AlPater Posted February 16, 2017 Author Report Share Posted February 16, 2017 (edited) A screening strategy for the discovery of drugs that reduce C/EBPβ-LIP translation with potential calorie restriction mimetic properties. Zaini MA, Müller C, Ackermann T, Reinshagen J, Kortman G, Pless O, Calkhoven CF. Sci Rep. 2017 Feb 15;7:42603. doi: 10.1038/srep42603. PMID: 28198412 http://www.nature.com/articles/srep42603?WT.feed_name=subjects_molecular-biology Abstract An important part of the beneficial effects of calorie restriction (CR) on healthspan and lifespan is mediated through regulation of protein synthesis that is under control of the mechanistic target of rapamycin complex 1 (mTORC1). As one of its activities, mTORC1 stimulates translation into the metabolic transcription factor CCAAT/Enhancer Binding Protein β (C/EBPβ) isoform Liver-specific Inhibitory Protein (LIP). Regulation of LIP expression strictly depends on a translation re-initiation event that requires a conserved cis-regulatory upstream open reading frame (uORF) in the C/EBPβ-mRNA. We showed before that suppression of LIP in mice, reflecting reduced mTORC1-signaling at the C/EBPβ level, results in CR-type of metabolic improvements. Hence, we aim to find possibilities to pharmacologically down-regulate LIP in order to induce CR-mimetic effects. We engineered a luciferase-based cellular reporter system that acts as a surrogate for C/EBPβ-mRNA translation, emulating uORF-dependent C/EBPβ-LIP expression under different translational conditions. By using the reporter system in a high-throughput screening (HTS) strategy we identified drugs that reduce LIP. The drug Adefovir Dipivoxil passed all counter assays and increases fatty acid β-oxidation in a hepatoma cell line in a LIP-dependent manner. Therefore, these drugs that suppress translation into LIP potentially exhibit CR-mimetic properties. The Hunger Gains: Extreme Calorie-Restriction Diet Shows Anti-Aging Results A new study shows five days of hunger a month may reduce risk factors for aging and age-related diseases By Richard Conniff on February 16, 2017 https://www.scientificamerican.com/article/the-hunger-gains-extreme-calorie-restriction-diet-shows-anti-aging-results/ The idea that organisms can live longer, healthier lives by sharply reducing their calorie intake is not exactly new. Laboratory research has repeatedly demonstrated the anti-aging value of calorie restriction, often called CR, in animals from nematodes to rats—with the implication that the same might be true for humans. In practice though, permanently reducing calorie intake by 25 to 50 percent or more sounds to many like a way to extend life by making it not worth living. Researchers have also warned that what works for nematodes or rats may not work—and could even prove dangerous—in humans, by causing muscle or bone density loss, for example. But now two new studies appear to move calorie restriction from the realm of wishful thinking to the brink of practical, and perhaps even tolerable, reality. Writing in Nature Communications, researchers at the University of Wisconsin–Madison and the National Institute on Aging reported last month chronic calorie restriction produces significant health benefits in rhesus monkeys—a primate with humanlike aging patterns—indicating “that CR mechanisms are likely translatable to human health.” The researchers describe one monkey they started on a 30 percent calorie restriction diet when he was 16 years old, late middle age for this type of animal. He is now 43, a longevity record for the species, according to the study, and the equivalent of a human living to 130. In the second study, published this week in Science Translational Medicine, a research team led by gerontologist Valter Longo at the University of Southern California (U.S.C.) suggests it is possible to gain anti-aging benefits without signing up for a lifetime of hunger. Instead, a “fasting-mimicking diet,” practiced just five days a month for three months—and repeated at intervals as needed—is “safe, feasible and effective in reducing risk factors for aging and age-related diseases.” Some researchers, however, still find the calorie-restriction argument unpersuasive. Leslie Robert, a biochemist and physician at the University of Paris who was not involved in the two new studies, says pharmaceutical approaches offer greater anti-aging potential than “inefficient and apparently harmful” diets. The important thing, adds Luigi Fontana, a longevity researcher at the Washington University School of Medicine in Saint Louis who also was not involved in the new work, is “if you’re doing a healthy diet, exercising, everything good, without doing anything extreme, without making life miserable by counting every single calorie.” Rozalyn Anderson, a researcher in the Wisconsin study, does not necessarily disagree. “Life is difficult enough without engaging in some bonkers diet,” she says. “We really study this as a paradigm to understand aging. We’re not recommending people do it.” The combined results in the Nature Communications paper show aging is “malleable” in primates, she explains, and that “aging itself presents a reasonable target for intervention.” Whereas conventional medicine views aging as a fight against cancer, cardiovascular issues, neural degeneration and other diseases, she adds, calorie restriction “delays the aging and vulnerability. Instead of going after diseases one at a time, you go after the underlying vulnerability and tackle them all at once.” Despite her reservations about recommending CR, Anderson praised the work of the research team in the Science Translational Medicine study for “pushing this forward for possible application in clinics.” In that study, test subjects followed a carefully designed 50 percent calorie restricted diet (totaling about 1,100 calories on the first day and 70 percent (about 700 calories) on the