Caloric Restriction Research Articles

Understanding the Multifaceted Process of Aging: Theories, Mechanisms, and Implications for Treatment

The aging process is a multifaceted biological phenomenon characterized by alterations at the molecular, cellular, and organ levels that culminate in a gradual, unavoidable, and unavoidable reduction in the body's capacity to react suitably to internal and/or external stimuli. Aging is a complex process that involves different mechanisms as The "Wear and Tear" Theory ,The Genetic Control Theory ,The Neuroendocrine Theory ,Waste Accumulation Theory ,Divisions Theory, Autoimmune Theory, Thymic-Stimulating Theory ,Mitochondrial Theory Mitochondria, Errors and Repairs Theory, Redundant DNA Theory Cross-Linkage Theory , Death Hormone Theory (DECO), Caloric Restriction Theory ,The Rate of Living Theory ,Gene Mutation Theory, Accumulated mutations Theory, Theory, Order to Disorder Theory, Disposable soma Theory, Antagonistic pleiotropy theory, The Telomerase Theory ,The free radical Theory. The two main categories of aging theories that explain cellular aging are structural damage and programmed theories. Different types of cells experience physiological stressors due to a range of circumstances. Notably, post-mitotic and mitotic cells have different capacities for proliferation and age differently in response to these pressures through different processes of cellular senescence and death, respectively. Over time, these aging cells build up and eventually cause old tissues to malfunction. The aim of this review is to throw light upon the effected of aging and who to treatment it.

Obesity and Colorectal Cancer: A Narrative Review.

Background and Objectives: Cancer is a multicausal disease, and environmental, cultural, socioeconomic, lifestyle, and genetic factors can influence the risk of developing cancer. Colorectal cancer (CRC) stands as the third most common cancer globally. Some countries have observed a rise in the incidence of CRC, especially among young people. This increase is associated with lifestyle changes over the last few decades, including changes in diet patterns, a sedentary lifestyle, and obesity. Currently, obesity and overweight account for approximately 39% of the world's population and increase the risk of overall mortality of certain cancer types. This study aims to conduct a literature review examining the association between obesity and CRC. Materials and Methods: This narrative review explored the pathophysiological mechanisms, treatment strategies, and challenges related to obesity and CRC. Results: Several studies have established a clear causal relationship between obesity and CRC, showing that individuals with morbid obesity are at a higher risk of developing colorectal cancer. The adipose tissue, particularly the visceral, secretes proinflammatory cytokines, such as TNF-alpha, interleukin-6, and C-reactive protein. Chronic inflammation is closely linked to cancer initiation and progression, with a complex interplay of molecular mechanisms underlying this association. Obesity can complicate the treatment of CRC due to several factors, reducing the therapeutic effectiveness and increasing the risk for adverse events during treatment. Dietary modification, calorie restriction, and other types of weight-control strategies can reduce the risk of CRC development and improve treatment outcomes. Conclusions: Obesity is intricately linked to CRC development and progression, making it a crucial target for intervention, whether through diet therapy, physical exercises, medical therapy, or bariatric surgery.

CYB5R3 overexpression exhibits sexual dimorphism: Mitochondrial and metabolic adaptations in transgenic female mice during calorie restriction

There is a pressing need to develop new strategies for enhancing health in the elderly and preventing the rise in age-related diseases. Calorie restriction without malnutrition (CR) stands among the different antiaging interventions. Lifelong CR leads to increased expression and activity of plasma membrane CYB5R3, and male mice overexpressing CYB5R3 exhibit some beneficial adaptations that are also seen with CR. However, the mechanisms involved in both interventions could be independent since key aspects of energy metabolism and tissue lipid profile do not coincide, and many of the changes induced by CR in mitochondrial abundance and dynamics in the liver and skeletal muscle could be counteracted by CYB5R3 overexpression. In this study, we sought to elucidate the impact of CR on key markers of metabolic status, mitochondrial function, and pro-oxidant/antioxidant balance in transgenic (TG) female mice overexpressing CYB5R3 compared to their WT littermates. In females fed ad libitum, CYB5R3 overexpression decreased fat mass, led to a preferred utilization of fatty acids as an energy source, upregulated key antioxidant enzymes, and boosted respiration both in skeletal muscle and liver mitochondria, supporting that CYB5R3 overexpression is phenotypic closer to CR in females than in males. Whereas some markers of mitochondrial biogenesis and dynamics were found decreased in TG females on CR, as also found for the levels of Estrogen Receptor α, mitochondrial abundance and activity were maintained both in skeletal muscle and in liver. Our results reveal overlapping metabolic adaptations resulting from the overexpression of CYB5R3 and CR in females, but a specific crosstalk occurs when both interventions are combined, differing from the adaptations observed in TG males.

