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Caloric restriction mimetics mimic the beneficial effects of dietary restriction approaches, such as caloric restriction approaches, without limiting the dietary intake. Chlorogenic acid (CGA) acts as a caloric restriction mimetic; however, its neuroprotective mechanisms remain ambiguous. Therefore, in this study, we aimed to elucidate the neuroprotective effects of CGA on SH‐SY5Y cells treated with amyloid‐beta (Aβ)1‐42. Aβ1‐42 (1.25 μM) induced oxidative stress by significantly increasing the pro‐oxidant levels and decreasing the antioxidant levels in the cells. Additionally, it decreased the Na+/K+‐ATPase and Ca2+‐ATPase ion transporter activities and enhanced the acetylcholinesterase activity. However, CGA (100 μM) reversed these Aβ1‐42‐induced changes in SH‐SY5Y cells. Overall, CGA exerted neuroprotective effects against Aβ1‐42‐induced oxidative stress and impaired ion transporter and acetylcholinesterase activities, serving as a promising therapeutic candidate for neurodegenerative diseases, such as Alzheimer's disease. [ABSTRACT FROM AUTHOR]

The gut microbiota (GM) produces various molecules that regulate the physiological functionality of the brain through the gut-brain axis (GBA). Studies suggest that alteration in GBA may lead to the onset and progression of various neurological dysfunctions. Moreover, aging is one of the prominent causes that contribute to the alteration of GBA. With age, GM undergoes a shift in population size and species of microflora leading to changes in their secreted metabolites. These changes also hamper communications among the HPA (hypothalamic–pituitary–adrenal), ENS (enteric nervous system), and ANS (autonomic nervous system). A therapeutic intervention that has recently gained attention in improving health and maintaining communication between the gut and the brain is calorie restriction (CR), which also plays a critical role in autophagy and neurogenesis processes. However, its strict regime and lifelong commitment pose challenges. The need is to produce similar beneficial effects of CR without having its rigorous compliance. This led to an exploration of calorie restriction mimetics (CRMs) which could mimic CR's functions without limiting diet, providing long-term health benefits. CRMs ensure the efficient functioning of the GBA through gut bacteria and their metabolites i.e., short-chain fatty acids, bile acids, and neurotransmitters. This is particularly beneficial for elderly individuals, as the GM deteriorates with age and the body's ability to digest the toxic accumulates declines. In this review, we have explored the beneficial effect of CRMs in extending lifespan by enhancing the beneficial bacteria and their effects on metabolite production, physiological conditions, and neurological dysfunctions including neurodegenerative disorders. [ABSTRACT FROM AUTHOR]

Caloric restriction (CR) and its related alternatives have been shown to be the only interventions capable of extending lifespan and decreasing the risk of cancer, along with a reduction in burden in pre-clinical trials. Nevertheless, the results from clinical trials have not been as conclusive as the pre-clinical results. Recognizing the challenges associated with long-term fasting, the application of caloric restriction mimetics (CRMs), pharmacological agents that mimic the molecular effects of CR, to harness the potential benefits while overcoming the practical limitations of fasting has resulted in an interesting alternative. This review synthesizes the findings of diverse clinical trials evaluating the safety and efficacy of CR and CRMs. In dietary interventions, a fast-mimicking diet was the most tolerated to reduce tumoral growth markers and chemotherapy side effects. CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients. The application of CR and/or CRMs shows promising effects in anti-cancer therapy; however, there is a need for more evidence to safely include these interventions in standard-of-care therapies. [ABSTRACT FROM AUTHOR]

Acyl CoA binding protein (ACBP) encoded by DBI is a tissue hormone that limits autophagy in multiple cell types, hence acting as an extracellular autophagy checkpoint. We recently reported in Molecular Cancer that monoclonal antibodies neutralizing ACBP improve immunosurveillance of breast and lung carcinomas. Moreover, ACBP neutralization improves the outcome of neoadjuvant chemoimmunotherapy with PD-1 blockade in preclinical models.

