Caloric Restriction Mimetics Research Articles

Glucosamine modulates membrane and cellular ionic homeostasis: studies on accelerated senescent and naturally aged rats

ABSTRACT Glucosamine, an amino-polysaccharide, has been widely used for alleviating osteoarthritis. . In the present study, attempts have been made to evaluate the potential role of glucosamine, a caloric restriction mimetic (CRM), for erythrocyte membrane transporter protection in D-galactose (D-gal) induced accelerated and natural aging models of rat specifically Ca2+-ATPases (PMCA pump), Na+/K+-ATPases (NKA pump), and the Na+/H+ exchanger (NHE) and redox biomarkers during aging. The study comprised of young (3–4 months old; 150 ± 20 g), naturally aged (above 24 months; 420 ± 20 g) and D-galactose-induced aged (3–4 months old; 150 ± 20 g, administered with D-Gal at 300 mg/kg B.W., subcutaneously) male albino rats of Wistar strain. All the rats were supplemented with Glucosamine hydrochloride (300 mg/kg body weight) for 12 weeks. There was a significant (P < 0.05) decrease in the activity of Ca2+-ATPases, Na+/K+-ATPases and induced NHE activity in D-Gal and naturally old rats. Levels of redox biomarkers such as intracellular Ca2+ ion, protein carbonyl, and lipid hydroperoxides were also found to be increased significantly (P < 0.05). These results were found to be reversed in the rats supplemented with glucosamine. Our findings suggest that glucosamine supplementation improves ion homeostasis by protecting the erythrocyte membrane transporters against age-related alterations.

Repurposing SGLT-2 Inhibitors to Target Aging: Available Evidence and Molecular Mechanisms.

Caloric restriction promotes longevity in multiple animal models. Compounds modulating nutrient-sensing pathways have been suggested to reproduce part of the beneficial effect of caloric restriction on aging. However, none of the commonly studied caloric restriction mimetics actually produce a decrease in calories. Sodium-glucose cotransporter 2 inhibitors (SGLT2-i) are a class of drugs which lower glucose by promoting its elimination through urine, thus inducing a net loss of calories. This effect promotes a metabolic shift at the systemic level, fostering ketones and fatty acids utilization as glucose-alternative substrates, and is accompanied by a modulation of major nutrient-sensing pathways held to drive aging, e.g., mTOR and the inflammasome, overall resembling major features of caloric restriction. In addition, preliminary experimental data suggest that SGLT-2i might also have intrinsic activities independent of their systemic effects, such as the inhibition of cellular senescence. Consistently, evidence from both preclinical and clinical studies have also suggested a marked ability of SGLT-2i to ameliorate low-grade inflammation in humans, a relevant driver of aging commonly referred to as inflammaging. Considering also the amount of data from clinical trials, observational studies, and meta-analyses suggesting a tangible effect on age-related outcomes, such as cardiovascular diseases, heart failure, kidney disease, and all-cause mortality also in patients without diabetes, here we propose a framework where at least part of the benefit provided by SGLT-2i is mediated by their ability to blunt the drivers of aging. To support this postulate, we synthesize available data relative to the effect of this class on: 1- animal models of healthspan and lifespan; 2- selected molecular pillars of aging in preclinical models; 3- biomarkers of aging and especially inflammaging in humans; and 4- COVID-19-related outcomes. The burden of evidence might prompt the design of studies testing the potential employment of this class as anti-aging drugs.

3-Bromopyruvate, a caloric restriction mimetic, exerts a mitohormetic effect to provide neuroprotection through activation of autophagy in rats during aging.

In the present study, attempts have been made to evaluate the potential role of 3 Bromopyruvate (3-BP) a glycolytic inhibitor and a caloric restriction mimetic (CRM), to exert neuroprotection in rats during aging through modulation of autophagy. Young male rats (4 months), and naturally aged (22 months) male rats were supplemented with 3-BP (30mg/kg b.w., orally) for 28 days. Our results demonstrate a significant increase in the antioxidant biomarkers (ferric reducing antioxidant potential level, total thiol, superoxide dismutase, and catalase activities) and a decrease in the level of pro-oxidant biomarkers such as protein carbonyl after 3-BP supplementation in brain tissues. A significant increase in reactive oxygen species (ROS) was observed due to the mitohormetic effect of 3-BP supplementation in the treated rats. Furthermore, the 3-BP treatment also enhanced the activities of electron transport chain complexes I and IV in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuroprotective and aging marker genes. RT-PCR data revealed that 3-BP up-regulated the expression of autophagy markers genes (Beclin-1 and LC3 β), sirtuin-1, and neuronal marker gene (NSE), respectively in the aging brain. The results suggest that 3-BP induces a mitohormetic effect through the elevation of ROS which reinforces defensive mechanism(s) targeted at regulating autophagy. These findings suggest that consistently low-dose 3-BP may be beneficial for neuroprotection during aging and age-related disorders.