V-ATPase Disassembly at the Yeast Lysosome-Like Vacuole Is a Phenotypic Driver of Lysosome Dysfunction in Replicative Aging.

Declines in lysosomal acidification and function with aging are observed in organisms ranging from yeast to humans. V-ATPases play a central role in organelle acidification and V-ATPase activity is regulated by reversible disassembly in many different settings. Using the yeast Saccharomyces cerevisiae as a replicative aging model, we demonstrate that V-ATPases disassemble into their V1 and V0 subcomplexes in aging cells, with release of V1 subunit C (Vma5) from the lysosome-like vacuole into the cytosol. Disassembly is observed after ≥5 cell divisions and results in overall vacuole alkalinization. Caloric restriction, an established mechanism for reversing many age-related outcomes, prevents V-ATPase disassembly in older cells and preserves vacuolar pH homeostasis. Reversible disassembly is controlled in part by the activity of two opposing and conserved factors, the RAVE complex and Oxr1. The RAVE complex promotes V-ATPase assembly and a rav1Δ mutant shortens replicative lifespan; Oxr1 promotes disassembly and an oxr1Δ mutation extends lifespan. Importantly, the level of Rav2, a key subunit of the RAVE complex, declines in aged cells. These data indicate that reduced V-ATPase assembly contributes to the loss of lysosome acidification with age, which affects replicative lifespan.

Dietary methionine functions in proliferative zone maintenance and production of eggs via sams-1 in Caenorhabditis elegans.

The maintenance of germ cells is critical for the prosperity of offspring. The amount of food consumption is known to be closely related to reproduction, i.e., the number of eggs decreases under calorie-restricted conditions in various organisms. Previous studies in Caenorhabditis elegans have reported that calorie restriction reduces the number of eggs and the reduction can be rescued by methionine. However, the effect of methionine on the reproductive process has not been fully understood. In this study, to assess the gonadal function of methionine metabolism, we firstly demonstrated that a depletion in dietary methionine resulted in reduced levels of S-adenosyl-l-methionine (SAM) and S-adenosyl homocysteine (SAH) in wild-type N2, but not in glp-1 mutants, which possess only a few germ cells. Second, we found no recovery in egg numbers upon methionine administration in SAM synthase (sams)-1 mutants. Furthermore, a reduced number of proliferative zone nuclei exhibited in the sams-1 mutants was not rescued via methionine. Thus, our results have shown that dietary methionine is required for the normal establishment of both the germline progenitor pool and fecundity, mediated by sams-1.

Dietary restriction and fasting alleviate radiation-induced intestinal injury by inhibiting cGAS/STING activation

Radiation injury to the intestine is one of the most common complications in patients undergoing abdominal or pelvic cavity radiotherapy, limiting the clinical application of this treatment. Evidence shows the potential benefits of dietary restriction in improving metabolic profiles and age-related diseases. The present study investigated the effects and mechanisms of dietary restriction in radiation-induced intestinal injury. The mice were randomly divided into the control group, 10 Gy total abdominal irradiation (TAI) group, and groups pretreated with 30% caloric restriction (CR) for 7 days or 24 h fasting before TAI. After radiation, the mice were returned to ad libitum. The mice were sacrificed 3.5 days after radiation, and tissue samples were collected. CR and fasting reduced radiation-induced intestinal damage and promoted intestinal recovery by restoring the shortened colon length, improving the impaired intestinal structure and permeability, and remodeling gut microbial structure. CR and fasting also significantly reduced mitochondrial damage and DNA damage, which in turn reduced activation of the cyclic GMP-AMP synthase/stimulator of interferon gene (cGAS/STING) pathway and the production of type I interferon and other chemokines in the jejunum. Since the cGAS/STING pathway is linked with innate immunity, we further showed that CR and fasting induced polarization to immunosuppressive M2 macrophage, decreased CD8+ cytotoxic T lymphocytes, and downregulated proinflammatory factors in the jejunum. Our findings indicated that CR and fasting alleviate radiation-induced intestinal damage by reducing cGAS/STING-mediated harmful immune responses.

