Extended lifespan in female Drosophila melanogaster through late-life calorie restriction.

Calorie restriction has many beneficial effects on healthspan and lifespan in a variety of species. However, how late in life application of caloric restriction can extend fly life is not clear. Here we show that late-life calorie restriction increases lifespan in female Drosophila melanogaster aged on a high-calorie diet. This shift results in rapid decrease in mortality rate and extends fly lifespan. In contrast, shifting female flies from a low- to a high-calorie diet leads to a rapid increase in mortality and shorter lifespan. These changes are mediated by immediate metabolic and physiological adaptations. One of such adaptation is rapid adjustment in egg production, with flies directing excess energy towards egg production when shifted to a high diet, or away from reproduction in females shifted to low-caloric diet. However, lifelong female fecundity reveals no associated fitness cost due to CR when flies are shifted to a high-calorie diet. In view of high conservation of the beneficial effects of CR on physiology and lifespan in a wide variety of organisms, including humans, our findings could provide valuable insight into CR applications that could provide health benefits later in life.

Feasibility, safety, and efficacy of dietary or lifestyle interventions for hypothalamic obesity: A systematic review.

BACKGROUND & AIMS: A dysfunctional hypothalamus may result in decreased feelings of satiety (hyperphagia), decreased energy expenditure, and increased fat storage as a consequence of hyperinsulinemia. Hypothalamic dysfunction may thus lead to morbid obesity and can be encountered in childhood as a consequence of congenital, genetic, or acquired disorders. There is currently no effective treatment for hypothalamic obesity (HO). However, comparable to alimentary obesity, dietary and lifestyle interventions may be considered the cornerstones of obesity treatment. We questioned the effect of dietary or lifestyle interventions for HO and systematically searched the literature for evidence on feasibility, safety, or efficacy of dietary or lifestyle interventions for childhood hypothalamic overweight or obesity. METHODS: A systematic search was conducted in MEDLINE (including Cochrane Library), EMBASE, and CINAHL (May 2023). Studies assessing feasibility, safety, or efficacy of any dietary or lifestyle intervention in children with hypothalamic overweight or obesity, were included. Animal studies, studies on non-diet interventions, and studies with no full text available were excluded. Because the number of studies to be included was low, the search was repeated for adults with hypothalamic overweight or obesity. Risk of bias was assessed with an adapted Cochrane Risk of Bias Tool. Level of evidence was assessed using the GRADE system. Descriptive data were described, as pooled-data analysis was not possible due to heterogeneity of included studies. RESULTS: In total, twelve studies were included, with a total number of 118 patients (age 1-19 years) of whom one with craniopharyngioma, one with ROHHAD-NET syndrome, 50 with monogenic obesity, and 66 with Prader-Willi syndrome (PWS). Four studies reported a dietary intervention as feasible. However, parents did experience difficulties with children still stealing food, and especially lowering carbohydrates was considered to be challenging. Seven studies reported on efficacy of a dietary intervention: a well-balanced restrictive caloric diet (30% fat, 45% carbohydrates, and 25% protein) and various hypocaloric diets (8-10 kcal/cm/day) were considered effective in terms of weight stabilization or decrease. No negative effect on linear growth was reported. Four studies reported on specific lifestyle interventions, of which three also included a dietary intervention. Combined dietary and lifestyle intervention resulted in decreased BMI, although BMI returned to baseline values on long-term. One additional study was identified in adults after brain trauma and showed a significant reduction in BMI in one out of eight patients after a combined dietary and lifestyle intervention. CONCLUSIONS: Hypocaloric diet or restrictive macronutrient diet with lower percentage of carbohydrates seems feasible and effective for childhood HO, although most of the studies had a high risk of bias, small cohorts without control groups, and were conducted in children with PWS only, compromising the generalizability. Lifestyle interventions only resulted in BMI decrease in short-term, indicating that additional guidance is needed to sustain its effect in the long-term. Literature on feasibility and efficacy of a dietary or lifestyle intervention for hypothalamic overweight or obesity is scarce, especially in children with acquired HO (following treatment for a suprasellar tumor). There is need for prospective (controlled) studies to determine which dietary and lifestyle intervention are most helpful for this specific patient group.

A Randomized Trial of the Efficacy of Three Weight Loss Diet Interventions in Overweight/Obese with Polycystic Ovary Syndrome.

