Longevity and stress resistance are affected by activation of TOR/Myc in progenitor cells of Drosophila gut

Diverse physiological pathways have been shown to regulate longevity, stress resistance, fecundity and feeding rates, and metabolism in Drosophila. Here we tesed physiological traits in flies with Rheb and Myc- Rheb overexpressed in gut progenitor cells, known as enteroblasts (EBs). We found that activation of TOR signaling by overexpression of Rheb in EBs decreases survival and stress resistance. Additionall, we showed that Myc co-expression in EBs reduces fly fecundity and feeding rate. Rheb overexpression enhanced the level of whole body glucose. Higher relative expression of the metabolic genes dilps, akh, tobi and pepck was, however, observed. The role of TOR/Myc in the regulation of genes involved in lipid metabolism and protein synthesis was established. We showed a significant role of TOR/Myc in EBs in the regulation of the JAK/STAT, EGFR and insulin signaling pathways in Drosophila gut. These results highlight the importance of the balance between all different types of cells and confirm previous studies demonstrating that promotion of homeostasis in the intestine of Drosophila may function as a mechanism for the extension of organismal lifespan. Overall, the results demonstrate a role of TOR signaling and its downstream target Myc in EB cells in the regulation of Drosophila physiological processes

Intermittent fasting

Over the course of evolution, long periods of fasting were inevitable and species have developed coping mechanisms for better survival. At the moment, most of the western world has reached a point where nutrients are abundant and excessive, leading to accumulation of metabolic problems and a rise in chronic diseases in the second half of life. Existing concepts of life- and healthspan extension promote caloric restriction and fasting as potential methods to alleviate risks of chronic diseases, activating autophagy, and regeneration. The current article describes molecular and cellular mechanisms involved in the physiological effects of intermittent fasting (IF) and provides an integrated overview of existing experimental data and clinical trials. In multiple models, different modifications of IF show promising results, prolonging lifespan and improving surrogate healthspan markers. In humans IF promoted modest results in weight loss and had positive effects on insulin sensitivity, lipid profile, and inflammation. High quality evidence about the feasibility and long-term outcomes of IF in humans is still lacking. It remains unclear whether IF provides sustainable improvements. Further research is warranted to evaluate the optimal duration of IF, frequency of IF cycles and meal composition for the feeding intervals. The safety of IF is another major concern and so potential patient cohorts where IF might not be the best option must also be determined

mTOR pharmacology

The mammalian target of rapamycin (mTOR) signaling pathway is a crucial mechanism for nutrient sensing and regulation of growth, development, and homeostasis. Dysregulation of mTOR is involved in a number of chronic conditions including obesity, type 2 diabetes, cancer, and neurodegenerative disorders. mTOR signaling is modulated by a variety of factors, including nutrient and oxygen availability, growth factors, and insulin. This evolutionary conserved pathway also plays an important role in aging and lifespan regulation. All of these involvements in central metabolic functions make mTOR an interesting target for pharmacological manipulation. In humans, rapamycin has been approved for use since 1999 and is prescribed for immunosuppression in transplant recipients or as an anticancer agent. Rapamycin and rapalogs have shown beneficial effects in health- and lifespan prolongation in model organisms and patient data from clinical trials has also provided some promising results in the suppression or prevention of age-related diseases. In this article, we analyze current evidence and discuss the potential role of mTOR-inhibitors and mTOR-activators in the battle against aging and age-related diseases

Metformin as geroprotector: experimental and clinical evidence

Apart from being a safe, effective and globally affordable glucose-lowering agent for the treatment of diabetes, metformin has earned much credit in recent years as a potential anti-aging formula. It has been shown to significantly increase lifespan and delay the onset of age-associated decline in several experimental models. The current review summarizes advances in clinical research on the potential role of metformin in the field of geroprotection, highlighting findings from pre-clinical studies on known and putative mechanisms behind its beneficial properties. A growing body of evidence from clinical trials demonstrates that metformin can effectively reduce the risk of many age-related diseases and conditions, including cardiometabolic disorders, neurodegeneration, cancer, chronic inflammation, and frailty. Metformin al