Calorie Restriction Attenuates Memory Impairment and Reduces Neuroinflammation in Obese Aged Rats.

Obesity and aging collectively potentiate inflammatory responses, particularly within the central nervous system. Managing obesity presents a significant challenge, even more so considering the context of aging. Caloric restriction (CR) has been extensively documented in the literature for its multiple health benefits. Motivated by these findings, we hypothesized that CR could serve as a valuable intervention to address the brain alterations and cognitive decline associated with obesity in aged rats. Our investigation revealed that cafeteria diet increased hippocampal and hypothalamic transcripts related to neuroinflammation, along with cognitive deficits determined in the object recognition test in 18-month-old male rats. Western blot data indicate that the obesogenic diet may disrupt the blood-brain barrier and lead to an increase in Toll-like receptor 4 in the hippocampus, events that could contribute to the cognitive deficits observed. Implementing CR after the onset of obesity mitigated neuroinflammatory changes and cognitive impairments. We found that CR increases GABA levels in the hippocampus of aged animals, as demonstrated by liquid chromatography coupled with mass spectrometry analysis. These findings underscore the potential of CR as a therapeutic opportunity to ameliorate the neuroinflammatory and cognitive alterations of obesity, especially in the context of aging.

Systemic aging fuels heart failure: Molecular mechanisms and therapeutic avenues.

Systemic aging influences various physiological processes and contributes to structural and functional decline in cardiac tissue. These alterations include an increased incidence of left ventricular hypertrophy, a decline in left ventricular diastolic function, left atrial dilation, atrial fibrillation, myocardial fibrosis and cardiac amyloidosis, elevating susceptibility to chronic heart failure (HF) in the elderly. Age-related cardiac dysfunction stems from prolonged exposure to genomic, epigenetic, oxidative, autophagic, inflammatory and regenerative stresses, along with the accumulation of senescent cells. Concurrently, age-related structural and functional changes in the vascular system, attributed to endothelial dysfunction, arterial stiffness, impaired angiogenesis, oxidative stress and inflammation, impose additional strain on the heart. Dysregulated mechanosignalling and impaired nitric oxide signalling play critical roles in the age-related vascular dysfunction associated with HF. Metabolic aging drives intricate shifts in glucose and lipid metabolism, leading to insulin resistance, mitochondrial dysfunction and lipid accumulation within cardiomyocytes. These alterations contribute to cardiac hypertrophy, fibrosis and impaired contractility, ultimately propelling HF. Systemic low-grade chronic inflammation, in conjunction with the senescence-associated secretory phenotype, aggravates cardiac dysfunction with age by promoting immune cell infiltration into the myocardium, fostering HF. This is further exacerbated by age-related comorbidities like coronary artery disease (CAD), atherosclerosis, hypertension, obesity, diabetes and chronic kidney disease (CKD). CAD and atherosclerosis induce myocardial ischaemia and adverse remodelling, while hypertension contributes to cardiac hypertrophy and fibrosis. Obesity-associated insulin resistance, inflammation and dyslipidaemia create a profibrotic cardiac environment, whereas diabetes-related metabolic disturbances further impair cardiac function. CKD-related fluid overload, electrolyte imbalances and uraemic toxins exacerbate HF through systemic inflammation and neurohormonal renin-angiotensin-aldosterone system (RAAS) activation. Recognizing aging as a modifiable process has opened avenues to target systemic aging in HF through both lifestyle interventions and therapeutics. Exercise, known for its antioxidant effects, can partly reverse pathological cardiac remodelling in the elderly by countering processes linked to age-related chronic HF, such as mitochondrial dysfunction, inflammation, senescence and declining cardiomyocyte regeneration. Dietary interventions such as plant-based and ketogenic diets, caloric restriction and macronutrient supplementation are instrumental in maintaining energy balance, reducing adiposity and addressing micronutrient and macronutrient imbalances associated with age-related HF. Therapeutic advancements targeting systemic aging in HF are underway. Key approaches include senomorphics and senolytics to limit senescence, antioxidants targeting mitochondrial stress, anti-inflammatory drugs like interleukin (IL)-1β inhibitors, metabolic rejuvenators such as nicotinamide riboside, resveratrol and sirtuin (SIRT) activators and autophagy enhancers like metformin and sodium-glucose cotransporter 2 (SGLT2) inhibitors, all of which offer potential for preserving cardiac function and alleviating the age-related HF burden.

