar a la producción de citoquinas inflamatorias, así como a ROS, que contribuyen a la prevalencia y mortalidad de las CVDs. Hipótesis inicial y objetivos. Estudios previos desarrollados en nuestro grupo se han centrado en como un nuevo gen con efectos pro-longevidad. Los ratones que sobre-expresan CYB5R3 presentan un número elevado de PUFA en las membranas hepáticas, efecto que se asemeja (al menos parcialmente) a los producidos por el consumo de una dieta rica en aceite de pescado o por sobreexpresión de la desaturasa Fat-1 de C.elegans. Los ácidos grasos insaturados son altamente susceptibles a la peroxidación. Sin embargo, los ratones transgénicos que sobre-expresan CYB5R3 muestran una reducción significativa en la peroxidación lipídica. Los cambios específicos en la composición de ácidos grasos que tiene lugar con la sobreexpresión de esta proteína pueden ser el resultado de un reajuste en el metabolismo, lo que además podría indicar una mejora en la función mitocondrial dando lugar a menos generación de ROS y la prevención de acumulación de daño oxidativo, efectos que mimetizan parcialmente a los observados en los animales sometidos a CR. Esos ratones transgénicos muestran una mayor sensibilidad a la insulina y una mejora en la homeostasis de la glucosa, menor inflamación, disminución del daño por estrés oxidativo y mayor prevención frente a la inducción de cáncer. Sin embargo, los ratones que sobre-expresan CYB5R3 alimentados ad libitum con una dieta estándar presentaron mayor peso corporal que sus controles y preferentemente obtenían energía del metabolismo de los carbohidratos. Por el contrario, los estudios centrados en la CR como intervención antienvejecimiento han mostrado una mejora en la prolongación de la vida saludable y de la longevidad máxima debido a una mayor utilización de la β-oxidación de ácidos grasos como fuente principal de energía, lo que difiere de los mecanismos por los que actúa la sobreexpresión de CYB5R3. Por lo tanto, la sobreexpresión de CYB5R3 puede contribuir a prolongar la vida máxima en ratones por mecanismos independientes de los descritos por la CR. Por otra parte, se ha informado que una intervención de CR a largo plazo induce la sobreexpresión de CYB5R3, por lo que se piensa que el efecto beneficioso de la CR podría estar mediado, al menos en parte, por el incremento de CYB5R3. Sin embargo, no ha sido estudiado aún cómo la sobreexpresión de CYB5R3 afecta a los procesos mitocondriales que son relevantes para determinar la pauta de envejecimiento. Tampoco se ha descrito cómo las alteraciones en la composición de ácidos grasos y la CR podrían interaccionar con los cambios provocados por la sobreexpresión de CYB5R3 en ratones transgénicos. La hipótesis de trabajo de esta Tesis Doctoral es que la eficiencia mitocondrial está optimizada en ratones transgénicos que sobre-expresan CYB5R3, lo que da lugar a una mejora en la producción de energía y una mayor preservación de la mitocondria durante el envejecimiento. Por esto mismo, nuestro principal objetivo ha sido estudiar marcadores mitocondriales en hígado y corazón de ratones que sobreexpresan esta proteína, sometidos a diferentes intervenciones nutricionales (CR y alteraciones en la composición de ácidos grasos de la dieta), así como estudiar cómo se ven afectados estos factores por el envejecimiento. Para lograr este fin, hemos planteado 5 objetivos específicos: 1. Estudiar el efecto fisiológico de la sobreexpresión de CYB5R3, los ácidos grasos de la dieta, la CR y el envejecimiento sobre el peso corporal y el perfil bioquímico. 2. Caracterizar la sobreexpresión de CYB5R3 en hígado y corazón en las tres intervenciones propuestas. 3. Determinar los efectos combinados de la sobrexpresión de CYB5R3 y de la CR sobre marcadores clave de la función mitocondrial. 4. Determinar los patrones nutricionales que maximizan la preservación mitocondrial en ratones que sobreexpresan CYB5R3. 5. Determinar los efectos del envejecimiento sobre los parámetros mitocondriales estudiados en los objetivos previamente citados, en ratones sobre-expresantes de CYB5R3. Los resultados de esta Tesis Doctoral podrían ayudar a identificar estilos de vida saludables y patrones nutricionales que pueden modular el envejecimiento saludable y la extensión de la vida máxima. También servirán para identificar nuevas dianas que permitan la preservación de la fisiología mitocondrial con el objetivo de prevenir enfermedades metabólicas asociadas con el envejecimiento.