BACKGROUND: Polycystic Ovary Syndrome (PCOS) is a highly prevalent, complex, heterogeneous, polygenic endocrine disorder characterized by metabolic and reproductive dysfunction that affects 8-13% of women of reproductive age worldwide. The pathogenesis of PCOS has not been fully clarified and includes genetics, obesity, and insulin resistance (IR). Oxidative stress (OS) of PCOS is independent of obesity. It can induce IR through post-insulin receptor defects, impair glucose uptake in muscle and adipose tissue, and exacerbate IR by reducing insulin secretion from pancreatic ß-cells. OBJECTIVE: To investigate the effects of Calorie Restricted Diet (CRD), High Protein Diet (HPD), and High Protein and High Dietary Fiber Diet (HPD+HDF) on body composition, insulin resistance, and oxidative stress in overweight/obese PCOS patients. METHODS: A total of 90 overweight/obese patients with PCOS were selected to receive an 8- week medical nutrition weight loss intervention at our First Hospital of Peking University, and we randomly divided them into the CRD group (group A), the HPD group (group B), and the HPD+HDF group (group C), with 30 patients in each group. We measured their body composition, HOMA-IR index, and oxidative stress indicators. The t-test, Mann-Whitney U test, analysis of variance (ANOVA), and Kruskal-Wallis H test were used to compare the efficacy of the three methods. RESULTS: After eight weeks, the body weights of the three groups decreased by 6.32%, 5.70% and 7.24%, respectively, and the Visceral Fat Area (VFA) values decreased by 6.8 cm2, 13.4 cm2 and 23.45 cm2, respectively, especially in group C (p >0.05). The lean body mass (LBM), also known as the Fat-Free Mass (FFM) values of group B and group C after weight loss, were higher than that of group A (p >0.05). After weight loss, the homeostatic model assessment of insulin resistance (HOMA-IR) index and malondialdehyde (MDA) were decreased. Superoxide dismutase (SOD) was increased in all three groups (p >0.05), and the changes in SOD and MDA in group B and group C were more significant (p >0.05). HOMA-IR index positively correlated with body mass index (BMI) (r=0.195; p >0.05); MDA positively correlated with percent of body fat (PBF) (r=0.186; p >0.05) and HOMA-IR index (r=0.422; p >0.01); SOD positively correlated with LMI/FFMI (r=0.195; p >0.05), negatively correlated with HOMA-IR index (r=-0.433; p >0.01). CONCLUSION: All three diets were effective in reducing the body weight of overweight/obese patients with PCOS by more than 5% within 8 weeks and could improve both insulin resistance and oxidative stress damage. Compared with CRD, HPD and HPD+HDF diets could better retain lean body mass and significantly improve oxidative stress damage. CLINICAL TRIAL NUMBER: ChiCTR2100054961.

Clinical implications of nutritional interventions reducing calories, a systematic scoping review.

BACKGROUND & AIMS: Caloric restriction (CR) constitutes a dietary approach of (temporarily) reducing calorie intake thereby inducing resilience and resistance mechanisms and promoting health. While CR's feasibility and safety have been proven in human trials, its full benefits and translation to different study populations warrants further exploration. METHODS: We here conducted a systematic scoping review adhering to Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Our search resulted in 3745 individual records, of which 40 were included. We showed that all studies consistently demonstrated the feasibility and safety of CR-like interventions. The specific effects of nutritional preconditioning vary, further underscoring the need for carefully crafted strategies, according to the intended effect, patient population, and logistical limitations. CONCLUSIONS: CR-like interventions (long-term CR or short-term fasting) are feasible in a broad range of patient populations. Whether it has clinical benefit, f.i. reducing treatment-induced side effects and enhancing therapy efficacy, has to be investigated further.

Caloric restriction leading to attenuation of experimental Alzheimer's disease results from alterations in gut microbiome.

BACKGROUND: Caloric restriction (CR) might be effective for alleviating/preventing Alzheimer's disease (AD), but the biological mechanisms remain unclear. In the current study, we explored whether CR caused an alteration of gut microbiome and resulted in the attenuation of cognitive impairment of AD animal model. METHODS: Thirty-week-old male APP/PS1 transgenic mice were used as AD models (AD mouse). CR was achieved by 30% reduction of daily free feeding (ad libitum, AL) amount. The mice were fed with CR protocol or AL protocol for six consecutive weeks. RESULTS: We found that with CR treatment, AD mice showed improved ability of learning and spatial memory, and lower levels of Aß40, Aß42, IL-1ß, TNF-α, and ROS in the brain. By sequencing 16S rDNA, we found that CR treatment resulted in significant diversity in composition and abundance of gut flora. At the phylum level, Deferribacteres (0.04%), Patescibacteria (0.14%), Tenericutes (0.03%), and Verrucomicrobia (0.5%) were significantly decreased in CR-treated AD mice; at the genus level, Dubosiella (10.04%), Faecalibaculum (0.04%), and Coriobacteriaceae UCG-002 (0.01%) were significantly increased in CR-treated AD mice by comparing with AL diet. CONCLUSIONS: Our results demonstrate that the attenuation of AD following CR treatment in APP/PS1 mice may result from alterations in the gut microbiome. Thus, gut flora could be a new target for AD prevention and therapy.