Implications of amino acid sensing and dietary protein to the aging process

Every organism must adapt and respond appropriately to the source of nutrients available in its environment. Different mechanisms and pathways are involved in detecting the intracellular and extracellular levels of macronutrients including amino acids. Detection of amino acids in food sources is provided by taste cells expressing T1R1 and T1R3 type receptors. Additionally, cells of the intestine, pancreas or heart sense amino acids extracellularly. Neuronal and hormonal regulation integrates and coordinates the signals at the organismal level. Amino acid-sensitive mechanisms including GCN2 protein, mTOR and LYNUS machinery adjust cellular process according to the availability of specific amino acids. Triggering these mechanisms by genetic manipulations or by external manipulations with diet

Within-diet variation in rates of macronutrient consumption and reproduction does not accompany changes in lifespan in Drosophila melanogaster

Interventions such as caloric or dietary restriction extend lifespan in organisms spanning from yeast to primates. Despite its positive influence on longevity, dietary restriction has been found to negatively affect reproduction. Many studies have reported negative correlations between lifespan and reproductive characteristics (such as mating rate, fecundity, reproductive period, and others). Such correlation gives the appearance of a resource-based trade-off between these two life-history traits. Here, we have used nutritional geometry to confirm previous findings in flies that dietary macronutrient balance (protein-to-carbohydrate ratio, P:C) impacts both lifespan and reproduction, such that across a series of diets differing in P:C, maximum lifespan was observed at a lower P:C (1:8) than that which supported highest fecundity (1:1.5). We have then addressed the question whether variation among Drosophila melanogasterMeigen (Diptera: Drosophilidae) fruit flies in food intake and egg production within a single dietary treatment is negatively associated with within-diet variation in lifespan, as might be expected under a resource-based trade-off. There was no such associat

Nanodelivery of phytobioactive compounds for treating aging-associated disorders

Aging population presents a major challenge for many countries in the world and has made the development of efficient means for healthspan extension a priority task for researchers and clinicians worldwide. Anti-aging properties including antioxidant, anti-inflammatory, anti-tumor, and cardioprotective activities have been reported for various phytobioactive compounds (PBCs) including resveratrol, quercetin, curcumin, catechin, etc. However, the therapeutic potential of orally administered PBCs is limited by their poor stability, bioavailability, and solubility in the gastrointestinal tract. Recently, innovative nanotechnology-based approaches have been developed to improve the bioactivity of PBCs and enhance their potential in preventing and/or treating age-associated disorders, primarily those caused by aging-related chronic inflammation. PBC-loaded nanoparticles designed for oral administration provide many benefits over conventional formulations, including enhanced stability and solubility, prolonged half-life, improved epithelium permeability and bioavailability, enhanced tissue targeting, and minimized side effects. The present review summarizes recent advances in this rapidly developing research area

Mating status affects Drosophila lifespan, metabolism and antioxidant system

In Drosophila melanogaster, lifespan and fitness traits were investigated as a function of mating status. Four mating protocols were used: virgin males and females, males and females allowed to copulate only once; males and females that had multiple copulations with one partner over the 5-day mating period; and polygamous males and females that had multiple copulations with different partners over the 5-day mating period. Virgin females had the longest lifespan, and polygamous females had the shortest lifespan, potentially due to injuries, infections or exposure to toxic accessory gland products obtained from different males. Reduced lifespan was also observed in males mated to multiple females. U

Parental dietary protein-to-carbohydrate ratio affects offspring lifespan and metabolism in drosophila

Non-genetic inheritance of metabolic state over multiple generations has been widely reported in insects. The present study uses the fruit fly, Drosophila melanogaster, to assess whether lifespan, physiological traits and metabolism are affected by the dietary protein-to-carbohydrate ratio (P:C) of the prior adult generation. Groups of parental flies were fed diets with different P:C ratios. Their progeny groups were raised on the same diet so the only variable in the experiments was the diet fed to the parents. Parental P:C affected the lifespan of female offspring, however had no impact on F1 males survival. Low parental P:C increased feeding rate in progeny. An increase in the P:C ratio from 0.03 to 0.65 decreased the levels of body glucose and trehalose in the offspring and a similar tendency was observed in the levels of circulating hemolymph glucose and trehalose. Offspring also accumulated less triglycerides but more glycogen when parents were fed a low P:C diet. Our study indicates that the parental dietary P:C ration has a strong impact on the lifespan, reproduction, appetite and metabolism in the offspring generation