The effect of exercise and nutritional support on elderly and senile patients with sarcopenic obesity

The aim of the review. To analyze the prevalence of sarcopenic obesity among elderly and senile people, to assess its causes, and to present modern methods for its prevention and physical rehabilitation.This review article discusses the most recent evidence on age-related changes in fat and muscle tissue, and on calorie restriction and exercise that have positive effect on physical performance in older people with sarcopenic obesity. In addition, potential gaps in clinical practice guidelines that merit attention in future research are identified and analyzed.Search strategy. We used the following key words to define participation in the review:“sarcopenic obesity”, “sarcopenia with obesity”, “sarcopenia”, “elderly/old age”. Inclusion and exclusion criteria. The review included original research results (reviews, meta-analyses). Editorials, proceeding of the conferences, and research protocols were excluded. The study sample included women and men of any race aged ≥ 60 years with a diagnosis of sarcopenic obesity and with preserved locomotion function. Articles involving hospital patients were also excluded. Non-human studies and studies that did not report precise intervention criteria (e. g., nutrition, exercise, duration, etc.) were excluded.The literature search was conducted in four electronic databases: PubMed, Cochrane Library, Springer, Scopus, for the period from 2013 to August 1, 2023. There were no restrictions on the language of the publication.

Mammal hibernation as a strategy for adaptation to unfavorable environmental conditions

To analyse the literature data on the survival pathways of heterothermic endotherms in unfavorable environmental conditions, during periods of low availability of food resources.The article provides data on the differences between daily and seasonal heterothermy. The features of preparation for hibernation in facultative and obligate hibernators are highlighted. Hypotheses of the origin and evolution of heterothermy are considered. The most probable causes of periodic awakenings of animals from hibernation during the hibernation period are summarised. Considerable attention is paid to the restructuring of energy metabolism during hibernation – the transition from carbohydrate to lipid metabolism. Data have been analysed indicating the importance of fatty acids obtained from food during the active summer period, both for the synthesis of reserve fats and in the regulation of hibernation. Based on data on the accumulation of monoenoic fatty acids in tissues during hibernation, it has been suggested that they have an adaptive significance aimed at limiting oxidative stress and preserving vital cell functions.The data presented can be used both for conducting fundamental research on the adaptive mechanisms of interaction of an organism with its environment, and for solving practical problems, especially when choosing models of calorie restriction or intermittent fasting, as well as studying tissue tolerance to oxidative stress and resistance to the damaging effects of ischemia – reperfusion.

The Impact of Weight Loss on Inflammation, Oxidative Stress, and Mitochondrial Function in Subjects with Obesity.

Inflammation, oxidative stress, and mitochondrial function are implicated in the development of obesity and its comorbidities. The purpose of this study was to assess the impact of weight loss through calorie restriction on the metabolic profile, inflammatory and oxidative stress parameters, and mitochondrial respiration in an obese population. A total of 109 subjects underwent two cycles of a very low-calorie diet alternated with a low-calorie diet (24 weeks). We analyzed biochemical and inflammatory parameters in serum, as well as oxidative stress markers, mRNA antioxidant gene expression, and mitochondrial respiration in peripheral blood mononuclear cells (PBMCs). After the intervention, there was an improvement in both insulin resistance and lipid profiles, including cholesterol subfractions. Weight loss produced a significant reduction in mitochondrial ROSs content and an increase in glutathione levels, coupled with an enhancement in the mRNA expression of antioxidant systems (SOD1, GSR, and CAT). In addition, a significant improvement in basal oxygen consumption, maximal respiration, and ATP production was observed. These findings demonstrate that moderate weight loss can improve insulin resistance, lipid profiles and subfractions, inflammatory and oxidative stress parameters, and mitochondrial respiration. Therefore, we can affirm that dietary intervention can simultaneously achieve significant weight loss and improve metabolic profile and mitochondrial function in obesity.

The Effects of Different Dietary Patterns on Bone Health.