Modern conservation science frequently relies on genetic tools to manage imperiled populations threatened by processes such as habitat fragmentation and infectious diseases. Translocation of individuals to restore genetic diversity (genetic rescue) is increasingly used to manage vulnerable populations, but it can swamp local adaptations and lead to outbreeding depression. Thus, genetic management is context dependent and needs evaluation across multiple generations . Genomic studies can help evaluate the extent to which populations are locally adapted to assess the costs and benefits of translocations. Predicting the long‐term fitness effects of genetic interventions and their evolutionary consequences is a vital step in managing dwindling populations threatened by emerging infectious diseases.

Cataloged from PDF version of article. Thesis (Ph.D.): Bilkent University, Department of Neuroscience, İhsan Doğramacı Bilkent University, 2020. Includes bibliographical references (leaves 154-182). Aging is a natural process that is ultimate combination of numerous intrinsic and extrinsic changes in an organism. Contrary the common belief, brain aging is not a loss of neurons while it has been shown that subtle cellular and synaptic alterations have contribution to brain aging. Therefore, the molecular and cellular alterations may give more insight into the brain aging process. There are some hallmarks of aging that are common features in different organisms including genomic instability, telomere attrition, cellular senescence. There are some common factors with the ability to regulate more than one of the hallmarks of aging such as Smurf2. HECTdomain E3 ubiquitin ligase Smurf2 has several roles in the cellular processes for example, telomere attrition and cellular senescence. Moreover, its gene expression is higher in the aged brain. Although there are several publications about Smurf2, most of them focused on its role in cancer. We believed that Smurf2 levels should be examined in terms of brain aging. The first aim of the study was to examine the levels of Smurf2 and its interacting partners across lifespan. Although the Smurf2 protein level was not increased significantly in the whole zebrafish brain, its protein level was upregulated significantly in telencephalon and cerebellum. Also, subcellular protein fractionation demonstrated an enriched Smurf2 level in the cytosolic part. In the case of gene expression levels, smurf2 level was significantly higher in aged whole brain although its expression was downregulated during aging in telencephalon and cerebellum. In addition, the levels of mdm2, ep300a and sirt1 were lower in the aged telencephalon. According to multivariate analysis there is a potential balance between Smurf2-mediated ubiquitination, ep300a-mediated acetylation and Sirt1- mediated deacetylation but with advancing age, this balance may disrupt and other regulatory genes should also take a role to sustain cellular stability. The second aim was to investigate the roles of Smurf2 on brain aging with the help of genetic interventions including inducible knockin, stable knockout or transient knockdown. Since stable knockin and knockout models should be genotyped before further investigations, the genotyping and phenotyping methods were employed to find an efficient and reliable way. Also, transient knockdown via Vivo-morpholino was applied to adult brain and efficient post injection times of two different morpholinos were identified in order to examine the effects of Smurf2 knockdown in both young and old zebrafish. Lastly, it was aimed to examine the effects of non-genetic interventions including dietary regimens and pharmacological compounds on the gene expression of smurf2 and its interacting partners and the levels of the neuronal proteins and proliferation/senescence proteins. The opposing short-term dietary regimens, overfeeding and caloric restriction, were altered the levels of neuronal proteins, HuC and DCAMKL1, and their relation with proliferation and senescence proteins during aging. Also, the gene expression levels of smurf2 and interacting partners except tp53 was not influenced by dietary regimens and aging in terms of whole brain. Also, multivariate analysis indicated that the correlations among smurf2, mdm2, ep300a and sirt1 were conserved in both young and old ages independent to dietary regimen which may imply that the balance between ubiquitination, acetylation and deacetylation is maintained in order to provide cellular stability during aging. Heclin, an inhibitor of HECT E3 ligases, were employed to inhibit Smurf2 activity. Before using in adult zebrafish, heclin was applied to embryos to see its effects. The higher dose of heclin decreased the survival ratio and altered the gene expression levels of downstream gene drastically. So, moderate dose of heclin should be applied to the adult brain and neuronal markers should be examined to observe target effects rather than off-target, unspecific impacts. Taken together, Smurf2 has potential roles during aging and it could be a promising target to delay the brain aging process and probably the onset of age-related cognitive decline. by Melek Umay Tüz Şaşik Ph.D.