Acyl CoA binding protein (ACBP) encoded by DBI is a tissue hormone that limits autophagy in multiple cell types, hence acting as an extracellular autophagy checkpoint. We recently reported in Molecular Cancer that monoclonal antibodies neutralizing ACBP improve immunosurveillance of breast and lung carcinomas. Moreover, ACBP neutralization improves the outcome of neoadjuvant chemoimmunotherapy with PD-1 blockade in preclinical models. [ABSTRACT FROM AUTHOR]

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

The dysfunction of myelinating glial cells, the oligodendrocytes, within the central nervous system (CNS) can result in the disruption of myelin, the lipid-rich multi-layered membrane structure that surrounds most vertebrate axons. This leads to axonal degeneration and motor/cognitive impairments. In response to demyelination in the CNS, the formation of new myelin sheaths occurs through the homeostatic process of remyelination, facilitated by the differentiation of newly formed oligodendrocytes. Apart from oligodendrocytes, the two other main glial cell types of the CNS, microglia and astrocytes, play a pivotal role in remyelination. Following a demyelination insult, microglia can phagocytose myelin debris, thus permitting remyelination, while the developing neuroinflammation in the demyelinated region triggers the activation of astrocytes. Modulating the profile of glial cells can enhance the likelihood of successful remyelination. In this context, recent studies have implicated autophagy as a pivotal pathway in glial cells, playing a significant role in both their maturation and the maintenance of myelin. In this Review, we examine the role of substances capable of modulating the autophagic machinery within the myelinating glial cells of the CNS. Such substances, called caloric restriction mimetics, have been shown to decelerate the aging process by mitigating age-related ailments, with their mechanisms of action intricately linked to the induction of autophagic processes.

Caloric restriction (CR) and its related alternatives have been shown to be the only interventions capable of extending lifespan and decreasing the risk of cancer, along with a reduction in burden in pre-clinical trials. Nevertheless, the results from clinical trials have not been as conclusive as the pre-clinical results. Recognizing the challenges associated with long-term fasting, the application of caloric restriction mimetics (CRMs), pharmacological agents that mimic the molecular effects of CR, to harness the potential benefits while overcoming the practical limitations of fasting has resulted in an interesting alternative. This review synthesizes the findings of diverse clinical trials evaluating the safety and efficacy of CR and CRMs. In dietary interventions, a fast-mimicking diet was the most tolerated to reduce tumoral growth markers and chemotherapy side effects. CRMs were well tolerated, and metformin and aspirin showed the most promising effect in reducing cancer risk in a selected group of patients. The application of CR and/or CRMs shows promising effects in anti-cancer therapy; however, there is a need for more evidence to safely include these interventions in standard-of-care therapies.

The medicinal fungus Ganoderma lucidum is used as a dietary supplement and health tonic, but whether it affects longevity remains unclear. We show here that a water extract of G. lucidum mycelium extends lifespan of the nematode Caenorhabditis elegans. The G. lucidum extract reduces the level of fibrillarin (FIB-1), a nucleolar protein that correlates inversely with longevity in various organisms. Furthermore, G. lucidum treatment increases expression of the autophagosomal protein marker LGG-1, and lifespan extension is abrogated in mutant C. elegans strains that lack atg-18, daf-16, or sir-2.1, indicating that autophagy and stress resistance pathways are required to extend lifespan. In cultured human cells, G. lucidum increases concentrations of the LGG-1 ortholog LC3 and reduces levels of phosphorylated mTOR, a known inhibitor of autophagy. Notably, low molecular weight compounds (

The nematode Caenorhabditis elegans is a useful model to study aging due to its short lifespan, ease of manipulation, and available genetic tools. Several molecules and extracts derived from plants and fungi extend the lifespan of C. elegans by modulating aging-related pathways that are conserved in more complex organisms. Modulation of aging pathways leads to activation of autophagy, mitochondrial biogenesis and expression of antioxidant and detoxifying enzymes in a manner similar to caloric restriction. Low and moderate concentrations of plant and fungal molecules usually extend lifespan, while high concentrations are detrimental, consistent with a lifespan-modulating mechanism involving hormesis. We review here molecules and extracts derived from plants and fungi that extend the lifespan of C. elegans, and explore the possibility that these natural substances may produce health benefits in humans.