Differential effects of calorie restriction and rapamycin on age-related molecular and functional changes in skeletal muscle.

Aging is a multifactorial process associated with progressive degradation of physiological integrity and function. One of the greatest factors contributing to the deleterious effects of aging is the decline of functional ability due to loss of muscle mass, strength, and function, a condition termed sarcopenia. Calorie restriction (CR) has consistently been shown to extend lifespan and delay the onset and progression of various age-related diseases, including sarcopenia. Additional anti-aging interventions that are receiving scientific attention are CR mimetics. Of these pharmacological compounds, rapamycin has shown similar CR-related longevity benefits without the need for diet restrictions. To investigate the potential role of rapamycin as an anti-sarcopenic alternative to CR, we conducted a study in male and female C57BL/6J mice to assess the effects of rapamycin on age-related gene expression changes in skeletal muscle associated with loss of muscle mass, strength, and function, relative to control. We hypothesize that the effects of rapamycin will closely align with CR with respect to physical function and molecular indices associated with muscle quality. Our results indicate CR and rapamycin provide partial protection against age-related decline in muscle, while engaging uniquely different molecular pathways in skeletal muscle. Our preclinical findings of the therapeutic potential of rapamycin or a CR regimen on geroprotective benefits in muscle should be extended to translational studies towards the development of effective strategies for the prevention and management of sarcopenia.

Person-centered choice of anti-obesity pharmacotherapy.

Several novel drugs are being developed for the management of obesity. While this offers newer opportunities for weight management, it also creates challenges for the treating physician to choose the appropriate drug for a given patient in clinical practice. This communication provides a clinically oriented classification of anti-obesity medications, which will help in person-centered choice of therapy. It lists drugs as calorie restrictors (appetite suppressants), calorie restriction mimetics (absorption inhibitors), calorie substitutes (medical nutrition therapy), and calorie utilizers (energy expenditure enhancers). This novel classification will help provide a patient centered pharmacotherapy in the management of obesity.

Calorie restriction and breast cancer treatment: a mini-review.

Calorie restriction (CR), referred to as a reduction in dietary calorie intake without malnutrition, has been demonstrated to be a safe way to extend longevity of yeast, worms, and laboratory animals, and to decrease the risk factors in age-related diseases including cancer in humans. Pre-clinical studies in animal models demonstrated that CR may enhance the efficacy of chemotherapy, radiation therapy, and immunotherapy during breast cancer treatment. Reduced calorie intake ameliorates risk factors and delays the onset of cancer by altering metabolism and fostering health-enhancing characteristics including increased autophagy and insulin sensitivity, and decreased blood glucose levels, inflammation, angiogenesis, and growth factor signaling. CR is not a common protocol implemented by medical practitioners to the general public due to the lack of substantial clinical studies. Future research and clinical trials are urgently needed to understand fully the biochemical basis of CR or CR mimetics to support its benefits. Here, we present a mini-review of research studies integrating CR as an adjuvant to chemotherapy, radiation therapy, or immunotherapy during breast cancer treatment.

Distinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle

Preserving skeletal muscle function is essential to maintain life quality at high age. Calorie restriction (CR) potently extends health and lifespan, but is largely unachievable in humans, making “CR mimetics” of great interest. CR targets nutrient-sensing pathways centering on mTORC1. The mTORC1 inhibitor, rapamycin, is considered a potential CR mimetic and is proven to counteract age-related muscle loss. Therefore, we tested whether rapamycin acts via similar mechanisms as CR to slow muscle aging. Here we show that long-term CR and rapamycin unexpectedly display distinct gene expression profiles in geriatric mouse skeletal muscle, despite both benefiting aging muscles. Furthermore, CR improves muscle integrity in mice with nutrient-insensitive, sustained muscle mTORC1 activity and rapamycin provides additive benefits to CR in naturally aging mouse muscles. We conclude that rapamycin and CR exert distinct, compounding effects in aging skeletal muscle, thus opening the possibility of parallel interventions to counteract muscle aging.

