Effects Of Caloric Restriction Research Articles

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 TGFβ1. 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.

Calorie restriction anti-hypertrophic effects are associated with improved mitochondrial content, blockage of Ca2+-induced mitochondrial damage, and lower reverse electron transport-mediated oxidative stress

Calorie restriction is a nutritional intervention that reproducibly protects against the maladaptive consequences of cardiovascular diseases. Pathological cardiac hypertrophy leads to cellular growth, dysfunction (with mitochondrial dysregulation), and oxidative stress. The mechanisms behind the cardiovascular protective effects of calorie restriction are still under investigation. In this study, we show that this dietetic intervention prevents cardiac protein elevation, avoids fetal gene reprogramming (atrial natriuretic peptide), and blocks the increase in heart weight per tibia length index (HW/TL) seen in isoproterenol-induced cardiac hypertrophy. Our findings suggest that calorie restriction inhibits cardiac pathological growth while also lowering mitochondrial reverse electron transport-induced hydrogen peroxide formation and improving mitochondrial content. Calorie restriction also attenuated the opening of the Ca2+-induced mitochondrial permeability transition pore. We also found that calorie restriction blocked the negative correlation of antioxidant enzymes (superoxide dimutase and glutatione peroxidase activity) and HW/TL, leading to the maintenance of protein sulphydryls and glutathione levels. Given the nature of isoproterenol-induced cardiac hypertrophy, we investigated whether calorie restriction could alter cardiac beta-adrenergic sensitivity. Using isolated rat hearts in a Langendorff system, we found that calorie restricted hearts have preserved beta-adrenergic signaling. In contrast, hypertrophic hearts (treated for seven days with isoproterenol) were insensitive to beta-adrenergic activation using isoproterenol (50 nM). Despite protecting against cardiac hypertrophy, calorie restriction did not alter the lack of responsiveness to isoproterenol in isolated hearts harvested from isoproterenol-treated rats. These results suggest (through a series of mitochondrial, oxidative stress, and cardiac hemodynamic studies) that calorie restriction possesses beneficial effects against hypertrophic cardiomyopathy.

Effects of Calorie Restriction on Preserving Male Fertility Particularly in a State of Obesity.

Highlight the importance of exploring nutritional interventions that could be applied as alternative or supplementary therapeutic strategies to enhance men's fertility. Lifestyle choices haveprompted extensive discussions regarding its implications and applications as a complementary therapy. The growing concern over the decline in sperm quality underscores the urgency of investigating these alternative interventions. Calorie restriction (CR) has emerged as a promising strategy to improve male fertility. The efficacy of CR depends on factors like age, ethnicity and genetics. Clinical studies, such as CALERIE,have shown an improvement in serum testosterone level and sexual drive in men with or without obesity. Additionally, CR has been shown to positively impact sperm count and motility; however, its effects on sperm morphology and DNA fragmentation remain less clear, and the literature has shown discrepancies, mainly due to the nature of technically dependent assessment tools. The review advocates a personalized approach to CR, considering individual health profiles to maximize its benefits. It underscores the need for routine, accessible diagnostic techniques in male reproductive health. Itsuggests that future research should focus on personalized dietary interventions to improve male fertility and overall well-being in individuals with or without obesity and unravel CR's immediate and lasting effects on semen parameters in men without obesity.

The impact of continuous calorie restriction and fasting on cognition in adults without eating disorders.

Research into the effects of calorie restriction continues to intrigue those interested in whether it may allow humans to live longer and healthier lives. Animal studies of continuous calorie restriction (CCR) and fasting have demonstrated substantial advantages to health and longevity. However, concerns remain about the impact of restricting calorie intake on human health and cognition. Given the emerging evidence of cognitive impairments in eating disorders, studies investigating restricted calorie intake in healthy humans (in an ethical way) may also have implications for understanding restrictive eating disorders. In this review, the published literature on the impact of CCR and fasting on cognitive function in healthy human participants is synthesized. Of the 33 studies of CCR and fasting in humans identified, 23 demonstrated significant changes in cognition. Despite variation across the cognitive domains, results suggest CCR benefits inhibition, processing speed, and working memory, but may lead to impairments in cognitive flexibility. The results of fasting studies suggest fasting is associated with impairments in cognitive flexibility and psychomotor abilities. Overall, the results of these studies suggest the degree (ie, the severity) of calorie restriction is what most likely predicts cognitive improvements as opposed to impairments. For individuals engaging in sustained restriction, this may have serious, irreversible consequences. However, there are mixed findings regarding the impact of CCR and fasting on this aspect of human functioning, suggesting further research is required to understand the costs and benefits of different types of calorie restriction.