In the last decades, important progress has been achieved in the understanding of the neurotrophic effects of intermittent fasting (IF), calorie restriction (CR) and exercise. Improved neuroprotection, synaptic plasticity and adult neurogenesis (NSPAN) are essential examples of these neurotrophic effects. The importance in this respect of the metabolic switch from glucose to ketone bodies as cellular fuel has been highlighted. More recently, calorie restriction mimetics (CRMs; resveratrol and other polyphenols in particular) have been investigated thoroughly in relation to NSPAN. In the narrative review sections of this manuscript, recent findings on these essential functions are synthesized and the most important molecules involved are presented. The most researched signaling pathways (PI3K, Akt, mTOR, AMPK, GSK3β, ULK, MAPK, PGC-1α, NF-κB, sirtuins, Notch, Sonic hedgehog and Wnt) and processes (e.g., anti-inflammation, autophagy, apoptosis) that support or thwart neuroprotection, synaptic plasticity and neurogenesis are then briefly presented. This provides an accessible entry point to the literature. In the annotated bibliography section of this contribution, brief summaries are provided of about 30 literature reviews relating to the neurotrophic effects of interest in relation to IF, CR, CRMs and exercise. Most of the selected reviews address these essential functions from the perspective of healthier aging (sometimes discussing epigenetic factors) and the reduction of the risk for neurodegenerative diseases (Alzheimer’s disease, Huntington’s disease, Parkinson’s disease) and depression or the improvement of cognitive function.

Nutrition affects all physiological processes including those linked to the development and function of our immune system. Here, we discuss recent evidence and emerging concepts supporting the idea that our newfound relationship with nutrition in industrialized countries has fundamentally altered the way in which our immune system is wired. This will be examined through the lens of studies showing that mild or transient reductions in dietary intake can enhance protective immunity while also limiting aberrant inflammatory responses. We will further discuss how trade-offs and priorities begin to emerge in the context of severe nutritional stress. In those settings, specific immunological functions are heightened to re-enforce processes and tissue sites most critical to survival. Altogether, these examples will emphasize the profound influence nutrition has over the immune system and highlight how a mechanistic exploration of this cross talk could ultimately lead to the design of novel therapeutic approaches that prevent and treat disease. Nutrition profoundly impacts the development and function of our immune system directly and via the microbiota. Developing a mechanistic understanding of this cross talk has great potential to promote the design of novel therapies that prevent and treat disease. [ABSTRACT FROM AUTHOR]

Caloric restriction (CR) has been shown to extend the lifespan of many species. Research to identify compounds that imitate the results of CR has shown extensions of both lifespan and healthspan via different mechanisms. For example, mechanistic target of rapamycin (mTOR) inhibitors such as rapamycin affect nutrient-sensing pathways; phenols and flavonoids show antioxidant characteristics; aspirin has anti-inflammatory effects, while spermidine induces autophagy. Herein, we summarize research progress and proposed mechanisms for the most well-known compounds showing lifespan-extending potential for anti-aging characteristics.

Neuropsychiatric disorders, including depression contribute significantly to global disability and possess high social and health burden. Management is dominated by pharmacotherapy and psychotherapy; nevertheless, such treatments prevent or treat less than half of the patients, suggesting that alternative approaches are required. Emerging data suggest that diet may be an adjustable risk factor for psychiatric disorders. Caloric restriction (CR) possesses protective effects in almost all organs including the brain. However, the precise molecular pathways of these effects remain uncertain. In this review, we will discuss the putative neurobiological mechanisms of CR on the brain. The article will address also the molecular basis of the antidepressant effects of CR, primarily including ghrelin signaling, CREB neurotropic effects and ketone bodies production. Then we will highlight the probable effect of CR on the neuroinflammation, which emerges as a key pathogenetic factor for the majority of neuropsychiatric disorders. Finally, we discuss the so called caloric restriction mimetics, compounds that reproduce properties of CR. Further research will be required to verify the safety and efficacy of CR before a general approval can be proposed to introduce it and its mimetics in clinical practice for the treatment of neuropsychiatric disorders.

The nematode Caenorhabditis elegans is a useful model to study aging due to its short lifespan, ease of manipulation, and available genetic tools. Several molecules and extracts derived from plants and fungi extend the lifespan of C. elegans by modulating aging-related pathways that are conserved in more complex organisms. Modulation of aging pathways leads to activation of autophagy, mitochondrial biogenesis and expression of antioxidant and detoxifying enzymes in a manner similar to caloric restriction. Low and moderate concentrations of plant and fungal molecules usually extend lifespan, while high concentrations are detrimental, consistent with a lifespan-modulating mechanism involving hormesis. We review here molecules and extracts derived from plants and fungi that extend the lifespan of C. elegans, and explore the possibility that these natural substances may produce health benefits in humans.

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.

