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.

Sex-specific heterothermy patterns in wintering captive Microcebus murinus do not translate into differences in energy balance.

The physiological mechanisms of responses to stressors are at the core of ecophysiological studies that examine the limits of an organism's flexibility. Interindividual variability in these physiological responses can be particularly important and lead to differences in the stress response among population groups, which can affect population dynamics. Some observations of intersexual differences in heterothermy raise the question of whether there is a difference in energy management between the sexes. In this study, we assessed male and female differences in mouse lemurs (Microcebus murinus), a highly seasonal malagasy primate, by measuring their physiological flexibility in response to caloric restriction and examining the subsequent impact on reproductive success. Using complementary methods aiming to describe large-scale and daily variations in body temperature throughout a 6-month winter-like short-day (SD) period, we monitored 12 males and 12 females, applying chronic 40% caloric restriction (CR) to 6 individuals in each group. We found variations in Tb modulation throughout the SD period and in response to caloric treatment that depended on sex, as females, regardless of food restriction, and CR males, only, entered deep torpor. The use of deeper torpor, however, did not translate into a lower loss of body mass in females and did not affect reproductive success. Captive conditions may have buffered the depth of torpor and minimised the positive effects of torpor on energy savings. However, the significant sex differences in heterothermy we observed may point to physiological benefits other than preservation of energy reserves.

Aging as a target for the prevention and treatment of Alzheimer's disease.

Alzheimer's disease (AD), the most common etiology of dementia in older adults, is projected to double in prevalence over the next few decades. Current treatments for AD manage symptoms or slow progressive decline, but are accompanied by significant inconvenience, risk, and cost. Thus, a better understanding of the risk factors and pathophysiology of AD is needed to develop novel prevention and treatment strategies. Aging is the most important risk factor for AD. Elucidating molecular mechanisms of aging may suggest novel therapeutic targets. While aging is inevitable, it may be accelerated by caloric excess and slowed by caloric restriction (CR) or intermittent fasting. As such, CR may slow aging and reduce the risk of all diseases of aging, including dementia due to AD. The literature on CR, intermittent fasting, and treatment with polyphenols such as resveratrol-a pharmacologic CR-mimetic-supports this hypothesis based on clinical outcomes as well as biomarkers of aging and AD. More studies exploring the role of CR in regulating aging and AD progression in man are needed to fill gaps in our understanding and develop safer and more effective strategies for the prevention and treatment of AD.

Sex-Dependent Metabolic Effects in Diet-Induced Obese Rats following Intermittent Fasting Compared with Continuous Food Restriction.

Recently, intermittent fasting has gained relevance as a strategy to lose weight and improve health as an alternative to continuous caloric restriction. However, the metabolic impact and the sex-related differences are not fully understood. The study aimed to compare the response to a continuous or intermittent caloric restriction in male and female rats following a previous induction of obesity through a cafeteria diet by assessing changes in body weight, energy intake, metabolic parameters, and gene expression in liver hepatic and adipose tissue. The continuous restriction reduced the energy available by 30% and the intermittent restriction consisted of a 75% energy reduction on two non-consecutive days per week. The interventions reduced body weight and body fat in both sexes, but the loss of WAT in females was more marked in both models of caloric restriction, continuous and intermittent. Both caloric restrictions improved insulin sensitivity, but more markedly in females, which showed a more pronounced decrease in HOMA-IR score and an upregulation of hepatic IRS2 and Sirt1 gene expression that was not observed in males. These findings suggest the fact that females are more sensitive than males to reduced caloric content in the diet.

Brain serotonin and serotonin transporter expression in male and female postnatal rat offspring in response to perturbed early life dietary exposures.