Intermittent Fasting Regulates Metabolic Homeostasis and Improves Cardiovascular Health.

Obesity is a leading cause of morbidity and mortality globally. While the prevalence of obesity has been increasing, the incidence of its related complications including dyslipidemia and cardiovascular disease (CVD) has also been rising. Recent research has focused on modalities aimed at reducing obesity. Several modalities have been suggested including behavioral and dietary changes, medications, and bariatric surgery. These modalities differ in their effectiveness and invasiveness, with dietary changes gaining more interest due to their minimal risks compared to other modalities. Specifically, intermittent fasting (IF) has been gaining interest in the past decade. IF is characterized by cycles of alternating fasting and eating windows, with several different forms practiced. IF has been shown to reduce weight and alleviate obesity-related complications. Our review of clinical and experimental studies explores the effects of IF on the lipid profile, white adipose tissue (WAT) dynamics, and the gut microbiome. Notably, IF corrects dyslipidemia, reduces WAT accumulation, and decreases inflammation, which reduces CVD and obesity. This comprehensive analysis details the protective metabolic role of IF, advocating for its integration into public health practices.

Preconceptional paternal caloric restriction of high-fat diet-induced obesity in Wistar rats dysregulates the metabolism of their offspring via AMPK/SIRT1 pathway.

BACKGROUND: Obesity is a metabolic syndrome where allelic and environmental variations together determine the susceptibility of an individual to the disease. Caloric restriction (CR) is a nutritional dietary strategy recognized to be beneficial as a weight loss regime in obese individuals. Preconceptional parental CR is proven to have detrimental effects on the health and development of their offspring. As yet studies on maternal CR effect on their offspring are well established but paternal CR studies are not progressing. In current study, the impact of different paternal CR regimes in diet-induced obese male Wistar rats (WNIN), on their offspring concerning metabolic syndrome are addressed. METHODS: High-fat diet-induced obese male Wistar rats were subjected to caloric restriction of 50% (HFCR-I) and 40% (HFCR-II) and then they were mated with normal females. The male parent's reproductive function was assessed by sperm parameters and their DNMT's mRNA expression levels were also examined. The offspring's metabolic function was assessed by physiological, biochemical and molecular parameters. RESULTS: The HFCR-I male parents have shown reduced body weights, compromised male fertility and reduced DNA methylation activity. Further, the HFCR-I offspring showed attenuation of the AMPK/SIRT1 pathway, which is associated with the progression of proinflammatory status and oxidative stress. In line, the HFCR-I offspring also developed altered glucose and lipid homeostasis by exhibiting impaired glucose tolerance & insulin sensitivity, dyslipidemia and steatosis. However, these effects were largely mitigated in HFCR-II offspring. Regarding the obesogenic effects, female offspring exhibited greater susceptibility than male offspring, suggesting that females are more prone to the influences of the paternal diet. CONCLUSION: The findings highlight that HFCR-I resulted in paternal undernutrition, impacting the health of offspring, whereas HFCR-II largely restored the effects of a high-fat diet on their offspring. As a result, moderate caloric restriction has emerged as an effective weight loss strategy with minimal implications on future generations. This underscores the shared responsibility of fathers in contributing to sperm-specific epigenetic imprints that influence the health of adult offspring.

Short lifespan is one's fate, long lifespan is one's achievement: lessons from Daphnia.