Bone metabolism is a process in which osteoclasts continuously clear old bone and osteoblasts form osteoid and mineralization within basic multicellular units, which are in a dynamic balance. The process of bone metabolism is affected by many factors, including diet. Reasonable dietary patterns play a vital role in the prevention and treatment of bone-related diseases. In recent years, dietary patterns have changed dramatically. With the continuous improvement in the quality of life, high amounts of sugar, fat and protein have become a part of people's daily diets. However, people have gradually realized the importance of a healthy diet, intermittent fasting, calorie restriction, a vegetarian diet, and moderate exercise. Although these dietary patterns have traditionally been considered healthy, their true impact on bone health are still unclear. Studies have found that caloric restriction and a vegetarian diet can reduce bone mass, the negative impact of a high-sugar and high-fat dietary (HSFD) pattern on bone health is far greater than the positive impact of the mechanical load, and the relationship between a high-protein diet (HPD) and bone health remains controversial. Calcium, vitamin D, and dairy products play an important role in preventing bone loss. In this article, we further explore the relationship between different dietary patterns and bone health, and provide a reference for how to choose the appropriate dietary pattern in the future and for how to prevent bone loss caused by long-term poor dietary patterns in children, adolescents, and the elderly. In addition, this review provides dietary references for the clinical treatment of bone-related diseases and suggests that health policy makers should consider dietary measures to prevent and treat bone loss.

Response of fruit fly (Drosophila pseudoobscura) to diet manipulation of nutrient density

AbstractCaloric intake can greatly affect many aspects of an organism's life. A deficiency of calories can lead to stress resulting in decreased fecundity, insufficient calories to maintain tissues and increased lifespan. Conversely, increasing caloric density increases fecundity and decreases lifespan. Despite decades of work exploring food quality and quantity on physiology in the model species Drosophila melanogaster Meigan 1830 (Diptera: Drosophilidae) and the melanogaster group in general, relatively little work explores the physiological responses to diet manipulation in other Drosophila species, like the obscura species group. Here, we looked at the effects of five different caloric densities (0.5×, 0.75×, 1.0×, 1.5× and 3.0×) on food intake, body weight, body fat, fecundity and longevity in D. pseudoobscura Frolova & Astaurov, 1929 (Diptera: Drosophilidae). Comparing longevity and fecundity across diets, we found that heavy caloric concentration (3.0×) decreases lifespan and that calorie restriction (0.5× and 0.75×) led to significant decreases in fecundity and body weight. However, calorie concentration did not significantly increase D. pseudoobscura body fat. By expanding our understanding of the physiological responses to diet stress to D. pseudoobscura, we establish the framework for comparative work across Drosophila species. With this information, we can then identify which physiological responses to diet manipulation might be most conserved and comparable across species.

The effectiveness of diet and exercise in the management of obesity

Background and objectives: Obesity is a growing global health problem and is becoming a significant challenge in the clinical and public health fields. One of the main concerns is the impact on an individual's quality of life. This review aims to evaluate the effectiveness of various interventions, including physical activity and diet, in the management of obesity. Methodology: The selected studies involved a population of adults who were obese (aged 18 years and over) and had made lifestyle modifications through pattern changes, eating, physical activity, or both. A total of 324 articles were screened, of which 25 were duplicates. After a screening process for suitability, 261 articles were excluded. A further 27 articles were excluded due to inappropriate study design or incomplete data. A total of 11 full-text articles were then reviewed and included in our analysis. The results showed that participants who followed a milk-based diet recorded a significant decrease in body weight of -1.16 kg (confidence interval -1.66, -0.66 kg; p < 0.001) as well as a decrease in body fat mass of -1.49 kg (confidence interval -2.06, -0.92 kg; p < 0.001). Participants who adopted an alternate day fasting (ADF) eating pattern achieved an average weight loss of -0.9% ± 0.6% in the low weight loss group and -9.9% ± 1.1% in the low weight loss group. Meanwhile, participants who restricted calorie intake (Caloric Restriction/CR) recorded a weight loss of -1.3% ± 0.7% in the low weight loss group and -9.2% ± 1.2% in the weight loss group tall body. Combining approximately 175 minutes of intense physical activity per week with a controlled diet results in significant weight loss of up to 5%. In conclusion, this systematic review confirms that the most effective approach in the management of obesity in adults is a combination of strength and cardiovascular training of at least 175 minutes per week and a low-calorie diet tailored to the individual's metabolic needs and health condition. Keywords: Obesity management; diet and exercise efficacy; obesity treatment; physical activity and weight loss

Caloric and time restriction diets improve acute kidney injury in experimental menopausal rats: role of silent information regulator 2 homolog 1 and transforming growth factor beta 1.