Introduction: Serotonin (5-HT) is critical for neurodevelopment and the serotonin transporter (SERT) modulates serotonin levels. Perturbed prenatal and postnatal dietary exposures affect the developing offspring predisposing to neurobehavioral disorders in the adult. We hypothesized that the postnatal brain 5-HT-SERT imbalance associated with gut dysbiosis forms the contributing gut-brain axis dependent mechanism responsible for such ultimate phenotypes. Methods: Employing maternal diet restricted (IUGR, n=8) and high fat+high fructose (HFhf, n=6) dietary modifications, rodent brain serotonin was assessed temporally by ELISA and SERT by quantitative Western blot analysis. Simultaneously, colonic microbiome studies were performed. Results: At early postnatal (P) day 2 no changes in the IUGR, but a ~24% reduction in serotonin (p = 0.00005) in the HFhf group occurred, particularly in the males (p = 0.000007) revealing a male versus female difference (p = 0.006). No such changes in SERT concentrations emerged. At late P21 the IUGR group reared on HFhf (IUGR/HFhf, (n = 4) diet revealed increased serotonin by ~53% in males (p = 0.0001) and 36% in females (p = 0.023). While only females demonstrated a ~40% decrease in serotonin (p = 0.010), the males only trended lower without a significant change within the HFhf group (p = 0.146). SERT on the other hand was no different in HFhf or IUGR/RC, with only the female IUGR/HFhf revealing a 28% decrease (p = 0.036). In colonic microbiome studies, serotonin-producing Bacteriodes increased with decreased Lactobacillus at P2, while the serotonin-producing Streptococcus species increased in IUGR/HFhf at P21. Sex-specific changes emerged in association with brain serotonin or SERT in the case of Alistipase, Anaeroplasma, Blautia, Doria, Lactococcus, Proteus, and Roseburia genera. Discussion: We conclude that an imbalanced 5-HT-SERT axis during postnatal brain development is sex-specific and induced by maternal dietary modifications related to postnatal gut dysbiosis. We speculate that these early changes albeit transient may permanently alter critical neural maturational processes affecting circuitry formation, thereby perturbing the neuropsychiatric equipoise.

Insight from Wild Yeast Isolates into the Molecular Mechanisms of Lifespan Variation Mediated by Caloric Restriction.

Caloric restriction (CR) is known to extend lifespan across different species and holds great promise for preventing human age-onset pathologies. However, two major challenges exist. First, despite extensive research, the mechanisms of lifespan extension in response to CR remain elusive. Second, genetic differences causing variations in response to CR and genetic factors contributing to variability of CR response on lifespan are largely unknown. Here, we took advantage of natural genetic variation across 46 diploid wild yeast isolates of Saccharomyces species and the lifespan variation under CR conditions to uncover the molecular factors associated with CR response types. We identified genes and metabolic pathways differentially regulated in CR-responsive versus non-responsive strains. Our analysis revealed that altered mitochondrial function and activation of GCN4-mediated environmental stress response are inevitably linked to lifespan variation in response to CR and a unique mitochondrial metabolite might be utilized as a predictive marker for CR response rate. In sum, our data suggests that the effects of CR on longevity may not be universal, even among closely related species or strains of a single species. Since mitochondrial mediated signaling pathways are evolutionarily conserved, the dissection of related genetic pathways will be relevant to understanding the mechanism by which CR elicits its longevity effect.

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.

Metabolic regulation of the Th17/Treg balance in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a long-lasting and inflammatory autoimmune condition affecting the gastrointestinal tract, impacting millions of individuals globally. The balance between T helper 17 (Th17) cells and regulatory T cells (Tregs) is pivotal in the pathogenesis and progression of IBD. This review summarizes the pivotal role of Th17/Treg balance in maintaining intestinal homeostasis, elucidating how its dysregulation contributes to the development and exacerbation of IBD. It comprehensively synthesizes the current understanding of how dietary factors regulate the metabolic pathways influencing Th17 and Treg cell differentiation and function. Additionally, this review presents evidence from the literature on the potential of dietary regimens to regulate the Th17/Treg balance as a strategy for the management of IBD. By exploring the intersection between diet, metabolic regulation, and Th17/Treg balance, the review reveals innovative therapeutic approaches for IBD treatment, offering a promising perspective for future research and clinical practice.

Exercise Combined with a Low-Calorie Diet Improves Body Composition, Attenuates Muscle Mass Loss, and Regulates Appetite in Adult Women with High Body Fat Percentage but Normal BMI.