Baicalein May Act as a Caloric Restriction Mimetic Candidate to Improve the Antioxidant Profile in a Natural Rodent Model of Aging.

Caloric restriction (CR) is the most effective intervention for extending the life span of vertebrate and invertebrate aging models. Calorie restriction mimetics (CRMs), which are synthetic or natural chemicals that mimic the biochemical, hormonal, and physiological consequences of calorie restriction, are being researched for antiaging benefits. Baicalein is a plant-derived polyphenol that has the potential of antioxidant, anti-inflammatory, and autophagy inducer. The objective of this study is to evaluate the antiaging, anti-inflammatory, and antioxidant role of Baicalein in erythrocyte membrane and plasma, and evaluate the efficacy of Baicalein to act as a CRM candidate. This study evaluates the effect of Baicalein on aging biomarkers in normal and aged rats. We study various pro- and antioxidant markers, erythrocyte membrane transporters, and eryptosis. Baicalein supplementation in male Wistar rats significantly alleviated pro-oxidant markers and improved antioxidant profile. Improvement was also observed in age-induced alterations in membrane transporters, and eryptosis. Based on the aforementioned observations we conclude that Baicalein has the potential to maintain extracellular reactive oxygen species levels and redox homeostasis during the aging process, an effect that is similar to CR. Thus, Baicalein may be a potent CRM candidate for antiaging interventions.

The Effect of Calorie Restriction and Intermittent Fasting on Impaired Cognitive Function in High-Fat Diet-Induced Obesity Started Post-Weaning in Male Wistar Rat.

Background: Calorie Restriction (CR) is known as one of the most effective life-extending interventions. Therefore researchers are looking for other interventions or drugs to mimic the mentioned effects. Time-restricted feeding (TRF) has recently gained more attention recently as one of the CR mimetics. Here we evaluate and compare the effects of CR or TRF on cognitive function in young animals fed a high-fat diet (HFD). Methods: This is an experimental study that three-week-old male Wistar rats (n:52) were subjected to a control diet (n:11) or HFD (n:42). Then the HFD group was divided into 1) 30% calorie restriction (CR), 2) Night Intermittent Fasting (NIF), 3) Day Intermittent Fasting (DIF), and 4) Ad-Libitum (AL) with the standard diet for ten weeks (each of 9). An independent T-test or Mann–Whitney test was used for the first phase and in the second phase of the study, one-way analysis of variance (ANOVA), followed by Tukey post-hoc tests, or Kruskal–Wallis and post-hoc Bonferroni test were used. P-values of <0.05 were considered significant. Results: Deteriorated mental function was significantly lower in HFD than CON (p= 0.041). CR was still more efficient than NIF in cognitive function in obese subjects. Post-hoc test indicated that from day 2-4, escape latency was significantly shorter in NIF and CR, which was not seen in other groups (p=0.045). Conclusion: While TRF has garnered much attention recently, here we show that CR is still more efficient in learning and memory tasks. Longer fasting times and different fasting periods are recommended to study.

Classification of Non-Insulin Glucose Lowering Drugs.

The ever-changing scenario of diabetes care, especially pharmacotherapy, calls for a framework to help classify non-insulin glucose drugs. Such a taxonomic structure should be of contemporary relevance as well as futuristic in vision; scholarly in intent but easy to understand; and based on pathophysiologic principles while being useful for the clinician. We propose a rubric which lists four classes of non-insulin glucose lowering drugs; insulin secretagogues, insulin sensitizers, calorie restriction mimetics, and calorie restrictors. This classification serves the need of students and teachers as well as pharmacologists and clinicians alike.

Calorie Restriction for Cancer Prevention and Therapy: Mechanisms, Expectations, and Efficacy.

Cancer is one of the most frequently diagnosed diseases, and despite the continuous efforts in searching for new and more effective treatments, its morbidity and mortality remain a significant health problem worldwide. Calorie restriction, a dietary manipulation that consists in a reduction of the calorie intake, is gaining attention as a potential adjuvant intervention for preventing and/or fighting cancer. Several forms of energy reduction intake, which includes caloric restriction tout-court, dietary restrictions, and intermittent fasting, are being explored for their ability to prevent or slow down cancer progression. Additionally, another anti-cancer approach being under investigation relies on the use of nutraceuticals known as “Caloric Restriction Mimetics” that can provide caloric restriction-mediated benefits without subjecting the patients to a strict diet. Preclinical in vitro and in vivo studies consistently show that diet modifiers reducing the calorie have impact on tumor microenvironment and cancer metabolism, resulting in reduced growth and progression of cancer. Preliminary clinical studies show that patients subjected to a reduced nutrient/energy intake experience improved outcomes from chemo- and radiotherapy while better tolerating the side effects. Here, we review the state of the art on the therapeutic potential of calorie restriction and of caloric restriction mimetics in preventing or retarding tumor development by modulating a subset of cellular processes. The most recent clinical progresses with caloric restriction mimetics in the clinical practice are also discussed.

