Role Of Sirtuins Research Articles

Sirtuin 7 ameliorates cuproptosis, myocardial remodeling and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling.

Myocardial fibrosis is a typical pathological manifestation of hypertension. However, the exact role of sirtuin 7 (SIRT7) in myocardial remodeling remains largely unclear. Here, spontaneously hypertensive rats (SHRs) and angiotensin (Ang) II-induced hypertensive mice were pretreated with recombinant adeno-associated virus (rAAV)-SIRT7, copper chelator tetrathiomolybdate (TTM) or copper ionophore elesclomol, respectively. Compared with normotensive controls, reduced SIRT7 expression and augmented cuproptosis were observed in hearts of hypertensive rats and mice with decreased FDX1 levels and increased HSP70 levels. Notably, intervention with rAAV-SIRT7 and TTM strikingly prevented DLAT oligomers aggregation, and elevated ATP7A and TOM20 expressions, contributing to the alleviation of cuproptosis, mitochondrial injury, myocardial remodeling and heart dysfunction in spontaneously hypertensive rats and Ang II-induced hypertensive mice. In cultured rat primary cardiac fibroblasts (CFs), rhSIRT7 alleviated CuCl2, Ang II or elesclomol-induced cuproptosis and fibroblast activation by blunting DLAT oligomers accumulation and downregulating α-SMA expression. Additionally, conditioned medium from rhSIRT7-pretreated CFs remarkably mitigated cellular hypertrophy and mitochondrial impairments of neonatal rat cardiomyocytes, as well as cell migration and polarization of RAW 264.7 macrophages. Importantly, verteporfin reduced CuCl2-induced cuproptosis, mitochondrial injury and fibrotic activation in CFs. Knockdown of ATP7A with si-ATP7A blocked cellular protective effects of rhSIRT7 and verteporfin in CFs. In conclusion, SIRT7 attenuates cuproptosis, myocardial fibrosis and heart dysfunction in hypertension through the modulation of YAP/ATP7A signaling. Targeting SIRT7 is of vital importance for developing therapeutic strategies in hypertension and hypertensive heart disorders.

Understanding the fundamental mechanisms and conditions of the tumor-suppressive and oncogenic roles of sirtuins in cancer: A review

Silent information regulators (SIRTs) or sirtuins represent a group of class III nicotinamide adenine dinucleotide–dependent histone deacetylases. In mammals, seven types of sirtuins are distinguished, differing in their target structures, enzymatic activities, and subcellular localization. Histone deacetylation is a form of epigenetic regulation of gene expression that can cause activation or deactivation of selected genetic targets. Activation of sirtuins is part of the response to nutritional and environmental stimuli (starvation, DNA damage, and oxidative stress). Activated sirtuins subsequently stimulate specific transcriptional programs to make mitochondrial oxidative metabolism more efficient in the fight against oxidative stress or regulate proteins responsible for DNA repair after damage. As a result of their multifunctional involvement in cellular metabolism, dysregulation and aberrant expression of sirtuins have been observed in various cancers. Sirtuins play a dual role in carcinogenesis, acting as either oncogenes or tumor suppressors and affecting the proliferation, apoptosis, and survival of cancerous cells.

Neurodegeneration: Effects of calorie restriction on the brain sirtuin protein levels