BACKGROUND: The present study aimed to examine the effects of a 500 kcal reduction in daily energy intake alone and in combination with 90 min of moderate-to-vigorous aerobic exercise per week on body weight, body composition, and appetite sensations in young women with normal BMI and abnormal body fat percentage. METHODS: sixty-six young women with normal BMI and abnormal body fat percentage (21.33 ± 1.20 kg/m2 and 34.32 ± 2.94%) were randomly assigned into three groups: (1) caloric restriction (CR; n = 22), (2) caloric restriction with exercise (CR-EX; n = 22), and (3) control (C; n = 22). Data on anthropometry, blood samples, and subjective appetite sensations pre- and post-intervention were collected. RESULTS: After 4 weeks of intervention, CR and CR-EX groups both reduced body weight, fat percentage, and waist and hip circumferences compared to the C group (p < 0.05). Muscle mass of the CR group was significantly lower than that of the C group (-1.21 ± 0.86 kg vs. -0.27 ± 0.82 kg, p < 0.05), and no significant difference between CR-EX and C groups was observed. For appetite sensations, the subjects of the CR group showed significant increases in change of scores in desire to eat and prospective consumption than that of the C group (p < 0.05), while no significant difference between CR-EX and C groups was observed. CONCLUSION: A 500 kcal reduction in daily energy intake alone and in combination with 90 min of moderate-to-vigorous aerobic exercise per week could both reduce weight and improve body composition in young adult women with normal BMI and abnormal body fat percentage. More importantly, calorie restriction combined with exercise intervention was superior to calorie restriction alone in improving muscle mass loss and regulating appetite sensations.

Effects of Prolonged Medical Fasting during an Inpatient, Multimodal, Nature-Based Treatment on Pain, Physical Function, and Psychometric Parameters in Patients with Fibromyalgia: An Observational Study.

Fibromyalgia syndrome (FMS) is a common chronic pain disorder and often occurs as a concomitant disease in rheumatological diseases. Managing FMS takes a complex approach and often involves various non-pharmacological therapies. Fasting interventions have not been in the focus of research until recently, but preliminary data have shown effects on short- and medium-term pain as well as on physical and psychosomatic outcomes in different chronic pain disorders. This single-arm observational study investigated the effects of prolonged fasting (3-12 days, <600 kcal/d) embedded in a multimodal treatment setting on inpatients with FMS. Patients who were treated at the Department of Internal Medicine and Nature-Based Therapies of the Immanuel Hospital Berlin, Germany, between 02/2018 and 12/2020 answered questionnaires at hospital admission (V0) and discharge (V1), and then again three (V2), six (V3), and 12 (V4) months later. Selected routine blood and anthropometric parameters were also assessed during the inpatient stay. A total of 176 patients with FMS were included in the study. The Fibromyalgia Impact Questionnaire (FIQ) total score dropped by 13.7 ± 13.9 (p < 0.001) by V1, suggesting an improvement in subjective disease impact. Pain (NRS: reduction by 1.1 ± 2.5 in V1, p < 0.001) and quality of life (WHO-5: +4.9 ± 12.3 in V1, p < 0.001) improved, with a sustainable effect across follow-up visits. In contrast, mindfulness (MAAS: +0.3 ± 0.7 in V1, p < 0.001), anxiety (HADS-A: reduction by 2.9 ± 3.5 in V1, p < 0.0001), and depression (HADS-D: reduction by 2.7 ± 3.0 in V1, p < 0.0001) improved during inpatient treatment, without longer-lasting effects thereafter. During the study period, no serious adverse events were reported. The results suggest that patients with FMS can profit from a prolonged therapeutic fasting intervention integrated into a complex multimodal inpatient treatment in terms of quality of life, pain, and disease-specific functional parameters. ClinicalTrials.gov Identifier: NCT03785197.

Requirements for essential micronutrients during caloric restriction and fasting.