Studies of longevity rely on baseline life expectancy of reference genotypes measured in standardized conditions. Variation among labs, protocols, and genotypes makes longevity intervention studies difficult to compare. Furthermore, extending lifespan under suboptimal conditions or that of a short-lived genotype may be of a lesser theoretical and translational value than extending the maximal possible lifespan. Daphnia is becoming a model organism of choice for longevity research complementing data obtained on traditional models. In this study, we report longevity of several genotypes of a long-lived species D. magna under a variety of protocols, aiming to document the highest lifespan, factors reducing it, and parameters that change with age and correlate with longevity. Combining longevity data from 25 experiments across two labs, we report a strong intraspecific variation, moderate effects of group size and medium composition, and strong genotype-by-environment interactions with respect to food level. Specifically, short-lived genotypes show no caloric restriction (CR) effect, while long-lived ones expand their lifespan even further under CR. We find that the CR non-responsive clones show little correlation between longevity and two measures of lipid peroxidation. In contrast, the long-lived, CR-responsive clones show a positive correlation between longevity and lipid hydroperoxide abundance, and a negative correlation with MDA concentration. This indicates differences among genotypes in age-related accumulation and detoxification of LPO products and their effects on longevity. Our observations support the hypothesis that a long lifespan can be affected by CR and levels of oxidative damage, while genetically determined short lifespan remains short regardless.

Caloric restriction reduces trabecular bone loss during aging and improves bone marrow adipocyte endocrine function in male mice.

Introduction: Caloric restriction (CR) is a nutritional intervention that increases life expectancy while lowering the risk for cardio-metabolic disease. Its effects on bone health, however, remain controversial. For instance, CR has been linked to increased accumulation of bone marrow adipose tissue (BMAT) in long bones, a process thought to elicit detrimental effects on bone. Qualitative differences have been reported in BMAT in relation to its specific anatomical localization, subdividing it into physiological and potentially pathological BMAT. We here examine the local impact of CR on bone composition, microstructure and its endocrine profile in the context of aging. Methods: Young and aged male C57Bl6J mice were subjected to CR for 8 weeks and were compared to age-matched littermates with free food access. We assessed bone microstructure and BMAT by micro-CT, bone fatty acid and transcriptomic profiles, and bone healing. Results: CR increased tibial BMAT accumulation and adipogenic gene expression. CR also resulted in elevated fatty acid desaturation in the proximal and mid-shaft regions of the tibia, thus more closely resembling the biochemical lipid profile of the distally located, physiological BMAT. In aged mice, CR attenuated trabecular bone loss, suggesting that CR may revert some aspects of age-related bone dysfunction. Cortical bone, however, was decreased in young mice on CR and remained reduced in aged mice, irrespective of dietary intervention. No negative effects of CR on bone regeneration were evident in either young or aged mice. Discussion: Our findings indicate that the timing of CR is critical and may exert detrimental effects on bone biology if administered during a phase of active skeletal growth. Conversely, CR exerts positive effects on trabecular bone structure in the context of aging, which occurs despite substantial accumulation of BMAT. These data suggest that the endocrine profile of BMAT, rather than its fatty acid composition, contributes to healthy bone maintenance in aged mice.

Deficiency of glucocorticoid receptor in bone marrow adipocytes has mild effects on bone and hematopoiesis but does not influence expansion of marrow adiposity with caloric restriction.

Introduction: Unlike white adipose tissue depots, bone marrow adipose tissue (BMAT) expands during caloric restriction (CR). Although mechanisms for BMAT expansion remain unclear, prior research suggested an intermediary role for increased circulating glucocorticoids. Methods: In this study, we utilized a recently described mouse model (BMAd-Cre) to exclusively target bone marrow adipocytes (BMAds) for elimination of the glucocorticoid receptor (GR) (i.e. Nr3c1) whilst maintaining GR expression in other adipose depots. Results: Mice lacking GR in BMAds (BMAd-Nr3c1 -/-) and control mice (BMAd-Nr3c1 +/+) were fed ad libitum or placed on a 30% CR diet for six weeks. On a normal chow diet, tibiae of female BMAd-Nr3c1-/- mice had slightly elevated proximal trabecular metaphyseal bone volume fraction and thickness. Both control and BMAd-Nr3c1-/- mice had increased circulating glucocorticoids and elevated numbers of BMAds in the proximal tibia following CR. However, no significant differences in trabecular and cortical bone were observed, and quantification with osmium tetroxide and µCT revealed no difference in BMAT accumulation between control or BMAd-Nr3c1 -/- mice. Differences in BMAd size were not observed between BMAd-Nr3c1-/- and control mice. Interestingly, BMAd-Nr3c1-/- mice had decreased circulating white blood cell counts 4 h into the light cycle. Discussion: In conclusion, our data suggest that eliminating GR from BMAd has minor effects on bone and hematopoiesis, and does not impair BMAT accumulation during CR.