BackgroundCalorie restriction (CR) is suggested to activate protective mechanisms in neurodegenerative diseases (NDDs). Despite existing literature highlighting the protective role of Sirtuin (SIRT) proteins against age-related neurodegeneration (ND), no study has explored the total levels of SIRT 1, 3, and 6 proteins simultaneously in brain homogenates by ELISA following intermittent calorie restriction. Applying CR protocols in mice to induce stress, we aimed to determine whether ND would be more pronounced with ad libitum (AL) or with CR. MethodsMice were randomly assigned to ad libitum (AL), Chronic CR (CCR), or Intermittent CR (ICR) groups at 10 weeks of baseline age (BL). SIRT 1, 3, and 6 protein levels were measured in the homogenized whole-brain supernatants of 49/50 weeks old mice by the ELISA method. Neuronal morphology was evaluated by the cresyl violet on the hippocampus. Neurodegeneration (ND) was assessed by the fluoro-jade and ImageJ was used for quantifications. ResultsIn the ICR group, SIRT1 levels were elevated compared to both the AL and BL groups. Similarly, the CCR group exhibited higher SIRT1 values compared to the AL and BL groups. While SIRT3 levels were higher in both the ICR and CCR groups compared to the AL and BL groups, this disparity did not reach statistical significance. SIRT6 levels were also higher in the ICR group compared to both the BL and AL groups, with the CCR group showing higher values compared to the BL and AL groups as well. Image quantification demonstrated significant neurodegeneration in the AL group compared to the CCR and ICR group, with no observed alterations in nerve cell morphology and number. ConclusionThis study revealed that the levels of SIRT 1, SIRT 3, and SIRT 6 in brain tissue were notably elevated, and there was less evidence of ND at the 50-week mark in groups undergoing continuous calorie restriction and intermittent calorie restriction compared to baseline and ad libitum groups. Our findings illustrate that CR promotes increased SIRT expression in the mouse brain, thereby potentially mitigating neurodegeneration.

Elucidating the Role of Sirtuin 3 in Mammalian Oocyte Aging.

The field of reproductive biology has made significant progress in recent years, identifying specific molecular players that influence oocyte development and function. Among them, sirtuin 3 (SIRT3) has attracted particular attention for its central role in mediating mitochondrial function and cellular stress responses in oocytes. So far, studies have demonstrated that the knockdown of SIRT3 leads to a decrease in blastocyst formation and an increase in oxidative stress within an embryo, underscoring the importance of SIRT3 in maintaining the cellular redox balance critical for embryonic survival and growth. Furthermore, the literature reveals specific signaling pathways, such as the SIRT3- Glycogen synthase kinase-3 beta (GSK3β) deacetylation pathway, crucial for mitigating oxidative stress-related anomalies in oocyte meiosis, particularly under conditions like maternal diabetes. Overall, the emerging role of SIRT3 in regulating oocyte mitochondrial function and development highlights the critical importance of understanding the intricate connections between cellular metabolism, stress response pathways, and overall reproductive health and function. This knowledge could lead to the development of novel strategies to support oocyte quality and fertility, with far-reaching implications for assisted reproductive technologies and women's healthcare. This commentary aims to provide an overview of the importance of SIRT3 in oocytes by synthesizing results from a multitude of studies. The aim is to elucidate the role of SIRT3 in oocyte development, maturation, and aging and to identify areas where further research is needed.

Shikonin mitigates cyclophosphamide-induced cardiotoxicity in mice: the role of sirtuin-1, NLRP3 inflammasome, autophagy, and apoptosis.

The aim of this study was to elucidate the protective potential of shikonin (SHK) on cyclophosphamide (CP)-induced cardiotoxicity in Swiss albino mice. Mice received SHK in three different doses by oral gavage daily for 14 days and CP at 100mg/kg, intraperitoneally once on the seventh day. On the 15th day, mice were euthanized, blood collected, and hearts were removed to estimate various biochemical and histopathological parameters. CP significantly increased serum lactate dehydrogenase, creatine kinase-MB, troponin I and NT pro-BNP, and cardiac malondialdehyde and decreased cardiac total antioxidant capacity and Nrf2, whereas increased inflammatory markers in the cardiac tissues. CP also caused hypertrophy and fibrosis in the cardiac tissues via activation of IL6/JAK2/STAT3 while depressed SIRT1 and PI3K/p-Akt pathway with consequent increased apoptosis and dysregulation of autophagy. SHK treatment reversed these changes in a dose-dependent manner and showed a significant protective effect against CP-induced cardiotoxicity via suppressing oxidative stress, inflammation, and apoptosis with modulation of autophagy via induction of SIRT1/PI3K/p-Akt signaling. Shikonin may be used as an adjuvant to cyclophosphamide in cancer treatment, but further research is needed to investigate its effects on cardiotoxicity in distinct animal cancer models.

The influential responsibility of sirtuins in senescence and associated diseases: A review.