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 (CRMs) are emerging as potential therapeutic agents for the treatment of cardiovascular diseases. CRMs include natural and synthetic compounds able to inhibit protein acetyltransferases, to interfere with acetyl coenzyme A biosynthesis, or to activate (de)acetyltransferase proteins. These modifications mimic the effects of caloric restriction, which is associated with the activation of autophagy. Previous evidence demonstrated the ability of CRMs to ameliorate cardiac function and reduce cardiac hypertrophy and maladaptive remodelling in animal models of ageing, mechanical overload, chronic myocardial ischaemia, and in genetic and metabolic cardiomyopathies. In addition, CRMs were found to reduce acute ischaemia–reperfusion injury. In many cases, these beneficial effects of CRMs appeared to be mediated by autophagy activation. In the present review, we discuss the relevant literature about the role of different CRMs in animal models of cardiac diseases, emphasizing the molecular mechanisms underlying the beneficial effects of these compounds and their potential future clinical application. [ABSTRACT FROM AUTHOR]

Spermidine (SPD) is a natural polyamine present in all living organisms and is involved in the maintenance of cellular homeostasis by inducing autophagy in different model organisms. Its role as a caloric restriction mimetic (CRM) is still being investigated. We have undertaken this study to investigate whether SPD, acting as a CRM, can confer neuroprotection in d-galactose induced accelerated senescence model rat and naturally aged rats through modulation of autophagy and inflammation. Young male rats (4 months), d-gal induced (500 mg/kg b.w., subcutaneously) aging and naturally aged (22 months) male rats were supplemented with SPD (10 mg/kg b.w., orally) for 6 weeks. Standard protocols were employed to measure prooxidants, antioxidants, apoptotic cell death and electron transport chain complexes in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy and inflammatory marker genes. Our data demonstrate that SPD significantly (p ≤ 0.05) decreased the level of pro-oxidants and increased the level of antioxidants. SPD supplementation also augmented the activities of electron transport chain complexes in aged brain mitochondria thus proving its antioxidant potential at the level of mitochondria. RT-PCR data revealed that SPD up-regulated the expression of autophagy genes (ATG-3, Beclin-1, ULK-1 and LC3B) and down-regulated the expression of the inflammatory gene (IL-6) in aging brain. Our results provide first line of evidence that SPD provides neuroprotection against aging-induced oxidative stress by regulating autophagy, antioxidants level and also reduces neuroinflammation. These results suggest that SPD may be beneficial for neuroprotection during aging and age-related disorders. [ABSTRACT FROM AUTHOR]

Caloric restriction mimetics (CRMs) are promising molecules to prevent age-related diseases as they activate pathways driven by a true caloric restriction. Hydroxycitric acid (HCA) is considered a bona fide CRM since it depletes acetyl-CoA pools by acting as a competitive inhibitor of ATP citrate lyase (ACLY), ultimately repressing protein acetylation and promoting autophagy. Importantly, it can reduce inflammation and tumour development. In order to identify phenotypically relevant new HCA targets we have investigated HCA effects in Saccharomyces cerevisiae, where ACLY is lacking. Strikingly, the drug revealed a powerful anti-aging effect, another property proposed to mark bona fide CRMs. Chronological life span (CLS) extension but also resistance to acetic acid of HCA treated cells were associated to repression of cell apoptosis and necrosis. HCA also largely prevented cell deaths caused by a severe oxidative stress. The molecule could act widely by negatively modulating cell metabolism, similarly to citrate. Indeed, it inhibited both growth reactivation and the oxygen consumption rate of yeast cells in stationary phase. Genetic analyses on yeast CLS mutants indicated that part of the HCA effects can be sensed by Sch9 and Ras2, two conserved key regulators of nutritional and stress signal pathways of primary importance. Our data together with published biochemical analyses indicate that HCA may act with multiple mechanisms together with ACLY repression and allowed us to propose an integrated mechanistic model as a basis for future investigations. [ABSTRACT FROM AUTHOR]

We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8+ T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents.

Dietary interventions have a profound impact on whole body metabolism, including oncometabolism (the metabolic features allowing cancer cells to proliferate) and immunometabolism (the catabolic and anabolic reactions that regulate immune responses). Recent preclinical studies demonstrated that multiple dietary changes can improve anticancer immunosurveillance of chemo-, radio- and immunotherapy. These findings have fostered the design of clinical trials evaluating the capacity of dietary interventions to synergize with treatment and hence limit tumor progression. Here, we discuss the scientific rationale for harnessing dietary interventions to improve the efficacy of anticancer therapy and present up-to-date information on clinical trials currently investigating this possibility.