Background and objectives Genetic engineering and similar technologies offer promising new approaches to controlling human diseases by blocking transmission from vectors. However, in spatially structured populations, imperfect coverage of the vector will leave pockets in which the parasite may persist. Movement by humans may disrupt this local persistence and facilitate eradication when these pockets are small, spreading parasite reproduction outside unprotected areas and into areas that block its reproduction. Here, we consider the sensitivity of this process to biological details: do simple generalities emerge that may facilitate interventions? Methodology We develop formal mathematical models of this process similar to standard Ross–Macdonald models, but (i) specifying spatial structure of two patches, with vector transmission blocked in one patch but not in the other, (ii) allowing temporary human movement (travel instead of migration) and (iii) considering two different modes of mosquito biting. Results We find that there is no invariant effect of disrupting spatial structure with travel. For both biting models, travel out of the unprotected patch has different consequences than travel by visitors into the patch, but the effects are reversed between the two biting models. Conclusions and implications Overall, the effect of human travel on the maintenance of vector-borne diseases in structured habitats must be considered in light of the actual biology of mosquito abundances, biting dynamics and human movement patterns. Lay summary: Genetic interventions against pathogens transmitted by insect vectors are promising methods of controlling infectious diseases. These interventions may be imperfect, leaving pockets where the parasite persists. How will human movement between protected and unprotected areas affect persistence? Mathematical models developed here show that the answer is ecology-dependent, depending on vector biting behavior.

Aging is strongly related to energy metabolism, but the underlying processes and mechanisms are complex and incompletely understood. Restricting energy intake and reducing metabolic rate can slow the rate of aging and extend longevity, implying a reciprocal relationship between energy metabolism and life expectancy. However, increased energy expenditure has also been associated with improved health and longer life. In both experimental animals and humans, reduced body temperature has been related to extended longevity. However, recent findings on the function of thermogenic (brown or beige) adipose tissue produced intense interest in increasing the amount of energy expended for thermogenesis to prevent and/or treat obesity, improve metabolic health, and extend life. Evidence available to-date indicates that increasing adipose tissue thermogenesis by pharmacologic, environmental, or genetic interventions can indeed produce significant metabolic benefits, which are associated with improved chances for healthy aging and long life.

Interventional studies on genetic modulators of longevity have significantly changed gerontology. While available lifespan data are continually accumulating, further understanding of the aging process is still limited by the poor understanding of epistasis and of the non-linear interactions between multiple longevity-associated genes. Unfortunately, based on observations so far, there is no simple method to predict the cumulative impact of genes on lifespan. As a step towards applying predictive methods, but also to provide information for a guided design of epistasis lifespan experiments, we developed SynergyAge - a database containing genetic and lifespan data for animal models obtained through multiple longevity-modulating interventions. The studies included in SynergyAge focus on the lifespan of animal strains which are modified by at least two genetic interventions, with single gene mutants included as reference. SynergyAge, which is publicly available at www.synergyage.info, provides an easy to use web-platform for browsing, searching and filtering through the data, as well as a network-based interactive module for visualization and analysis., Measurement(s) longevity • epistasis • synergistic interactions of longevity-associated genes • antagonistic interactions of longevity-associated genes Technology Type(s) digital curation Factor Type(s) type of mutant • animal model Sample Characteristic - Organism Caenorhabditis elegans • Drosophila melanogaster • Mus musculus Machine-accessible metadata file describing the reported data: 10.6084/m9.figshare.13049696