Independent and combined effects of calorie restriction and AICAR on glucose uptake and insulin signaling in skeletal muscles from 24-month-old female and male rats.

We assessed the effects of two levels of calorie restriction (CR; eating either 15% or 35% less than ad libitum, AL, food intake for 8 weeks) by 24-month-old female and male rats on glucose uptake (GU) and phosphorylation of key signaling proteins (Akt; AMP-activated protein kinase, AMPK; Akt substrate of 160kDa, AS160) measured in isolated skeletal muscles that underwent four incubation conditions (without either insulin or AICAR, an AMPK activator; with AICAR alone; with insulin alone; or with insulin and AICAR). Regardless of sex: (1) neither CR group versus the AL group had greater GU by insulin-stimulated muscles; (2) phosphorylation of Akt in insulin-stimulated muscles was increased in 35% CR versus AL rats; (3) prior AICAR treatment of muscle resulted in greater GU by insulin-stimulated muscles, regardless of diet; and (4) AICAR caused elevated phosphorylation of acetyl CoA carboxylase, an indicator of AMPK activation, in all diet groups. There was a sexually dimorphic diet effect on AS160 phosphorylation, with 35% CR exceeding AL for insulin-stimulated muscles in male rats, but not in female rats. Our working hypothesis is that the lack of a CR-effect on GU by insulin-stimulated muscles was related to the extended duration of the ex vivo incubation period (290 min compared to 40-50 min that was previously reported to be effective). The observed efficacy of prior treatment of muscles with AICAR to improve glucose uptake in insulin-stimulated muscles supports the strategy of targeting AMPK with the goal of improving insulin sensitivity in older females and males.

Understanding the Intense Effects of Caloric Restriction and Overfeeding on Zebrafish (Danio Rerio) Behaviour and Biochemical Processes, Along With Their Implications for Offspring

Understanding the Intense Effects of Caloric Restriction and Overfeeding on Zebrafish (Danio Rerio) Behaviour and Biochemical Processes, Along With Their Implications for Offspring

PRESIDENTIAL SYMPOSIUM: EXTENDING HEALTHSPAN AND LONGEVITY

Abstract Aging is associated with a functional decline in physiological, metabolic, proliferative, and tissue homeostasis leading to deterioration at an organismal level and an increase in risk for disease and death. To prevent or postpone such deterioration, genetic, pharmacological, and nutritional interventions have been successfully utilized, which lead to preserved healthspan and extended longevity. This symposium will discuss new approaches to target aging and the mechanisms underlying interventions that extend healthspan and longevity. The speakers of this symposium include internationally distinguished aging researchers who have dedicated their research to reveal new approaches to extending healthy lifespan. Rafael de Cabo, from NIA, Co-Chair and speaker in this symposium, will talk about the effects of calorie restriction on physiology, metabolism and health in a variety of organisms. Ana Gomes, from Moffitt Cancer Center, will talk about how aging promotes cancer resistance to therapy. Vishwa Deep Dixit, from Yale University, will discuss immunometabolic checkpoints of aging and lessons learned from CALERIE studies in humans. Payel Sen, from NIA, will present her studies on epigenetic mechanisms underlying tissue aging.