In line with the increase in the number of older people in the world, the focus of scientists is directed at examining mechanisms of the aging process as well as establishing strategies/interventions in order to slow down aging and achieve longevity. On preclinical testing models, the most effective strategy for this purpose, as well as for the purpose of delaying age-related diseases, nutritional intervention- restriction of calorie (CR) has been demonstrated, but also some alternative forms of calorie restriction. Possible undesirable effects of restriction are still in the testing phase, and it is known that it is generally difficult to implement in humans. Therefore, the new area of research in gerontology has become the discovery and examination of the effects of compounds that mimic the effects of caloric restriction, so called caloric restriction mimetics (CRM). These compounds include numerous compounds of natural origin but also approved medicaments with certain indications. This overview summarizes the latest data on known mechanisms of caloric restriction and more familiar caloric restriction mimetics. [ABSTRACT FROM AUTHOR]

We have recently shown that chemotherapy with immunogenic cell death (ICD)-inducing agents can be advantageously combined with fasting regimens or caloric restriction mimetics (CRMs) to achieve superior tumor growth control via a T cell-dependent mechanism. Here, we show that the blockade of the CD11b-dependent extravasation of myeloid cells blocks such a combination effect as well. Based on the characterization of the myeloid and lymphoid immune infiltrates, including the expression pattern of immune checkpoint proteins (and noting a chemotherapy-induced overexpression of programmed death-ligand 1, PD-L1, on both cancer cells and leukocytes, as well as a reduced frequency of exhausted CD8+ T cells positive for programmed cell death 1 protein, PD-1), we then evaluated the possibility to combine ICD inducers, CRMs and targeting of the PD-1/PD-L1 interaction. While fasting or CRMs failed to improve tumor growth control by PD-1 blockade, ICD inducers alone achieved a partial sensitization to treatment with a PD-1-specific antibody. However, definitive cure of most of the tumor-bearing mice was only achieved by a tritherapy combining (i) ICD inducers exemplified by mitoxantrone and oxaliplatin, (ii) CRMs exemplified by hydroxycitrate and spermidine and substitutable for by fasting, and (iii) immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 interaction. Altogether, these results point to the possibility of synergistic interactions among distinct classes of anticancer agents. [ABSTRACT FROM AUTHOR]

The dysfunction of myelinating glial cells, the oligodendrocytes, within the central nervous system (CNS) can result in the disruption of myelin, the lipid-rich multi-layered membrane structure that surrounds most vertebrate axons. This leads to axonal degeneration and motor/cognitive impairments. In response to demyelination in the CNS, the formation of new myelin sheaths occurs through the homeostatic process of remyelination, facilitated by the differentiation of newly formed oligodendrocytes. Apart from oligodendrocytes, the two other main glial cell types of the CNS, microglia and astrocytes, play a pivotal role in remyelination. Following a demyelination insult, microglia can phagocytose myelin debris, thus permitting remyelination, while the developing neuroinflammation in the demyelinated region triggers the activation of astrocytes. Modulating the profile of glial cells can enhance the likelihood of successful remyelination. In this context, recent studies have implicated autophagy as a pivotal pathway in glial cells, playing a significant role in both their maturation and the maintenance of myelin. In this Review, we examine the role of substances capable of modulating the autophagic machinery within the myelinating glial cells of the CNS. Such substances, called caloric restriction mimetics, have been shown to decelerate the aging process by mitigating age-related ailments, with their mechanisms of action intricately linked to the induction of autophagic processes.

Senescence is related to the loss of cellular homeostasis and functions, which leads to a progressive decline in physiological ability and to aging-associated diseases. Since mitochondria are essential to energy supply, cell differentiation, cell cycle control, intracellular signaling and Ca2+ sequestration, fine-tuning mitochondrial activity appropriately, is a tightrope walk during aging. For instance, the mitochondrial oxidative phosphorylation (OXPHOS) ensures a supply of adenosine triphosphate (ATP), but is also the main source of potentially harmful levels of reactive oxygen species (ROS). Moreover, mitochondrial function is strongly linked to mitochondrial Ca2+ homeostasis and mitochondrial shape, which undergo various alterations during aging. Since mitochondria play such a critical role in an organism's process of aging, they also offer promising targets for manipulation of senescent cellular functions. Accordingly, interventions delaying the onset of age-associated disorders involve the manipulation of mitochondrial function, including caloric restriction (CR) or exercise, as well as drugs, such as metformin, aspirin, and polyphenols. In this review, we discuss mitochondria's role in and impact on cellular aging and their potential to serve as a target for therapeutic interventions against age-related cellular dysfunction. [ABSTRACT FROM AUTHOR]