Caloric restriction (CR) or energy restriction, when carefully designed, monitored, and implemented in self-motivated and compliant individuals, proves to be a viable non-pharmacologic strategy for human weight control and obesity management. Beyond its role in weight management, CR has the potential to impede responses involved not only in the pathogenesis of various diseases but also in the aging process in adults, thereby being proposed to promote a healthier and longer life. The core objective of implementing caloric restriction is to establish a balance between energy intake and expenditure, typically involving a reduction in intake and an increase in expenditure-a negative balance at least initially. It may transition toward and maintain a more desired equilibrium over time. However, it is essential to note that CR may lead to a proportional reduction in micronutrient intake unless corresponding supplementation is provided. Historical human case reports on CR have consistently maintained adequate intakes (AI) or recommended dietary allowances (RDA) for essential micronutrients, including vitamins and minerals. Similarly, longevity studies involving non-human primates have upheld micronutrient consumption levels comparable to control groups or baseline measures. Recent randomized controlled trials (RCTs) have also endorsed daily supplementation of multivitamins and minerals to meet micronutrient needs. However, aside from these human case reports, limited human trials, and primate experiments, there remains a notable gap in human research specifically addressing precise micronutrient requirements during CR. While adhering to AI or RDA for minerals and vitamins appears sensible in the current practice, it's important to recognize that these guidelines are formulated for generally healthy populations under standard circumstances. The adequacy of these guidelines in the setting of prolonged and profound negative energy balance remains unclear. From perspectives of evidence-based medicine and precision nutrition, this field necessitates comprehensive exploration to uncover the intricacies of absorption, utilization, and metabolism and the requirement of each hydrophilic and lipophilic vitamin and mineral during these special periods. Such investigations are crucial to determine whether existing daily dietary recommendations for micronutrients are quantitatively inadequate, excessive, or appropriate when energy balance remains negative over extended durations.

Effect of long-term caloric restriction on telomere length in healthy adults: CALERIE™ 2 trial analysis.

Caloric restriction (CR) modifies lifespan and aging biology in animal models. The Comprehensive Assessment of Long-Term Effects of Reducing Intake of Energy (CALERIE™) 2 trial tested translation of these findings to humans. CALERIE™ randomized healthy, nonobese men and premenopausal women (age 21-50y; BMI 22.0-27.9 kg/m2 ), to 25% CR or ad-libitum (AL) control (2:1) for 2 years. Prior analyses of CALERIE™ participants' blood chemistries, immunology, and epigenetic data suggest the 2-year CR intervention slowed biological aging. Here, we extend these analyses to test effects of CR on telomere length (TL) attrition. TL was quantified in blood samples collected at baseline, 12-, and 24-months by quantitative PCR (absolute TL; aTL) and a published DNA-methylation algorithm (DNAmTL). Intent-to-treat analysis found no significant differences in TL attrition across the first year, although there were trends toward increased attrition in the CR group for both aTL and DNAmTL measurements. When accounting for adherence heterogeneity with an Effect-of-Treatment-on-the-Treated analysis, greater CR dose was associated with increased DNAmTL attrition during the baseline to 12-month weight-loss period. By contrast, both CR group status and increased CR were associated with reduced aTL attrition over the month 12 to month 24 weight maintenance period. No differences were observed when considering TL change across the study duration from baseline to 24-months, leaving it unclear whether CR-related effects reflect long-term detriments to telomere fidelity, a hormesis-like adaptation to decreased energy availability, or measurement error and insufficient statistical power. Unraveling these trends will be a focus of future CALERIE™ analyses and trials.

Perspective: The Impact of Fasting and Caloric Restriction on Neurodegenerative Diseases in Humans.

Neurodegenerative diseases (NDs) are characterized by the progressive functional and structural denaturation of neurons in the central and peripheral nervous systems. Despite the wide range of genetic predispositions, the increased emergence of these disorders has been associated with a variety of modifiable risk factors, including lifestyle factors. Diet has been shown to influence cognitive alterations in the elderly population with age-related brain pathologies, and specific dietary interventions might, therefore, confer preservatory protection to neural structures. Although Mediterranean and ketogenic diets have been studied, no clear guidelines have been implemented for the prevention or treatment of ND in clinical practice. Murine models have shown that intermittent fasting and caloric restriction (CR) can counteract disease processes in various age-related disorders, including NDs. The objective of this perspective is to provide a comprehensive, comparative overview of the available primary intervention studies on fasting and CR in humans with ND and to elucidate possible links between the mechanisms underlying the effects of fasting, CR, and the neuropathology of ND. We also included all currently available studies in older adults (with and without mild cognitive impairment) in which the primary endpoint was cognitive function to provide further insights into the feasibility and outcomes of such interventions. Overall, we conclude that nutritional intervention trials focusing on fasting and CR in humans with ND have been neglected, and more high-quality studies, including longitudinal clinical intervention trials, are urgently needed to elucidate the underlying immune-metabolic mechanisms in diet and ND.