Estrogen has a protective impact on acute kidney injury (AKI); moreover, reducing the daily intake of calories impedes developing diseases. The present study aimed to determine the effects of calorie restriction (CR) and time restriction (TR) diets on the expression of silent information regulator 2 homolog 1 (SIRT1), transforming growth factor beta 1 (TGF-β1), and other indicators in the presence and absence of ovaries in AKI female rats. The female rats were divided into two groups, ovariectomized (OVX) and sham, and were placed on CR and TR diets for eight weeks; afterward, AKI was induced by injecting glycerol, and kidney injury indicators and biochemical parameters were measured before and after AKI. After AKI, the levels of urine albumin excretion rate, urea, and creatinine in serum, and TGF-β1 increased, while creatinine clearance and SIRT1 decreased in kidney tissue. CR improved kidney indicators and caused a reduction in TGF-β1 and an increase in SIRT1 in ovary-intact rats. Moreover, CR prevented total antioxidant capacity (TAC) decrease and malondialdehyde (MDA) increase resulting from AKI. Before AKI, an increase in body weight, fasting blood sugar (FBS), low-density lipoprotein (LDL), triglyceride (TG), and total cholesterol (TC), and a decrease in high-density lipoprotein (HDL) were observed in OVX rats compared to sham rats, but CR prevented these changes. The effects of TR were similar to those of CR in all indicators except for TGF-β1, SIRT1, urea, creatinine, and albumin. The present study indicated that CR is more effective than TR in preventing AKI, probably by increasing SIRT1 and decreasing TGF-β1 in ovary-intact animals.

Comparative effects of 8-week combined resistance exercise training and alternate-day calorie restriction on soluble epidermal growth factor receptor (sEGFR) and adipsin in obese men

This study investigated the combined effects of resistance exercise training (RET) and alternate-day calorie restriction (ADCR) on body composition, insulin resistance (IR), insulin resistance-related biomarkers (adipokine adipsin and hepatokine soluble EFGR), and weight loss in obese men. The findings revealed that RET + ADCR induced the greatest reductions in body weight, body fat percentage, and waist-to-hip ratio (WHR) compared to RET and ADCR alone (p < 0.05). Additionally, RET + ADCR resulted in the most significant improvements in IR, as measured by HOMA-IR, and in circulating levels of adipsin and soluble EFGR (p < 0.05). These findings suggest that combining RET and ADCR may be a more effective strategy for improving metabolic health, including body composition, IR, and metabolic tissues’ functions, in obese men than either intervention alone.

Advances in Diet and Physical Activity in Breast Cancer Prevention and Treatment.

There is currently a growing interest in diets and physical activity patterns that may be beneficial in preventing and treating breast cancer (BC). Mounting evidence indicates that indeed, the so-called Mediterranean diet (MedDiet) and regular physical activity likely both help reduce the risk of developing BC. For those who have already received a BC diagnosis, these interventions may decrease the risk of tumor recurrence after treatment and improve quality of life. Studies also show the potential of other dietary interventions, including fasting or modified fasting, calorie restriction, ketogenic diets, and vegan or plant-based diets, to enhance the efficacy of BC therapies. In this review article, we discuss the biological rationale for utilizing these dietary interventions and physical activity in BC prevention and treatment. We highlight published and ongoing clinical studies that have applied these lifestyle interventions to BC patients. This review offers valuable insights into the potential application of these dietary interventions and physical activity as complimentary therapies in BC management.

Hyperpolarized 13C and 31P MRS detects differences in cardiac energetics, metabolism, and function in obesity, and responses following treatment.