Aerobic Exercise and Calorie Restriction Alter Mitochondrial Biogenesis and Dynamics in Male Wistar Rats with Nonalcoholic Fatty Liver Disease

Background: Non-alcoholic fatty liver disease (NAFLD) is one of the most common liver diseases. limited studies has been done on the effects of calorie restriction (CR) and aerobic exercise (AE) on mitochondrial biogenesis (PGC1α, NRF2) and dynamics (MFN2, DRP1) in NAFLD rats. In this present, the changes on PGC1α, NRF2, MFN2 and DRP1 Proteins expression after 12 weeks of CR and AE intervention in the NAFLD rat model were evaluated. Methods: 40 rats were used, with 32 of them being induced to develop NAFLD through an 8-week high-fat diet. These rats were then divided into five groups: control (ate fatty food), sham (ate normal food), CR, AE, and CA (CR & AE). The CA and CR groups received 60% of their daily diet, while the AE and CA groups participated in treadmill aerobic exercise sessions five times a week for 12 weeks. After the intervention period, protein expression levels were measured in all groups. Data analysis utilized one-way ANOVA with a significance level set at P<0.05. Results: As shown by the findings, there are significant differences in the expression of proteins between the groups. In PGC1α, NRF2, MFN2 proteins, CA group showed higher protein expression than CR group (respectively P=0.045, P=0.028, P=0.025). However, it presented a significant reduction in DRP1 protein. (P=0.015), and there was no significant difference between CA and AE in expression of PGC1α, NRf2, MFN2 and DRP1 proteins (P=0.995, P=0.44, P=0.635, P=0.076). Conclusion: The results showed that AE combined with CR is able to improve NAFLD.

The effect of calorie-restriction along with thylakoid membranes of spinach on the gut-brain Axis Pathway and oxidative stress biomarkers in obese women with polycystic ovary syndrome: a Randomized, Double-blind, placebo-controlled clinical trial

BackgroundWomen with polycystic ovary syndrome (PCOS) have higher intestinal mucosal permeability, leading to the lipopolysaccharide (LPS) leakage and endotoxemia. This, in turn, leads to oxidative stress (OS) and neuro-inflammation caused by the gut-brain axis, affecting the neurotrophic factors levels such as brain-derived neurotrophic factor (BDNF) and S100 calcium-binding protein B (S100 B) levels. In this study, it was hypothesized that the thylakoid membranes of spinach supplementation along with a hypocaloric diet may have improved the LPS levels, neurotrophic factors, and OS in PCOS patients.MethodsIn this double-blind, randomized, placebo-controlled, and clinical trial, 48 women with obesity and diagnosed with PCOS based on Rotterdam criteria were randomly assigned to thylakoid (N = 21) and placebo groups (N = 23). A personalized hypocaloric diet with 500 calories less than the total energy expenditure was prescribed to all patients. The participants were daily supplemented with either a 5 g/day thylakoid-rich spinach extract or a placebo (5 g cornstarch) for 12 weeks along with a prescribed low-calorie diet. Anthropometric measurements and biochemical parameters were assessed at baseline and after the 12-week intervention.ResultsA statistically significant decrease in the LPS levels (P < 0.001) and an increase in the BDNF levels (P < 0.001) were recorded for the participants receiving the oral thylakoid supplements and a low-calorie diet. Furthermore, significant decreases were observed in fasting blood glucose, insulin, homeostatic model of assessment for insulin resistance, free testosterone index, and follicle-stimulating hormone / luteinizing hormone ratio in both groups (P < 0.05). No significant differences were detected between the two groups regarding the changes in malondialdehyde, catalase, total antioxidant capacity, and S100B levels (P > 0.05).ConclusionsIn sum, the thylakoid membranes of spinach supplemented with a hypocaloric diet reduced the LPS levels, increased the BDNF levels, and improved the glycemic profile and sex-hormone levels; however, they had no effects on the OS markers levels after 12 weeks of intervention.

Cardioprotective effects of calorie restriction against inflammation and apoptosis in ovariectomized obese rats: Role of classical estrogen receptors and SIRT1