An integrative pan-cancer analysis of the molecular characteristics of dietary restriction in tumour microenvironment.

BACKGROUND: Dietary restriction (DR), a general term for dieting, has been demonstrated as an effective intervention in reducing the occurrence of cancers. Molecular activities associated with DR are crucial in mediating its anti-cancer effects, yet a comprehensive exploration of the landscape of these activities at the pan-cancer level is still lacking. METHODS: We proposed a computational approach for quantifying DR-related molecular activities and delineating the landscape of these activities across 33 cancer types and 30 normal tissues within 27,320 samples. We thoroughly examined the associations between DR-related molecular activities and various factors, including the tumour microenvironment, immunological phenotypes, genomic features, and clinical prognosis. Meanwhile, we identified two DR genes that show potential as prognostic predictors in hepatocellular carcinoma and verified them by immunohistochemical assays in 90 patients. FINDINGS: We found that DR-related molecular activities showed a close association with tumour immunity and hold potential for predicting immunotherapy responses in various cancers. Importantly, a higher level of DR-related molecular activities is associated with improved overall survival and cancer-specific survival. FZD1 and G6PD are two DR genes that serve as biomarkers for predicting the prognosis of patients with hepatocellular carcinoma. INTERPRETATION: This study presents a robust link between DR-related molecular activities and tumour immunity across multiple cancer types. Our research could open the path for further investigation of DR-related molecular processes in cancer treatment. FUNDING: National Natural Science Foundation of China (Grant No. 82000628) and the Guangdong-Hong Kong-Macao University Joint Laboratory of Interventional Medicine Foundation of Guangdong Province (Grant No. 2023LSYS001).

Alternate Day Fasting Leads to Improved Post-Stroke Motor Recovery in Mice.

BACKGROUND: Caloric restriction promotes neuroplasticity and recovery after neurological injury. In mice, we tested the hypothesis that caloric restriction can act post-stroke to enhance training-associated motor recovery. METHODS: Mice were trained to perform a skilled prehension task. We then induced a photothrombotic stroke in the caudal forelimb area, after which we retrained animals on the prehension task following an 8-day delay. Mice underwent either ad libitum feeding or alternate day fasting beginning 1-day after stroke and persisting for either 7 days or the entire post-stroke training period until sacrifice. RESULTS: Prior studies have shown that post-stroke recovery of prehension can occur if animals receive rehabilitative training during an early sensitive period but is incomplete if rehabilitative training is delayed. In contrast, we show complete recovery of prehension, despite a delay in rehabilitative training, when mice underwent alternate day fasting beginning 1-day post-stroke and persisting for either 7 days or the entire post-stroke training period until sacrifice. Recovery was independent of weight loss. Stroke volumes were similar across groups. CONCLUSIONS: Post-stroke caloric restriction led to recovery of motor function independent of a protective effect on stroke volume. Prehension recovery improved even after ad libitum feeding was reinstituted suggesting that the observed motor recovery was not merely a motivational response. These data add to the growing evidence that post-stroke caloric restriction can enhance recovery.

Caloric restriction reduces proteinuria in male rats with established nephropathy.

Reducing proteinuria is a crucial approach in preventing kidney function loss. Previous preclinical studies indicated that caloric restriction (CR) imposed at a young age protects against age-related proteinuria. However, these studies have not explored CR in established renal disease. Therefore, this study aimed to investigate the impact of CR on established proteinuria. Rats, aged 12 ± 2 weeks, were administered 2.1 mg/kg of Adriamycin. Six weeks after injection, protein excretion was measured, and a [13 N]ammonia positron emission tomography (PET) scan was conducted to assess kidney perfusion. After 7 weeks rats were divided into four groups: ad libitum (AL) and CR groups fed either a 12% or a 20% protein diet. All groups were treated for 12 weeks. Blood pressure was measured and a second PET scan was acquired at the end of the study. The animals subjected to CR exhibited a 20.3% decrease in protein excretion (p = 0.003) compared to those in the AL groups. Additionally, blood pressure in the CR group was 21.2% lower (p < 0.001) than in the AL groups. While kidney function declined over time in all groups, the 20% CR group demonstrated the smallest decline. Thus CR effectively reduces urinary protein excretion and lowers blood pressure in rats with established proteinuria.