Aim In the present study, attempts have been made to evaluate the potential role of fisetin, a caloric restriction mimetic (CRM), for neuroprotection in D-galactose (D-gal) induced accelerated and natural aging models of rat. Main methods Fisetin was supplemented (15 mg/kg b.w., orally) to young, D-gal induced aged (D-gal 500 mg/kg b.w subcutaneously) and naturally aged rats for 6 weeks. Standard protocols were employed to measure pro-oxidants, antioxidants and mitochondrial membrane potential in brain tissues. Gene expression analysis with reverse transcriptase-polymerase chain reaction (RT-PCR) was performed to assess the expression of autophagy, neuronal, aging as well as inflammatory marker genes. We have also evaluated apoptotic cell death and synaptosomal membrane-bound ion transporter activities in brain tissues. Key findings Our data demonstrated that fisetin significantly decreased the level of pro-oxidants and increased the level of antioxidants. Furthermore, fisetin also ameliorated mitochondrial membrane depolarization, apoptotic cell death and impairments in the activities of synaptosomal membrane-bound ion transporters in aging rat brain. RT-PCR data revealed that fisetin up-regulated the expression of autophagy genes (Atg-3 and Beclin-1), sirtuin-1 and neuronal markers (NSE and Ngb), and down-regulated the expression of inflammatory (IL-1β and TNF-α) and Sirt-2 genes respectively in aging brain. Significance The present study suggests that fisetin supplementation may provide neuroprotection against aging-induced oxidative stress, apoptotic cell death, neuro-inflammation, and neurodegeneration in rat brain. [ABSTRACT FROM AUTHOR]

Caloric restriction (CR), defined as decreased nutrient intake without causing malnutrition, has been documented to increase both health and lifespan across numerous organisms, including humans. Many drugs and other compounds naturally occurring in our diet (nutraceuticals) have been postulated to act as mimetics of caloric restriction, leading to a wave of research investigating the efficacy of these compounds in preventing age-related diseases and promoting healthier, longer lifespans. Although well studied at the biochemical level, there are still many unanswered questions about how CR and CR mimetics impact genome function and structure. Here we discuss the impact of CR and potential CR mimetics on genome function and structure, including changes in gene expression profiles and epigenetic modifications and their potential to identify the genetic fountain of youth.

In the last decades, important progress has been achieved in the understanding of the neurotrophic effects of intermittent fasting (IF), calorie restriction (CR) and exercise. Improved neuroprotection, synaptic plasticity and adult neurogenesis (NSPAN) are essential examples of these neurotrophic effects. The importance in this respect of the metabolic switch from glucose to ketone bodies as cellular fuel has been highlighted. More recently, calorie restriction mimetics (CRMs; resveratrol and other polyphenols in particular) have been investigated thoroughly in relation to NSPAN. In the narrative review sections of this manuscript, recent findings on these essential functions are synthesized and the most important molecules involved are presented. The most researched signaling pathways (PI3K, Akt, mTOR, AMPK, GSK3β, ULK, MAPK, PGC-1α, NF-κB, sirtuins, Notch, Sonic hedgehog and Wnt) and processes (e.g., anti-inflammation, autophagy, apoptosis) that support or thwart neuroprotection, synaptic plasticity and neurogenesis are then briefly presented. This provides an accessible entry point to the literature. In the annotated bibliography section of this contribution, brief summaries are provided of about 30 literature reviews relating to the neurotrophic effects of interest in relation to IF, CR, CRMs and exercise. Most of the selected reviews address these essential functions from the perspective of healthier aging (sometimes discussing epigenetic factors) and the reduction of the risk for neurodegenerative diseases (Alzheimer's disease, Huntington's disease, Parkinson's disease) and depression or the improvement of cognitive function., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Mayor.)