next four days, then ate whatever they wanted for the rest of the month. Longo, the gerontologist at U.S.C., says the underlying theory of the on-again/off-again approach is that the regenerative effects of the regimen occur not so much from the fasting itself as from the recovery afterward. By contrast, long-term, uninterrupted calorie restriction can lead to the sort of negative effects seen in extreme conditions like anorexia. The calorie-restricted diet in Longo’s study was 100 percent plant-based and featured vegetable soups, energy bars, energy drinks and a chip snack as well as mineral and vitamin supplements. It included nutrients designed to manipulate the expression of genes involved in aging-related processes, Longo explains. (Longo and U.S.C. are both owners of L-Nutra, the company that manufactures the diet. But he says he takes no salary or consulting fees from the company and has assigned his shares to a nonprofit organization established to support further research.) Even the five-day-a-month calorie restriction regimen was apparently a struggle for some test subjects, resulting in a 25 percent dropout rate. But health benefits in the form of decreased body mass and better levels of glucose, triglycerides and cholesterol, along with other factors, showed up after the third month and persisted for at least three months—even after subjects had returned full-time to a normal diet. Notably, given concerns about other forms of calorie restriction, lean muscle mass remained unchanged. The benefits were greater for people who were obese or otherwise unhealthy, Longo says. But those individuals might also need to repeat the five-day regimen as often as once a month to the point of recovery, he adds, whereas individuals who are already healthy and athletic might repeat it just twice a year. Neither of the two new studies argues the benefits of CR necessarily add up to a longer life. Longevity in humans is still an unpredictable by-product of our myriad variations in individual biology, behavior and circumstance. The objective, according to researchers, is merely to make the healthy portion of our lives last longer. >>>>>>>>>>>>>>>>>>>>>>>>>>>> Caloric restriction improves health and survival of rhesus monkeys. Mattison JA, Colman RJ, Beasley TM, Allison DB, Kemnitz JW, Roth GS, Ingram DK, Weindruch R, de Cabo R, Anderson RM. Nat Commun. 2017 Jan 17;8:14063. doi: 10.1038/ncomms14063. PMID: 28094793 Free PMC Article https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5247583/pdf/ncomms14063.pdf >>>>>>>>>>>>>>>>>>>>>>>>>>>>> Fasting-mimicking diet and markers/risk factors for aging, diabetes, cancer, and cardiovascular disease BY MIN WEI, SEBASTIAN BRANDHORST, MAHSHID SHELEHCHI, HAMED MIRZAEI, CHIA WEI CHENG, JULIA BUDNIAK, SUSAN GROSHEN, WENDY J. MACK, ESRA GUEN, STEFANO DI BIASE, PINCHAS COHEN, TODD E. MORGAN, TANYA DORFF, KURT HONG, ANDREAS MICHALSEN, ALESSANDRO LAVIANO, VALTER D. LONGO Science Translational Medicine 15 Feb 2017: Vol. 9, Issue 377, DOI: 10.1126/scitranslmed.aai8700 http://sci-hub.cc/10.1126/scitranslmed.aai8700 A periodic fasting diet improves markers of metabolic dysfunction, particularly in people already at risk. Editor's Summary Fasting: More than a fad Mice that fast periodically are healthier, metabolically speaking. To explore whether fasting can help people as well, Wei et al. studied 71 people who either consumed a fasting-mimicking diet for 5 days each month for 3 months or maintained their normal diet for 3 months and then switched to the fasting schedule. The fasting-like diet reduced body weight and body fat, lowered blood pressure, and decreased the hormone IGF-1, which has been implicated in aging and disease. A post hoc analysis replicated these results and also showed that fasting decreased BMI, glucose, triglycerides, cholesterol, and C-reactive protein (a marker for inflammation). These effects were generally larger in the subjects who were at greater risk of disease at the start of the study. A larger study is needed to replicate these results, but they raise the possibility that fasting may be a practical road to a healthy metabolic system. Abstract Calorie restriction or changes in dietary composition can enhance healthy aging, but the inability of most subjects to adhere to chronic and extreme diets, as well as potentially adverse effects, limits their application. We randomized 100 generally healthy participants from the United States into two study arms and tested the effects of a fasting-mimicking diet (FMD)—low in calories, sugars, and protein but high in unsaturated fats—on markers/risk factors associated with aging and age-related diseases. We compared subjects who followed 3 months of an unrestricted diet to subjects who consumed the FMD for 5 consecutive days per month for 3 months. Three FMD cycles reduced body weight, trunk, and total body fat; lowered blood pressure; and decreased insulin-like growth factor 1 (IGF-1). No serious adverse effects were reported. After 3 months, control diet subjects were crossed over to the FMD program, resulting in a total of 71 subjects completing three FMD cycles. A post hoc analysis of subjects from both FMD arms showed that body mass index, blood pressure, fasting glucose, IGF-1, triglycerides, total and low-density lipoprotein cholesterol, and C-reactive protein were more beneficially affected in participants at risk for disease than in subjects who were not at risk. Thus, cycles of a 5-day FMD are safe, feasible, and effective in reducing markers/risk factors for aging and age-related diseases. Larger studies in patients with diagnosed diseases or selected on the basis of risk factors are warranted to confirm the effect of the FMD on disease prevention and treatment. Edited February 16, 2017 by AlPater Quote Link to comment Share on other sites More sharing options...
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