AimObesity is a metabolic complication linked with bad eating habits and a sedentary lifestyle, and the heart is one of the target organs damaged by it. Estrogen deficiency during menopause worsens the situation. Calorie restriction (CR) can contribute to reducing cardiovascular disease (CVD) in postmenopausal conditions. Thus, the effects of CR on inflammation and apoptosis in ovariectomized rats' hearts with obesity were studied. MethodFemale Wistar rats were categorized into Sham and OVX (ovariectomized) groups and received a standard diet (SD) or high-fat diet (60%HFD) or calorie restriction (30% CR) for 16 weeks. The real-time PCR method was used to evaluate the inflammatory markers and estrogen receptors gene expression. Western-blot and ELISA methods were respectively used for the measurement of apoptosis and SIRT1 protein expression. ResultsHFD led to the elevation of body weight, IL-6 (interleukin-6) and TNF-α (tumor necrosis factor-α) and reduction of IL-10 (interleukin-10) gene expressions, and also an increment in protein levels of cleaved caspase-3, Bax and Bax/Bcl2 ratio and decrement in Bcl-2 in OVX rats (P < 0.001). Additionally, HFD reduced SIRT1 (sirtuin1) protein levels, ERα (estrogen receptor α), and ERβ (estrogen receptor β) gene expressions (P < 0.001). In contrast, CR declined body weight, IL-6 and TNF-α (P < 0.001), increased IL-10 expressions (P < 0.05), decreased cleaved caspase-3 (P < 0.001), Bax (P < 0.01), and Bax/Bcl2 ratio (P < 0.05), enhanced Bcl-2 (P < 0.001), increased SIRT1 (P < 0.05) and ERα (P < 0.001) and ERβ (P < 0.01) expressions. ConclusionCR through the SIRT1 regulation and estrogen receptors attenuate obesity-induced-cardiac inflammation and apoptosis. CR can be a cardioprotective candidate in postmenopausal conditions.

Effect of calorie restriction on redox status during chemically induced estropause in female mice.

In females, there is a continuous decline of the ovarian reserve with age, which results in menopause in women or estropause in mice. Loss of ovarian function results in metabolic alterations in mice and women. Based on this, we aimed to evaluate the effect of caloric restriction (CR) on redox status and metabolic changes in chemically induced estropause in mice. For this, mice were divided into four groups (n = 10): cyclic ad libitum (AL), cyclic 30% CR, AL estropause, and estropause 30% CR. Estropause was induced using 4-vinylcyclohexene diepoxide (VCD) for 20 consecutive days in 2-month-old females. The CR protocol started at 5 months of age and the treatments lasted for 4 months. The CR females gained less body weight than AL females (p < 0.001) and had lower glycemic curves in response to glucose tolerance test (GTT). The AL estropause females had the highest body weight and body fat, despite having lower food intake. However, the estropause females on 30% CR lost the most body weight and had the lowest amount of body fat compared to all groups. The effect of 30% CR on redox status in fat and liver tissue was similar for cyclic and estropause females. Interestingly, estropause decreased ROS in adipose tissue, while increasing it in the liver. No significant effects of CR on redox status were observed. Chemically induced estropause did not influence the response to 30% CR on glucose tolerance and redox status; however, weight loss was exarcebated compared to cyclic females.

Effects of caloric restriction and ketogenic diet on renal fibrosis after ischemia/reperfusion injury

The beneficial effects of caloric restriction (CR) and a ketogenic diet (KD) have been previously shown when performed prior to kidney injury. We investigated the effects of CR and KD on fibrosis development after unilateral kidney ischemia/reperfusion (UIR). Post-treatment with CR significantly (p < 0.05) affected blood glucose (2-fold decrease), ketone bodies (3-fold increase), lactate (1.5-fold decrease), and lipids (1.4-fold decrease). In the kidney, CR improved succinate dehydrogenase and malate dehydrogenase activity by 2-fold each, but worsened fibrosis progression. Similar results were shown for the KD, which restored the post-UIR impaired activities of succinate dehydrogenase, malate dehydrogenase, and α-ketoglutarate dehydrogenase (which was decreased 2-fold) but had no effect on fibrosis progression. Thus, our study shows that the use of CR or KD after UIR did not reduce the development of fibrosis, as shown by hydroxyproline content, western-blotting, and RT-PCR, whereas it caused significant metabolic changes in kidney tissue after UIR.

Metabolites in aging and aging-relevant diseases: Frailty, sarcopenia and cognitive decline.

Aging shows biologically complex features with high individual variability, which reflects the exposure to several stimuli and the adaptation to them. Among them, metabolic changes are well observed as consequences or possible causes of aging. Calorie restriction extends organismal life span in experimental models. Several metabolites; for example, resveratrol or nicotinamide mononucleotide, are reported to mimic calorie restriction effects in vivo. Metabolomic research would be useful to evaluate metabolites as biomarkers in aging-relevant events and to identify metabolic regulation of aging. We recently developed the metabolomic approach for whole blood analysis, which functions as strong tool for this purpose. We review the update findings in aging-relevant metabolites detected by this method. Geriatr Gerontol Int 2024; 24: 44-48.