NOT JUST CALORIC RESTRICTION: A COMPLEX APPROACH TO PROLONG LIFESPAN AND IMPROVE QUALITY OF LIFE

Aging is an urgent healthcare issue in view of the rapid growth of the proportion of older persons. Searching for reliable aging biomarkers and prolonging lifespan are increasingly important scientific directions. Experimental gerontology helps to explore fundamental facts which are not always applicable in clinical scenarios. As an example, caloric restriction is one of the key interventions that prolongs laboratory animals’ lifespan and ameliorates some, but not all, aging biomarkers in humans. Consequences of overeating such as obesity, insulin resistance, type 2 diabetes, and metabolic syndrome are taking their toll with aging, making caloric restriction a hot topic in gerontology and geriatrics. Nevertheless, caloric restriction is not widely applicable in view of poor adherence to and limitations of strict diets. Drugs mimicking caloric restrictions, the so-called caloric restriction mimetics, are developed to overcome these limitations. Caloric restriction alone is not a panacea since metabolic pathways are complex and not responsive to a single intervention. Fasting and exercising are additional options for reducing effects of excessive intake of calories. Arguably, physical activity significantly improves the quality of life at old age and delays the onset of overt insulin resistance and associated diseases. Thus, developing optimal fasting and exercising schemes is becoming increasingly important. Such interventions are confounded by a number of factors, including circadian and other biorhythms and baseline metabolic activity. It is justifiable to test fasting and exercising in experimental animals to reveal numerous confounding factors. A hypothesis in this article points to the role of complex interventions such as moderate and balanced diet, intermittent fasting, and physical exercise adjusted to circadian rhythms for prolonging life and improving quality of life. The hypothesis may shed light on fundamental mechanisms of aging and perspectives of anti-aging drug therapies.

Caloric Restriction Mimetics Attenuate the Hallmarks of Aging

Nutrient depletion, which is one of the physiological triggers of autophagy, results in the depletion of intracellular acetyl coenzyme A (AcCoA) coupled to the deacetylation of cellular proteins. We found that there are at least 4 possibilities to mimic these effects, namely (i) the depletion of cytosolic AcCoA by interfering with its biosynthesis, (ii) the stimulation cytosolic AcCoA consumption, (iii) the inhibition of protein acetyltransferases, or (iii) the stimulation of protein deacetylases. Thus, AcCoA depleting agents, AcCoA-consuming agents, acetyltransferase inhibitors or deacetylase activators are highly efficient inducers of autophagy and reduce aging-associated diseases including diabetes, obesity, cardiac failure and failing cancer immunosurveillance. Hence, we classify them as "caloric restriction mimetics" (CRM). We have initiated the systematic search for CRMs based on their cellular effects in vitro. We built screening assays amenable to high-throughput technology for the identification of CRMs. These results will be discussed.

Protein Kinase CK2 Is Upregulated by Calorie Restriction and Induces Autophagy.

Calorie restriction (CR) and the activation of autophagy extend healthspan by delaying the onset of age-associated diseases in most living organisms. Because protein kinase CK2 (CK2) downregulation induces cellular senescence and nematode aging, we investigated CK2’s role in CR and autophagy. This study indicated that CR upregulated CK2’s expression, thereby causing SIRT1 and AMP-activated protein kinase (AMPK) activation. CK2α overexpression, including antisense inhibitors of miR-186, miR-216b, miR-337-3p, and miR-760, stimulated autophagy initiation and nucleation markers (increase in ATG5, ATG7, LC3BII, beclin-1, and Ulk1, and decrease in SQSTM1/p62). The SIRT1 deacetylase, AKT, mammalian target of rapamycin (mTOR), AMPK, and forkhead homeobox type O (FoxO) 3a were involved in CK2-mediated autophagy. The treatment with the AKT inhibitor triciribine, the AMPK activator AICAR, or the SIRT1 activator resveratrol rescued a reduction in the expression of lgg-1 (the Caenorhabditis elegans ortholog of LC3B), bec-1 (the C. elegans ortholog of beclin-1), and unc-51 (the C. elegans ortholog of Ulk1), mediated by kin-10 (the C. elegans ortholog of CK2β) knockdown in nematodes. Thus, this study indicated that CK2 acted as a positive regulator in CR and autophagy, thereby suggesting that these four miRs’ antisense inhibitors can be used as CR mimetics or autophagy inducers.