Caloric restriction (CR), defined as decreased nutrient intake without causing malnutrition, has been documented to increase both health and lifespan across numerous organisms, including humans. Many drugs and other compounds naturally occurring in our diet (nutraceuticals) have been postulated to act as mimetics of caloric restriction, leading to a wave of research investigating the efficacy of these compounds in preventing age-related diseases and promoting healthier, longer lifespans. Although well studied at the biochemical level, there are still many unanswered questions about how CR and CR mimetics impact genome function and structure. Here we discuss how genome function and structure are influenced by CR and potential CR mimetics, including changes in gene expression profiles and epigenetic modifications and their potential to identify the genetic fountain of youth. [ABSTRACT FROM AUTHOR]

Highlights: [•] Caloric restriction (CR) and rapamycin extended the chronological lifespan (CLS) of yeast. [•] Caffeine, curcumin, dapsone, metformin, resveratrol, and spermidine did not extend the CLS. [•] Rapamycin prevented total ROS, and increased MMP and ATP at the exponential phase. [•] CR reduced the mito-superoxide, and enhanced MMP and ATP at the stationary phase. [•] Rapamycin and CR worked via mitochondrial functions, but at different timeframes. [ABSTRACT FROM AUTHOR]

Background: We review studies showing that CR acts rapidly, even in late adulthood, to extend health-and lifespan in mice. These rapid physiological effects are closely linked to patterns of gene expression in liver and heart. Non-human primate and human studies suggest that the signal transduction pathways responsible for the lifespan and health effects of caloric restriction (CR) may also be involved in human longevity. Thus, pharmaceuticals capable of mimicking the effects of CR (and other methods of lifespan extension) may have application to human health. Objective: We show that lifespan studies are an inefficient and theoretically problematic way of screening for longevity therapeutics. We review studies suggesting that rapid changes in patterns of gene expression can be used to identify pharmaceuticals capable of mimicking some positive effects of caloric restriction. Results: We present a traditional study of the effects of melatonin, melatonin and pregnenolone, aminoguanidine, aminoguanidine and α-lipoic acid, aminoguanidine, α-lipoic acid, pregnenolone, and coenzyme-Q10 on the lifespan of mice. No treatment extended lifespan. However, because the mice die mostly of cancer, only chemopreventives active against specific cancers can be identified by such studies. The studies were also time-consuming and expensive. We discuss high-density microarray studies of the effectiveness of glucoregulatory drugs and putative cancer chemopreventatives at reproducing the hepatic gene-expression profiles of long-term and short-term CR. We describe the identification of one compound, metformin, which reproduces a subset of the gene-expression and physiological effects of CR. Conclusion: Taken together, our results suggest that gene-expression biomarkers may be superior to lifespan studies for initial screening of candidate longevity therapeutics. [ABSTRACT FROM AUTHOR]

Epidemiological studies suggest that Mediterranean diets rich in resveratrol are associated with reduced risk of coronary artery disease. However, the mechanisms by which resveratrol exerts its vasculoprotective effects are not completely understood. Because oxidative stress and endothelial cell injury play a critical role in vascular aging and atherogenesis, we evaluated whether resveratrol inhibits oxidative stress-induced endothelial apoptosis. We found that oxidized LDL and TNF-α elicited significant increases in caspase-3/7 activity in endothelial cells and cultured rat aortas, which were prevented by resveratrol pretreatment (10-6-10-4 mol/l). The protective effect of resveratrol was attenuated by inhibition of glutathione peroxidase and heme oxygenase-1, suggesting a role for antioxidant systems in the antiapoptotic action of resveratrol. Indeed, resveratrol treatment protected cultured aortic segments and/or endothelial cells against increases in intracellular H2O2 levels and H2O2-mediated apoptotic cell death induced by oxidative stressors (exogenous H2O2, paraquat, and UV light). Resveratrol treatment also attenuated UV-induced DNA damage (comet assay). Resveratrol treatment upregulated the expression of glutathione peroxidase, catalase. and heme oxygenase-1 in cultured arteries, whereas it had no significant effect on the expression of SOD isoforms. Resveratrol also effectively scavenged H2O2 in vitro. Thus resveratrol seems to increase vascular oxidative stress resistance by scavenging H2O2 and preventing oxidative stress-induced endothelial cell death. We propose that the antioxidant and antiapoptotic effects of resveratrol, together with its previously described anti-inflammatory actions, are responsible, at least in part, for its cardioprotective effects. [ABSTRACT FROM AUTHOR]