Sex-specific metabolic adaptations in transgenic mice overexpressing cytochrome b5 reductase-3.

Cytochrome b5 reductase 3 (CYB5R3) activates respiratory metabolism in cellular systems and exerts a prolongevity action in transgenic mice overexpressing this enzyme, mimicking some of the beneficial effects of calorie restriction. The aim of our study was to investigate the role of sex on metabolic adaptations elicited by CYB5R3 overexpression, and how key markers related with mitochondrial function are modulated in skeletal muscle, one of the major contributors to resting energy expenditure. Young CYB5R3 transgenic mice did not exhibit the striking adaptations in carbon metabolism previously detected in older animals. CYB5R3 was efficiently overexpressed and targeted to mitochondria in skeletal muscle from transgenic mice regardless sex. Overexpression significantly elevated NADH in both sexes, although differences were not statistically significant for NAD+, and increased the abundance of cytochrome c and the fission protein DRP-1 in females but not in males. Moreover, while mitochondrial biogenesis and function markers (as TFAM, NRF-1 and cleaved SIRT3) were markedly upregulated by CYB5R3 overexpression in females, a downregulation was observed in males. Ultrastructural changes were also highlighted, with an increase in the number of mitochondria per surface unit, and in the size of intermyofibrillar mitochondria in transgenic females compared with their wild-type controls. Our results support that CYB5R3 overexpression upregulates markers consistent with enhanced mitochondrial biogenesis and function, and increases mitochondrial abundance in skeletal muscle, producing most of these potentially beneficial actions in females.

Effects of Calorie Restriction and Fasting on Macrophage: Potential Impact on Disease Outcomes?

Energy restriction, including calorie restriction and fasting, has garnered significant attention for its potential therapeutic effects on a range of chronic diseases (such as diabetes, obesity, and cancer) and aging. Since macrophages are critical players in many diseases, their response to energy restriction may impact disease outcomes. However, the diverse metabolic patterns and functions of macrophages can lead to variability in the effects of energy restriction on macrophages across different tissues and disease states. This review outlines the effects of energy restriction on macrophages in several diseases, offering valuable guidance for future studies and insights into the clinical applications of calorie restriction and fasting.

Effect of Calorie Restriction on the Expression of Sirtuin1 as an Antiaging Biomarker

Effect of Calorie Restriction on the Expression of Sirtuin1 as an Antiaging Biomarker

Caloric Restriction Mitigates Kidney Fibrosis in an Aged and Obese Rat Model.

Caloric restriction is an effective intervention to protract healthspan and lifespan in several animal models from yeast to primates, including humans. Caloric restriction has been found to induce cardiometabolic adaptations associated with improved health and to delay the onset and progression of kidney disease in different species, particularly in rodent models. In both aging and obesity, fibrosis is a hallmark of kidney disease, and epithelial-mesenchymal transition is a key process that leads to fibrosis and renal dysfunction during aging. In this study, we used an aged and obese rat model to evaluate the effect of long-term (6 months) caloric restriction (-40%) on renal damage both from a structural and functional point of view. Renal interstitial fibrosis was analyzed by histological techniques, whereas effects on mesenchymal (N-cadherin, Vimentin, Desmin and α-SMA), antioxidant (SOD1, SOD2, Catalase and GSTP1) inflammatory (YM1 and iNOS) markers and apoptotic/cell cycle (BAX, BCL2, pJNK, Caspase 3 and p27) pathways were investigated using Western blot analysis. Our results clearly showed that caloric restriction promotes cell cycle division and reduces apoptotic injury and fibrosis phenotype through inflammation attenuation and leukocyte infiltration. In conclusion, we highlight the beneficial effects of caloric restriction to preserve elderly kidney function.

The Role of Organokines in Obesity and Type 2 Diabetes and Their Functions as Molecular Transducers of Nutrition and Exercise.