Overnutrition, Hyperinsulinemia and Ectopic Fat: It Is Time for A Paradigm Shift in the Management of Type 2 Diabetes.

The worldwide incidence of prediabetes/type 2 has continued to rise the last 40 years. In the same period, the mean daily energy intake has increased, and the quality of food has significantly changed. The chronic exposure of pancreatic ß-cells to calorie excess (excessive energy intake) and food additives may increase pancreatic insulin secretion, decrease insulin pulses and/or reduce hepatic insulin clearance, thereby causing chronic hyperinsulinemia and peripheral insulin resistance. Chronic calorie excess and hyperinsulinemia may promote lipogenesis, inhibit lipolysis and increase lipid storage in adipocytes. In addition, calorie excess and hyperinsulinemia can induce insulin resistance and contribute to progressive and excessive ectopic fat accumulation in the liver and pancreas by the conversion of excess calories into fat. The personal fat threshold hypothesis proposes that in susceptible individuals, excessive ectopic fat accumulation may eventually lead to hepatic insulin receptor resistance, the loss of pancreatic insulin secretion, hyperglycemia and the development of frank type 2 diabetes. Thus, type 2 diabetes seems (partly) to be caused by hyperinsulinemia-induced excess ectopic fat accumulation in the liver and pancreas. Increasing evidence further shows that interventions (hypocaloric diet and/or bariatric surgery), which remove ectopic fat in the liver and pancreas by introducing a negative energy balance, can normalize insulin secretion and glucose tolerance and induce the sustained biochemical remission of type 2 diabetes. This pathophysiological insight may have major implications and may cause a paradigm shift in the management of type 2 diabetes: avoiding/reducing ectopic fat accumulation in the liver and pancreas may both be essential to prevent and cure type 2 diabetes.

Twice-Weekly 36-Hour Intermittent Fasting Practice Attenuates Hunger, Quadruples ß-Hydroxybutyrate, and Maintains Weight Loss: A Case Report.

Intermittent fasting (IF) approach to weight loss obviates the inconvenience of calorie counting required in daily caloric restriction (DCR). A metabolic defense mechanism (MDM) obstructs weight loss and facilitates weight regain possibly by increasing hunger and efficiency of exercise energy expenditure (EEf), and by reducing resting metabolic rate (RMR) and energy expenditure (EE) including physical activity (PA). IF may test whether its paradigm can better counteract MDM than DCR. A knowledge gap exists about whether the duration of weekly uninterrupted fasts (UFs), when the IF protocols are isocaloric, affects the MDM. The aim and objective of this 82-week study were to determine whether 36 hours of near-absolute twice-weekly UF will exacerbate MDM but generate similar rates of weight and fat losses compared to four IF studies featuring 20 hours of weekly UF with both IF protocols matched for weekly hours of fast (108) and free access to food (60), a fasting-to-eating (F/E) ratio of 1.8. This case report presents results of twice-weekly fasting on non-consecutive days (5:2-NC) and compares them to results from a 4:3-NC protocol with a 20-hour UF caused by a modification of providing a 500-600 kcal meal on three fasting days (M4:3-NC). Because the large meal raises insulin concentration for four hours at the start of the fasting day, the 20-hour UF consists of the remaining eight hours on the fasting day, followed by 12 additional nocturnal hours of fasting. The hypotheses were that (1) because of their matched F/E ratio, the rates of weight and fat losses will be similar in both protocols, and (2) because of its longer UF period, hunger will be higher and RMR and EE will be lower, in 5:2-NC than in M4:3-NC protocol. The main findings were that the 5:2-NC protocol produced (1) slower rates of weight and fat losses, (2) modest reduction in the sensation of hunger and substantial decline in fullness, (3) no change in RMR and EE, and (4) fourfold post-fast increase in the circulating concentration of the ketone body ß-hydroxybutyrate (BHB), 2.5 greater than in the M4:3-NC protocol. The absence of increased hunger and changes in EE, the variability of the rate of weight loss in the 5:2-NC protocol, plus increased EEf in one M4:3-NC study, suggest that IF does not mitigate MDM, but that shortened UF period in M4:3-NC reduces the rise in BHB. Thus, the addition of a large meal on fasting days is unnecessary for the prevention of hunger and is counterproductive for increases in BHB and its potential health benefits. Continuous practice of the 5:2-NC protocol allows sustained weight loss and maintenance of lost weight with diminished hunger for as long as it is implemented.

How Dietary Choices and Nutritional Knowledge Relate to Eating Disorders and Body Esteem of Medical Students? A Single-Center Cross-Sectional Study.