[Regulation of Aging and Lifespan by White Adipose Tissue].

Long-term caloric restriction (CR) is an effective intervention that improves whole-body metabolism, suppresses age-related pathophysiology, and extends lifespan. Although the beneficial effects of caloric restriction mediated by growth hormone/insulin-like growth factor-1 (GH/IGF-1) have been extensively studied, the mechanisms independent of GH/IGF-1 remain largely unknown. In this review, we focus on these GH/IGF-1-independent mechanisms, with a particular emphasis on the role of sterol regulatory element-binding protein 1c (SREBP-1c). CR increases the expression of SREBP-1c through the suppression of leptin signaling and enhances downstream factors involved in fatty acid synthesis in white adipose tissue (WAT). SREBP-1c also directly and indirectly increases the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha, a master regulator of mitochondrial biogenesis, leading to an increase in the number of mitochondria. Furthermore, SREBP-1c elevates expression of mitochondrial intermediate peptidase, which contributes to improving mitochondrial quality through the processing of sirtuin 3 into its mature form. Thus, it appears that CR exerts beneficial effects by modulating mitochondrial quantity and quality in WAT in a GH/IGF-1 signal-independent manner.

How calorie restriction slows aging: an epigenetic perspective.

Genomic instability and epigenetic alterations are some of the prominent factors affecting aging. Age-related heterochromatin loss and decreased whole-genome DNA methylation are associated with abnormal gene expression, leading to diseases and genomic instability. Modulation of these epigenetic changes is crucial for preserving genomic integrity and controlling cellular identity is important for slowing the aging process. Numerous studies have shown that caloric restriction is the gold standard for promoting longevity and healthy aging in various species ranging from rodents to primates. It can be inferred that delaying of aging through the main effector such as calorie restriction is involved in cellular identity and epigenetic modification. Thus, an understanding of aging through calorie restriction may seek a more in-depth understanding. In this review, we discuss how caloric restriction promotes longevity and healthy aging through genomic stability and epigenetic alterations. We have also highlighted how the effectors of caloric restriction are involved in modulating the chromatin-based barriers.

Liver-derived plasminogen mediates muscle stem cell expansion during caloric restriction through the plasminogen receptor Plg-RKT.

An intriguing effect of short-term caloric restriction (CR) is the expansion of certain stem cell populations, including muscle stem cells (satellite cells), which facilitate an accelerated regenerative program after injury. Here, we utilized the MetRSL274G (MetRS) transgenic mouse to identify liver-secreted plasminogen as a candidate for regulating satellite cell expansion during short-term CR. Knockdown of circulating plasminogen prevents satellite cell expansion during short-term CR. Furthermore, loss of the plasminogen receptor KT (Plg-RKT) is also sufficient to prevent CR-related satellite cell expansion, consistent with direct signaling of plasminogen through the plasminogen receptor Plg-RKT/ERK kinase to promote proliferation of satellite cells. Importantly, we are able to replicate many of these findings in human participants from the CALERIE trial. Our results demonstrate that CR enhances liver protein secretion of plasminogen, which signals directly to the muscle satellite cell through Plg-RKT to promote proliferation and subsequent muscle resilience during CR.

Dietary restriction and hepatic cancer: Systematic review and meta-analysis of animal studies.

The effect of calorie restriction, fasting, and ketogenic diets on the treatment of liver cancer remains uncertain. Therefore, we conducted a systematic review to evaluate the effect of restrictive diets on the development and progression of liver cancer in animal models. We did a meta-analysis using the Cochrane Collaboration's Review Manager software, with the random effects model and the inverse variance technique. We examined 19 studies that were conducted between 1983 and 2020. Of these, 63.2% investigated calorie restriction, 21.0% experimented with a ketogenic diet, and 15.8% investigated the effects of fasting. The intervention lasted anything from 48 h to 221 weeks. Results showed that restrictive diets may reduce tumor incidence and progression, with a significant reduction in the risk of liver cancer development. Thereby, our results suggest that putting limits on what you eat may help treat liver cancer in more ways than one.