Maintaining systemic homeostasis requires the coordination of different organs and tissues in the body. Our bodies rely on complex inter-organ communications to adapt to perturbations or changes in metabolic homeostasis. Consequently, the liver, muscle, and adipose tissues produce and secrete specific organokines such as hepatokines, myokines, and adipokines in response to nutritional and environmental stimuli. Emerging evidence suggests that dysregulation of the interplay of organokines between organs is associated with the pathophysiology of obesity and type 2 diabetes (T2D). Strategies aimed at remodeling organokines may be effective therapeutic interventions. Diet modification and exercise have been established as the first-line therapeutic intervention to prevent or treat metabolic diseases. This review summarizes the current knowledge on organokines secreted by the liver, muscle, and adipose tissues in obesity and T2D. Additionally, we highlighted the effects of diet/nutrition and exercise on the remodeling of organokines in obesity and T2D. Specifically, we investigated the ameliorative effects of caloric restriction, selective nutrients including ω3 PUFAs, selenium, vitamins, and metabolites of vitamins, and acute/chronic exercise on the dysregulation of organokines in obesity and T2D. Finally, this study dissected the underlying molecular mechanisms by which nutrition and exercise regulate the expression and secretion of organokines in specific tissues.

Regulation of IGF1R by MicroRNA-15b Contributes to the Anticancer Effects of Calorie Restriction in a Murine C3-TAg Model of Triple-Negative Breast Cancer.

Calorie restriction (CR) inhibits triple-negative breast cancer (TNBC) progression in several preclinical models in association with decreased insulin-like growth factor 1 (IGF1) signaling. To investigate the impact of CR on microRNAs (miRs) that target the IGF1/IGF1R pathway, we used the spontaneous murine model of TNBC, C3(1)/SV40 T-antigen (C3-TAg). In C3-TAg mice, CR reduced body weight, IGF1 levels, and TNBC progression. We evaluated the tumoral expression of 10 miRs. CR increased the expression of miR-199a-3p, miR-199a-5p, miR-486, and miR-15b. However, only miR-15b expression correlated with tumorigenicity in the M28, M6, and M6C C3-TAg cell lines of TNBC progression. Overexpressing miR-15b reduced the proliferation of mouse (M6) and human (MDA-MB-231) cell lines. Serum restriction alone or in combination with low levels of recombinant IGF1 significantly upregulated miR-15b expression and reduced Igf1r in M6 cells. These effects were reversed by the pharmacological inhibition of IGFR with BMS754807. In silico analysis using miR web tools predicted that miR-15b targets genes associated with IGF1/mTOR pathways and the cell cycle. Our findings suggest that CR in association with reduced IGF1 levels could upregulate miR-15b to downregulate Igf1r and contribute to the anticancer effects of CR. Thus, miR-15b may be a therapeutic target for mimicking the beneficial effects of CR against TNBC.

Glycerol 3-phosphate phosphatase/PGPH-2 counters metabolic stress and promotes healthy aging via a glycogen sensing-AMPK-HLH-30-autophagy axis in C. elegans

Metabolic stress caused by excess nutrients accelerates aging. We recently demonstrated that the newly discovered enzyme glycerol-3-phosphate phosphatase (G3PP; gene Pgp), which operates an evolutionarily conserved glycerol shunt that hydrolyzes glucose-derived glycerol-3-phosphate to glycerol, counters metabolic stress and promotes healthy aging in C. elegans. However, the mechanism whereby G3PP activation extends healthspan and lifespan, particularly under glucotoxicity, remained unknown. Here, we show that the overexpression of the C. elegans G3PP homolog, PGPH-2, decreases fat levels and mimics, in part, the beneficial effects of calorie restriction, particularly in glucotoxicity conditions, without reducing food intake. PGPH-2 overexpression depletes glycogen stores activating AMP-activate protein kinase, which leads to the HLH-30 nuclear translocation and activation of autophagy, promoting healthy aging. Transcriptomics reveal an HLH-30-dependent longevity and catabolic gene expression signature with PGPH-2 overexpression. Thus, G3PP overexpression activates three key longevity factors, AMPK, the TFEB homolog HLH-30, and autophagy, and may be an attractive target for age-related metabolic disorders linked to excess nutrients.