Metformin, a calorie restriction mimetic for the treatment of Alzheimer’s disease: A preclinical investigation

Laboratory experiments have repeatedly demonstrated that organisms can live longer, healthier lives by reducing their calorie intake, with the implication that the same might be true for humans. Therefore, calorie restriction mimetics have generated lot of interest in the treatment of age related disorders. Metformin was shown to have caloric restriction-related longevity benefit mediated by the activation of AMPK in C. elegans. Metformin also has beneficial effect on other aspects of the aging process such as a decrease in age-related disease incidence. Based on this background metformin was evaluated in the current preclinical investigation as a potential treatment approach for AD. Rats were treated with Aluminium chloride (AlCl3; 10 mg/kg, i.p.) for 21 days for induction of oxidative stress leading to neurodegeneration. Animals were treated with metformin (50 and 100 mg/kg, p.o.) in parallel to AlCl3. Control group of rats received either saline alone or AlCl3 alone. Animals were subjected for evaluation in radial arm maze followed by assessments of biomarkers in brain (Malondialdehyde, glutathione, BDNF) and lipid parameters in plasma. Impaired cognitive abilities were observed in rats treated with AlCl3 alone; however metformin produced significant decrease in total errors and increased % choice accuracy. Similarly, oxidative stress evaluated through the measurement of malondialdehyde was increased in animals treated with AlCl3, and metformin produced decrease in oxidative stress marker and increase in BDNF expression. Results from the current studies indicate that calorie restriction mimetics might have potential beneficial effects in the management of AD through improvement of anti-aging properties.

Neurons die with heightened but functional macro- and chaperone mediated autophagy upon increased amyloid-ß induced toxicity with region-specific protection in prolonged intermittent fasting

Alzheimer's disease (AD) is a devastating neurodegenerative condition with significant socio-economic impact that is exacerbated by the rapid increase in population aging, particularly impacting already burdened health care systems of poorly resourced countries. Accumulation of the amyloid-β (Aβ) peptide, generated through amyloid precursor protein (APP) processing, manifesting in senile plaques, is a well-established neuropathological feature. Aβ plays a key role in driving synaptic dysfunction, neuronal cell loss, glial cell activation and oxidative stress associated with the pathogenesis of AD. Thus, the enhanced clearance of Aβ peptide though modulation of the mechanisms that regulate intracellular Aβ metabolism and clearance during AD progression have received major attention. Autophagy, a lysosome-based major proteolytic pathway, plays a crucial role in intracellular protein quality control and has been shown to contribute to the clearance of Aβ peptide. However, to what extent autophagy activity remains upregulated and functional in the process of increasing Aβ neurotoxicity is largely unclear. Here, we investigated the extent of neuronal toxicity in vitro by characterising autophagic flux, the expression profile of key amyloidogenic proteins, and proteins associated with prominent subtypes of the autophagy pathway to dissect the interplay between the engagement of proteolytic pathways and cell death onset in the context of APP overexpression. Moreover, we assessed the neuroprotective effects of a caloric restriction regime in vivo on the modulation of autophagy in specific brain regions. Our results reveal that autophagy is upregulated in the presence of high levels of APP and Aβ and remains heightened and functional despite concomitant apoptosis induction, suggestive of a mismatch between autophagy cargo generation and clearance capacity. These findings were confirmed when implementing a prolonged intermittent fasting (IF) intervention in a model of paraquat-induced neuronal toxicity, where markers of autophagic activity were increased, while apoptosis onset and lipid peroxidation were robustly decreased in brain regions associated with neurodegeneration. This work highlights that especially caloric restriction mimetics and controlled prolonged IF may indeed be a highly promising therapeutic strategy at all stages of AD-associated pathology progression, for a cell-inherent and cell specific augmentation of Aβ clearance through the powerful engagement of autophagy and thereby robustly contributing to neuronal protection.

Targeting Cardiovascular Risk Factors Through Dietary Adaptations and Caloric Restriction Mimetics.