Eating disorders and body image concerns are increasingly prevalent issues among young individuals, with medical students being particularly vulnerable due to heightened stress levels. This study enrolled 879 medical students to investigate these concerns. The KomPAN questionnaire was utilized to assess dietary habits and knowledge, the Body Esteem Scale (BES) to evaluate body satisfaction, and The Eating Attitudes Test (EAT-26) to identify eating disorders. A higher level of nutritional knowledge was found to be statistically significantly associated with attempts at excessive calorie restriction among women (ß = 0.0864) and negatively among men (ß = -0.2039). Moreover, it was negatively associated with self-control of food intake only among men (ß = -0.2060). Furthermore, a higher BMI was associated with attempts of excessive calorie restriction in both women and men (ß = 0.1052 and ß = 0.1656, respectively) and negatively with self-control of food intake (ß = -0.0813 and ß = -0.1453, respectively). A higher BMI was associated with poorer body esteem across all variables in both genders, except for upper body strength among men. Nutritional knowledge did not correspond with any of these variables, while dietary quality was positively associated with physical condition in women and with physical condition, physical attractiveness, and upper body strength in men. Our study findings suggest that dietary interventions could be improved by considering gender-based behavioral differences and focusing on portion control for individuals with a higher BMI. Caution is warranted in extrapolating the results to the general population due to the specific nature of the study population.

The Effects of Caloric Restriction on Inflammatory Targets in the Prostates of Aged Rats.

Numerous animal models have demonstrated that caloric restriction (CR) is an excellent tool to delay aging and increase the quality of life, likely because it counteracts age-induced oxidative stress and inflammation. The aging process can affect the prostate in three ways: the onset of benign prostatic hyperplasia, prostatitis, and prostate cancer. In this study, we used 14 aged male Sprague Dawley rats, which were allocated into two groups, at the age of 18 months old. One group was fed ad libitum (a normal diet (ND)), and the other group followed a caloric restriction diet with a 60% decrease in intake. The rats were sacrificed at the age of 24 months. By immunohistochemical (IHC) and Western blot (WB) analyses, we studied the variations between the two groups in immune inflammation and fibrosis-related markers in aged prostate tissues. Morphological examinations showed lower levels of prostatic hyperplasia and fibrosis in the CR rats vs. the ND rats. The IHC results revealed that the prostates of the CR rats exhibited a lower immune proinflammatory infiltrate level and a reduced expression of the NLRP3 inflammasome pathway, together with significantly reduced expressions of mesenchymal markers and the profibrotic factor TGFß1. Finally, by WB analysis, we observed a reduced expression of ERα, which is notoriously implicated in prostate stromal proliferation, and increased expressions of SOD1 and Hsp70, both exerting protective effects against oxidative stress. Overall, these data suggest that CR brings potential benefits to prostatic tissues as it reduces the physiological immune-inflammatory processes and the tissue remodeling caused by aging.

Curcumin protects against aging-related stress and dysfunction through autophagy activation in rat brain.

BACKGROUND: Curcumin (Curcuma longa) is a well-known medicinal plant that induces autophagy in various model species, helping maintain cellular homeostasis. Its role as a caloric restriction mimetic (CRM) is being investigated. This study explores the potential of curcumin (CUR), as a CRM, to provide neuroprotection in D galactose induced accelerated senescence model of rats through modulation of autophagy. For six weeks, male rats received simultaneous supplementation of D-gal (300 mg/kg b.w., subcutaneously) and CUR (200 mg/kg b.w., oral). METHOD AND RESULTS: The oxidative stress indices, antioxidants, and electron transport chain complexes in brain tissues were measured using standard methods. Reverse transcriptase-polymerase chain reaction (RT-PCR) gene expression analysis was used to evaluate the expression of autophagy, neuroprotection, and aging marker genes. Our results show that curcumin significantly (p ≤ 0.05) enhanced the level of antioxidants and considerably lowered the level of oxidative stress markers. Supplementing with CUR also increased the activity of electron transport chain complexes in the mitochondria of aged brain tissue, demonstrating the antioxidant potential of CUR at the mitochondrial level. CUR was found to upregulate the expression of the aging marker gene (SIRT-1) and the genes associated with autophagy (Beclin-1 and ULK-1), as well as neuroprotection (NSE) in the brain. The expression of IL-6 and TNF-α was downregulated. CONCLUSION: Our findings demonstrate that CUR suppresses oxidative damage brought on by aging by modulating autophagy. These findings imply that curcumin might be beneficial for neuroprotection in aging and age-related disorders.