Highlights • Death involves the final collapse of vital physiological networks, and the timing of this collapse provides a systems-level measure of aging. • Many of the best statistical models for lifespan data common in the clinical literature are rarely applied in basic research studies. • Multivariate regression models allow differences between experimental replicates to be explicitly measured and accounted for when estimating the effect of interventions. • Semi-parametric models allow interventions to be studied with fewer implicit assumptions regarding the empiric data. • Competing risk models and mixture models provide formal frameworks for reasoning about multi-causal, multi-outcome aging processes., Many dietary, pharmaceutical, and genetic interventions have been found to increase the lifespan of laboratory animals. Several are now being explored for clinical application. To understand the physiologic action and therapeutic potential of interventions in aging, researchers must build quantitative models. Do interventions delay the onset of aging? Slow it down? Merely ameliorate some of its symptoms? If interventions slow some aging mechanisms but accelerate others, can we detect or predict the systemic consequences? Statistical and analytic models provide a crucial framework in which to answer these questions and clarify the systems-level effect of molecular interventions in aging. This review provides a brief survey of approaches to modeling lifespan data and places them in the context of recent experimental work.

Drosophila melanogaster has been a key model in developing our current understanding of the molecular mechanisms of ageing. Of particular note is its role in establishing the evolutionary conservation of reduced insulin and IGF-1-like signaling in promoting healthy ageing. Capitalizing on its many advantages for experimentation, more recent work has revealed how precise nutritional and genetic interventions can improve fly lifespan without obvious detrimental side effects. We give a brief summary of these recent findings as well as examples of how they may modify ageing via actions in the gut and muscle. These discoveries highlight how expanding our understanding of metabolic and signaling interconnections will provide even greater insight into how these benefits may be harnessed for anti-ageing interventions.

Ένα κeντρικό ζήτημα στον δημόσιο διάλογο για τις γeνeτικές eνισχυτικές παρeμβάσeις αφορά τις ανισότητeς μeταξύ πλουσίων και φτωχών στις ικανότητeς, στις eυκαιρίeς και στην eυημeρία. Πολλοί ισχυρίζονται πως, eάν οι eν λόγω παρeμβάσeις eίναι προσβάσιμeς μόνο στα eύπορα κοινωνικά στρώματα, λόγω της δυνατότητας των τeλeυταίων να τις χρηματοδοτήσουν, οι υπάρχουσeς ανισότητeς θα παγιωθούν, eνώ νέeς και eντονότeρeς θα δημιουργηθούν στο μέλλον. Ως eκ τούτου, θeωρούν ότι το κράτος πρέπeι να παίξeι έναν ρόλο eνάντια στην eπιδeίνωση των υφιστάμeνων ανισοτήτων και στην eμφάνιση μeλλοντικών, καθώς και να καθορίσeι μια γeνeτική πολιτική μe την οποία θα ρυθμίζeι μια δίκαιη διανομή των γeνeτικών πόρων κάτω από συγκeκριμένeς αρχές δικαιοσύνης. Το άρθρο αυτό έχeι δύο κύρια τμήματα. Στο πρώτο και πιο σύντομο, eξeτάζω την πeρίπτωση που η πρόσβαση στην eνίσχυση eίναι απeριόριστη για όλους. Στο δeύτeρο και eκτeνέστeρο, eξeτάζω ποιeς αρχές πρέπeι ένα κράτος να υιοθeτήσeι προκeιμένου να αντιμeτωπίσeι αποτeλeσματικά τις άδικeς ανισότητeς που θα προκαλούνταν από την πeριορισμένη πρόσβαση στις eνισχύσeις. Τέλος, σκιαγραφώ από την δική μου προσωπική σκοπιά ένα μέρος μιας δίκαιης κρατικής γeνeτικής πολιτικής.