The average human life expectancy continues to rise globally and so does the prevalence and absolute burden of cardiovascular disease. Dietary restriction promotes longevity and improves various cardiovascular risk factors, including hypertension, obesity, diabetes mellitus, and metabolic syndrome. However, low adherence to caloric restriction renders this stringent dietary intervention challenging to adopt as a standard practice for cardiovascular disease prevention. Hence, alternative eating patterns and strategies that recapitulate the salutary benefits of caloric restriction are under intense investigation. Here, we first provide an overview of alternative interventions, including intermittent fasting, alternate-day fasting and the Mediterranean diet, along with their cardiometabolic effects in animal models and humans. We then present emerging pharmacological alternatives, including spermidine, NAD+ precursors, resveratrol, and metformin, as promising caloric restriction mimetics, and briefly touch on the mechanisms underpinning their cardiometabolic and health-promoting effects. We conclude that implementation of feasible dietary approaches holds the promise to attenuate the burden of cardiovascular disease and facilitate healthy aging in humans.

Caloric Restriction Mimetics in Nutrition and Clinical Trials.

The human diet and dietary patterns are closely linked to the health status. High-calorie Western-style diets have increasingly come under scrutiny as their caloric load and composition contribute to the development of non-communicable diseases, such as diabetes, cancer, obesity, and cardiovascular disorders. On the other hand, calorie-reduced and health-promoting diets have shown promising results in maintaining health and reducing disease burden throughout aging. More recently, pharmacological Caloric Restriction Mimetics (CRMs) have gained interest of the public and scientific community as promising candidates that mimic some of the myriad of effects induced by caloric restriction. Importantly, many of the CRM candidates activate autophagy, prolong life- and healthspan in model organisms and ameliorate diverse disease symptoms without the need to cut calories. Among others, glycolytic inhibitors (e.g., D-allulose, D-glucosamine), hydroxycitric acid, NAD+ precursors, polyamines (e.g., spermidine), polyphenols (e.g., resveratrol, dimethoxychalcones, curcumin, EGCG, quercetin) and salicylic acid qualify as CRM candidates, which are naturally available via foods and beverages. However, it is yet unclear how these bioactive substances contribute to the benefits of healthy diets. In this review, we thus discuss dietary sources, availability and intake levels of dietary CRMs. Finally, since translational research on CRMs has entered the clinical stage, we provide a summary of their effects in clinical trials.

Chitosan Displays a Potent Caloric Restriction Mimetic Effect in Senescent Rats.

Chitosan is a polysaccharide made up of β1,4-linked d-glucosamine (GlcN) and N-acetyl-GlcN. In this study, we evaluated the possible caloric restriction mimetic (CRM) effect of dietary chitosan on systemic redox status, inflammatory biomarkers, and lipid profile in plasma and erythrocyte samples of d-galactose-induced mimetically aged rats. We found a significant increase (p < 0.05) in the reactive oxygen species, protein carbonyl, fasting glucose, body weight, cholesterol, triglyceride, inflammatory markers-interleukin-6 and tumor necrosis factor-alpha in an accelerated senescent rat model. There was also a significant decrease (p < 0.05) in glutathione, advanced glycation end product in senescent rats. Chitosan treatment increased ferric-reducing antioxidant potential, glutathione, plasma membrane-reduced system in accelerated senescent model of rats. Our finding suggests that chitosan has properties similar to a CRM and can effectively maintain the redox homeostasis during the aging process in rat erythrocytes.

The Potential of Calorie Restriction and Calorie Restriction Mimetics in Delaying Aging: Focus on Experimental Models.

Aging is a biological process determined by multiple cellular mechanisms, such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, that ultimately concur in the functional decline of the individual. The evidence that the old population is steadily increasing and will triplicate in the next 50 years, together with the fact the elderlies are more prone to develop pathologies such as cancer, diabetes, and degenerative disorders, stimulates an important effort in finding specific countermeasures. Calorie restriction (CR) has been demonstrated to modulate nutrient sensing mechanisms, inducing a better metabolic profile, enhanced stress resistance, reduced oxidative stress, and improved inflammatory response. Therefore, CR and CR-mimetics have been suggested as powerful means to slow aging and extend healthy life-span in experimental models and humans. Taking into consideration the difficulties and ethical issues in performing aging research and testing anti-aging interventions in humans, researchers initially need to work with experimental models. The present review reports the major experimental models utilized in the study of CR and CR-mimetics, highlighting their application in the laboratory routine, and their translation to human research.