Obesity is associated with important changes in cardiac energetics and function, and an increased risk of adverse cardiovascular outcomes. Multi-nuclear MRS and MRI techniques have the potential to provide a comprehensive non-invasive assessment of cardiac metabolic perturbation in obesity. A rat model of obesity was created by high-fat diet feeding. This model was characterized using in vivo hyperpolarized [1-13C]pyruvate and [2-13C]pyruvate MRS, echocardiography and perfused heart 31P MRS. Two groups of obese rats were subsequently treated with either caloric restriction or the glucagon-like peptide-1 analogue/agonist liraglutide, prior to reassessment. The model recapitulated cardiovascular consequences of human obesity, including mild left ventricular hypertrophy, and diastolic, but not systolic, dysfunction. Hyperpolarized 13C and 31P MRS demonstrated that obesity was associated with reduced myocardial pyruvate dehydrogenase flux, altered cardiac tricarboxylic acid (TCA) cycle metabolism, and impaired myocardial energetic status (lower phosphocreatine to adenosine triphosphate ratio and impaired cardiac ΔG~ATP). Both caloric restriction and liraglutide treatment were associated with normalization of metabolic changes, alongside improvement in cardiac diastolic function. In this model of obesity, hyperpolarized 13C and 31P MRS demonstrated abnormalities in cardiac metabolism at multiple levels, including myocardial substrate selection, TCA cycle, and high-energy phosphorus metabolism. Metabolic changes were linked with impairment of diastolic function and were reversed in concert following either caloric restriction or liraglutide treatment. With hyperpolarized 13C and 31P techniques now available for human use, the findings support a role for multi-nuclear MRS in the development of new therapies for obesity.

Calorie restriction in mice impairs cortical but not trabecular peak bone mass by suppressing bone remodeling.

Calorie restriction (CR) can lead to weight loss and decreased substrate availability for bone cells. Ultimately, this can lead to impaired peak bone acquisition in children and adolescence and bone loss in adults. But the mechanisms that drive diet-induced bone loss in humans are not well characterized. To explore those in greater detail, we examined the impact of 30% CR for 4 and 8wk in both male and female 8-wk-old C57BL/6J mice. Body composition, areal bone mineral density (aBMD), skeletal microarchitecture by micro-CT, histomorphometric parameters, and in vitro trajectories of osteoblast and adipocyte differentiation were examined. After 8wk, CR mice lost weight and exhibited lower femoral and whole-body aBMD vs ad libitum (AL) mice. By micro-CT, CR mice had lower cortical bone area fraction vs AL mice, but males had preserved trabecular bone parameters and females showed increased bone volume fraction compared to AL mice. Histomorphometric analysis revealed that CR mice had a profound suppression in trabecular as well as endocortical and periosteal bone formation in addition to reduced bone resorption compared to AL mice. Bone marrow adipose tissue was significantly increased in CR mice. In vitro, the pace of adipogenesis in bone marrow stem cells was greatly accelerated with higher markers of adipocyte differentiation and more oil red O staining, whereas osteogenic differentiation was reduced. qRT-PCR and western blotting suggested that the expression of Wnt16 and the canonical β-catenin pathway was compromised during CR. In sum, CR causes impaired peak cortical bone mass due to a profound suppression in bone remodeling. The increase in marrow adipocytes in vitro and in vivo is related to both progenitor recruitment and adipogenesis in the face of nutrient insufficiency. Long-term CR may lead to lower bone mass principally in the cortical envelope, possibly due to impaired Wnt signaling.

Time-Restricted Feeding Protects against Renal Ischemia-Reperfusion Injury in Mice.

Ischemia-reperfusion injury (IRI) in the kidneys is a major cause of acute kidney injury (AKI). Time-restricted feeding (TRF), known for its metabolic health benefits and alleviation of various chronic diseases without calorie restriction, was investigated for its potential protective effects against IRI-induced AKI. Male C57BL/6 mice underwent unilateral IRI, with their kidneys collected after two days. For two weeks before IRI induction, the TRF group had unlimited access to standard chow but within an 8-hour feeding window during the dark cycle. The study groups were Control, TRF, IRI, and TRF + IRI. In the TRF + IRI group, tubular damage scores significantly decreased compared to the IRI group. Furthermore, the TRF + IRI mice had lower levels of phosphorylated NF-κB and fewer F4/80-positive macrophages than the IRI group. Oxidative stress markers for lipids and proteins were also notably lower in the TRF + IRI group. Additionally, TUNEL-positive tubular cells and cleaved caspase-3 expression were reduced in the TRF + IRI group. Without calorie restriction, TRF mitigated renal damage by reducing inflammation, oxidative stress, and tubular apoptosis in renal IRI. This suggests that TRF could be a promising dietary strategy to prevent IRI-induced AKI.