The ICL1 and MLS1 Genes, Integral to the Glyoxylate Cycle, are Essential and Specific for Caloric Restriction-Mediated Extension of Lifespan in Budding Yeast.

The regulation of complex energy metabolism is intricately linked to cellular energy demands. Caloric restriction (CR) plays a pivotal role in modulating the expression of genes associated with key metabolic pathways, including glycolysis, the tricarboxylic acid (TCA) cycle, and the glyoxylate cycle. In this study, the chronological lifespan (CLS) of 35 viable single-gene deletion mutants under both non-restricted and CR conditions, focusing on genes related to these metabolic pathways is evaluated. CR is found to increase CLS predominantly in mutants associated with the glycolysis and TCA cycle. However, this beneficial effect of CR is not observed in mutants of the glyoxylate cycle, particularly those lacking genes for critical enzymes like isocitrate lyase 1 (icl1Δ) and malate synthase 1 (mls1Δ). This analysis revealed an increase in isocitrate lyase activity, a key enzyme of the glyoxylate cycle, under CR, unlike the activity of isocitrate dehydrogenase, which remains unchanged and is specific to the TCA cycle. Interestingly, rapamycin, a compound known for extending lifespan, does not increase the activity of the glyoxylate cycle enzyme. This suggests that CR affects lifespan through a distinct metabolic mechanism.

Caloric restriction mitigates age-associated senescence characteristics in subcutaneous adipose tissue-derived stem cells.

Adipose tissue regulates metabolic balance, but aging disrupts it, shifting fat from insulin-sensitive subcutaneous to insulin-resistant visceral depots, impacting overall metabolic health. Adipose-derived stem cells (ASCs) are crucial for tissue regeneration, but aging diminishes their stemness and regeneration potential. Our findings reveal that aging is associated with a decrease in subcutaneous adipose tissue mass and an increase in the visceral fat depots mass. Aging is associated with increase in adipose tissue fibrosis but no significant change in adipocyte size was observed with age. Long term caloric restriction failed to prevent fibrotic changes but resulted in significant decrease in adipocytes size. Aged subcutaneous ASCs displayed an increased production of ROS. Using mitochondrial membrane activity as an indicator of stem cell quiescence and senescence, we observed a significant decrease in quiescence ASCs with age exclusively in subcutaneous adipose depot. In addition, aged subcutaneous adipose tissue accumulated more senescent ASCs having defective autophagy activity. However, long-term caloric restriction leads to a reduction in mitochondrial activity in ASCs. Furthermore, caloric restriction prevents the accumulation of senescent cells and helps retain autophagy activity in aging ASCs. These results suggest that caloric restriction and caloric restriction mimetics hold promise as a potential strategy to rejuvenate the stemness of aged ASCs. Further investigations, including in vivo evaluations using controlled interventions in animals and human studies, will be necessary to validate these findings and establish the clinical potential of this well-established approach for enhancing the stemness of aged stem cells.

Effects of food restriction on voluntary wheel-running behavior and body mass in selectively bred High Runner lines of mice.