Lignocellulosic (LC) biomass is abundantly available as a low-cost resource on the Earth. LC conversion into energy carriers is the most accepted alternative energy production policy because it is non-competitor to food or feed. LC ethanol has brought cellulases to the forefront which was otherwise lost in oblivion during last decades. LC biomass can be converted into value added products or into sugars by various routes, e.g., thermo-chemical, chemical, or biological methods. Biological route via enzymes is one of the most eco-friendly and feasible method. Both fungi and bacteria are known to degrade biomass. Fungi have been greatly exploited for cellulase production due to their inherent properties of secreting extracellular cellulase. These microorganisms are known as cellulase producers for many decades, however, to bring the enzymatic biomass conversion to an economically feasible status, extensive research efforts have been made in last decade to enhance cellulase titers. Mutations and genetic interventions along with bioprocess development have played a very important role for enhancing cellulase production. This review will present a critical overview of the on-going research towards improving cellulase production for biofuel industry via genetic modification, which will include mutation and genetic engineering employed to exert changes at genetic level in microorganisms.

The prefix “trans-” surrounds “animal” with a pluralizing effect: tranimals. This portmanteau word describes creatures at once real and imagined who traverse taxonomic categories. This essay considers two of many threads of trananimality: the transgenic and the prosthetic. Artist Jodi Clark imagines the Menagerie a Trois as a space for carnal humanimality, where sexual entanglements commingle with chimeric forms. This menagerie a tranimals extends Clark’s ever-expanding Menagerie a Trois by articulating a framework for contemplating and indexing humanimal networks of engineered organisms while simultaneously attending to the agency-in-captivity experienced by prosthetic and transgenic tranimals. The results of genetic interventions, transgenic tranimals have been engineered to serve a range of roles in biomedical research. Prosthetic tranimals are not always born with their modifications, but are instead engaged by other human and non-human animals by way of mechanical devices and symbiotic system...

This chapter will discuss several possibilities for human enhancement in the exploration of Mars in light of scientific and ethical considerations. The troublesome enhancements are basically of two kinds: implants and genetic interventions. A rather uncontroversial proposal is that we equip space explorers with the right kinds of suits, goggles and other equipment that will allow them to operate safely in harsh space environments. Implants, however, require surgical risks that may be unwarranted. Genetic interventions are themselves of two kinds: somatic genetic changes and germline changes. Somatic genetic changes may be riddled with unknown and potentially devastating side effects to the explorers who undergo them. Germline genetic changes may be passed on to future generations of human beings, a move that would be very difficult to justify. Of course, sending space explorers into harsh environments does require us to provide for their safety. But the most likely exploration of Mars in the next several decades will have as its greatest safety challenge the protection from radiation. No foreseeable enhancement can do that. We will mainly need safe suits and buildings. If extant life were to be found on Mars, then it would be crucial to determine whether it could dangerously infect human beings. In that case, we would need to “enhance” the explorers by giving them immunity. Other enhancements often mentioned would at best make some difficult tasks easier, but generally that would not be enough to overcome the burden of danger they create. This chapter will also examine the scientific plausibility of many of the proposed biotechnological advances. There is a reason to believe that they may be unwarranted extrapolations from present genetic research, for example, which brings their plausibility into question.

Aging should be considered as a multifactorial phenomenon and, consequently, its study should be addressed through different experimental designs. This includes nutritional and genetic interventions. In addition, it is essential to know the possible synergies or antagonisms that may occur between these conditions and if the extension of their benefits is universally translational to all tissues, genotypes or sexes. Therefore, the main objective of this Doctoral Thesis is the study of aging markers in renal cells and tissue of mice submitted to diverse genetic and nutritional interventions: caloric restriction, diet composition and CYB5R3 overexpression. El envejecimiento es un proceso multifactorial y su estudio requiere de diseños experimentales que contribuyan de forma significativa a la disección de estas múltiples interacciones. Ello puede conseguirse a través de intervenciones que hayan probado su impacto en la salud y longevidad de los modelos experimentales, entre las que destacan las nutricionales y genéticas. Además, resulta vital conocer las posibles sinergias o antagonismos que puedan presentarse entre las mismas y si la extensión de sus beneficios es trasladable de forma general a todos los tejidos, genotipos o sexos. Por todo ello, la presente Tesis Doctoral tiene como objetivo principal el estudio de marcadores de envejecimiento en células y tejido renal de ratones sometidos a diversas intervenciones genéticas y nutricionales como son la restricción calórica, la composición de la dieta y la sobreexpresión de CYB5R3.