Food restriction can have profound effects on various aspects of behavior, physiology, and morphology. Such effects might be amplified in animals that are highly active, given that physical activity can represent a substantial fraction of the total daily energy budget. More specifically, some effects of food restriction could be associated with intrinsic, genetically based differences in the propensity or ability to perform physical activity. To address this possibility, we studied the effects of food restriction in four replicate lines of High Runner (HR) mice that have been selectively bred for high levels of voluntary wheel running. We hypothesized that HR mice would respond differently than mice from four non-selected Control (C) lines. Healthy adult females from generation 65 were housed individually with wheels and provided access to food and water ad libitum for experimental days 1-19 (Phase 1), which allowed mice to attain a plateau in daily running distances. Ad libitum food intake of each mouse was measured on days 20-22 (Phase 2). After this, each mouse experienced a 20 % food restriction for 7 days (days 24-30; Phase 3), and then a 40 % food restriction for 7 additional days (days 31-37; Phase 4). Mice were weighed on experimental days 1, 8, 9, 15, 20, and 23-37 and wheel-running activity was recorded continuously, in 1-minute bins, during the entire experiment. Repeated-measures ANOVA of daily wheel-running distance during Phases 2-4 indicated that HR mice always ran much more than C, with values being 3.29-fold higher during the ad libitum feeding trial, 3.58-fold higher with -20 % food, and 3.06-fold higher with -40 % food. Seven days of food restriction at -20 % did not significantly reduce wheel-running distance of either HR (-5.8 %, P = 0.0773) or C mice (-13.3 %, P = 0.2122). With 40 % restriction, HR mice showed a further decrease in daily wheel-running distance (P = 0.0797 vs. values at 20 % restriction), whereas C mice did not (P = 0.4068 vs. values at 20 % restriction) and recovered to levels similar to those on ad libitum food (P = 0.3634). For HR mice, daily running distances averaged 11.4 % lower at -40 % food versus baseline values (P = 0.0086), whereas for C mice no statistical difference existed (-4.8 %, P = 0.7004). Repeated-measures ANOVA of body mass during Phases 2-4 indicated a highly significant effect of food restriction (P = 0.0001), but no significant effect of linetype (P = 0.1764) and no interaction (P = 0.8524). Both HR and C mice had a significant reduction in body mass only when food rations were reduced by 40 % relative to ad libitum feeding, and even then the reductions averaged only -0.60 g for HR mice (-2.6 %) and -0.49 g (-2.0 %) for C mice. Overall, our results indicate a surprising insensitivity of body mass to food restriction in both high-activity (HR) and ordinary (C) mice, and also insensitivity of wheel running in the C lines of mice, thus calling for studies of compensatory mechanisms that allow this insensitivity.

Deletion of Hsd11b1 suppresses caloric restriction-induced bone marrow adiposity in male but not female mice.

Bone marrow adipose tissue (BMAT) comprises >10% of total adipose mass in healthy humans. It increases in diverse conditions, including ageing, obesity, osteoporosis, glucocorticoid therapy, and notably, during caloric restriction (CR). BMAT potentially influences skeletal, metabolic, and immune functions, but the mechanisms of BMAT expansion remain poorly understood. Our hypothesis is that, during CR, excessive glucocorticoid activity drives BMAT expansion. The enzyme 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) amplifies glucocorticoid activity by catalysing intracellular regeneration of active glucocorticoids from inert 11-keto forms. Mice lacking 11ß-HSD1 resist metabolic dysregulation and bone loss during exogenous glucocorticoid excess; thus, we hypothesised that 11ß-HSD1 knockout mice would also resist excessive glucocorticoid action during CR, thereby restrining BMAT expansion and bone loss. To test this, we first confirmed that 11ß-HSD1 is expressed in mouse and human bone marrow. We then investigated the effects of CR in male and female control and 11ß-HSD1 knockout mice from 9 to 15 weeks of age. CR increased Hsd11b1 mRNA in adipose tissue and bone marrow. Deletion of Hsd11b1 did not alter bone or BMAT characteristics in mice fed a control diet and had little effect on tibial bone microarchitecture during CR. Notably, Hsd11b1 deletion attenuated the CR-induced increases in BMAT and prevented increases in bone marrow corticosterone in males but not females. This was not associated with suppression of glucocorticoid target genes in bone marrow. Instead, knockout males had increased progesterone in plasma and bone marrow. Together, our findings show that knockout of 11ß-HSD1 prevents CR-induced BMAT expansion in a sex-specific manner and highlights progesterone as a potential new regulator of bone marrow adiposity.

Effects of Dietary Restriction on PGC-1α Regulation in the Development of Age-associated Diseases.

Ageing is the most significant risk factor for a number of non-communicable diseases, manifesting as cognitive, metabolic, and cardiovascular diseases. Although multifactorial, mitochondrial dysfunction and oxidative stress have been proposed to be the driving forces of ageing. Peroxisome proliferator-activated receptor γ coactivator α (PGC-1α) is a transcriptional coactivator central to various metabolic functions, of which mitochondrial biogenesis is the most prominent function. Inducible by various stimuli, including nutrient limitations, PGC-1α is a molecule of interest in the maintenance of mitochondrial function and, therefore, the prevention of degenerative diseases. This review involves a literature search for articles retrieved from PubMed using PGC-1α, ageing, and dietary restriction as keywords. Dietary restriction has been shown to promote tissue-specific PGC-1α expression. Both dietary restriction and PGC-1α upregulation have been shown to prolong the lifespans of both lower and higher-level organisms; the incidence of non-communicable diseases also decreased in fasting mammals. In conclusion, dietary interventions may delay ageing by regulating healthy mitochondria in various organs, presenting the possibility of a new primary prevention for many age-related diseases.