Aging is a process of time-associated depletion in the physiological functions, essential for the survival and reproducibility of living beings. Some age-related disorders can be successfully controlled with some biomedical techniques or pharmaceutical approaches. There are some precise remedies that demonstrate conspicuous promise in the preclinical and clinical setup of extending lifespan or enhancing health by altering natural senescence. The sirtuin family of proteins is one of the most favorable targets for antiaging strategies. Sirtuins were initially identified as transcription repressors in yeast, but today they are known to exist in bacteria and eukaryotes, as well as humans. The SIRT (1-7) family of proteins in humans is made up of seven members, each of which has either mono-ADP ribosyl transferase or deacetylase activity. Researchers suggest that sirtuins are essential for cell metabolism and play a major role in how cells react to various stimuli, such as oxidative or genotoxic stress. A healthy lifestyle, which includes exercise and a balanced diet, has been demonstrated to impact health span by adjusting the levels of sirtuins, suggesting the involvement of sirtuins in extending human longevity. The hunt for sirtuin activators is among the most extensive and comprehensive research subjects in the present scenario. Some optimism has been generated to investigate antiaging therapies by natural compounds, such as curcumin and others. This review article highlights the role of sirtuins in native senescence and their primordial roles in the progression of several life-threatening diseases. Further, it also provides recent information on the sirtuin activators and inhibitors and their therapeutic benefits.

The effect of weight loss therapies on sirtuin 1 regulation: a systematic review and meta-analysis of randomized controlled trials

BackgroundRecent evidence shows the role of sirtuin 1(SIRT1), a family of evolutionarily conserved proteins, as a potential therapeutic target in the prevention and treatment of obesity and metabolic diseases. Some evidence shows the moderating effects of weight loss interventions on this factor. However, the findings are contradictory. In order to obtain a better viewpoint from them, this study aimed to comprehensively investigate the effects of weight loss interventions on SIRT 1 modulation.MethodsFor this study, we searched four electronic databases using predefined keywords from inception until March 2024. We includedrandomized controlled trials that evaluated the effect of weight reduction strategies on SIRT1 levels. The random-effects model analysis was used to obtain the pooled weighted mean difference (WMD) and 95% confidence intervals (95% CI). The meta-analysis was conducted using RevMan version 5.3 software and Stata version 12.0.ResultsTwelve studies with 627 volunteers were included. The pooled findings showed that weight loss interventions have no significant effect on the modulation of SIRT1 compared to the control group (pooled WMD of 0.58 ng/mL; 95% confidence interval [CI] -0.17 to 1.33; p = 0.130). However, subgroup analysis showed that weight loss interventions significantly modulate SIRT1 at metabolic disease (WMD: 1.2 ng/mL, 95% CI: 0.11 to 2.62, I2 = 82.9%). In addition, subgroup findings indicated health status and body mass index (BMI) as sources of high and potential heterogeneity.ConclusionsBased on the findings, weight loss therapies in individuals having a metabolic disorder appear to generate a considerable increase in SIRT1 levels.

Emerging role of sirtuins in non‑small cell lung cancer (Review).

Non‑small cell lung cancer (NSCLC) is a highly prevalent lung malignancy characterized by insidious onset, rapid progression and advanced stage at the time of diagnosis, making radical surgery impossible. Sirtuin (SIRT) is a histone deacetylase that relies on NAD+ for its function, regulating the aging process through modifications in protein activity and stability. It is intricately linked to various processes, including glycolipid metabolism, inflammation, lifespan regulation, tumor formation and stress response. An increasing number of studies indicate that SIRTs significantly contribute to the progression of NSCLC by regulating pathophysiological processes such as energy metabolism, autophagy and apoptosis in tumor cells through the deacetylation of histones or non‑histone proteins. The present review elaborates on the roles of different SIRTs and their mechanisms in NSCLC, while also summarizing novel therapeutic agents based on SIRTs. It aims to present new ideas and a theoretical basis for NSCLC treatment.

Overexpression of METTL14 mediates steatohepatitis and insulin resistance in mice

BackgroundLipid accumulation and redox imbalance, resulting from dysregulation of hepatic fatty acids oxidation, contribute to the development of steatohepatitis and insulin resistance. Recently, dysregulated RNA N6-methyladenosine (m6A) methylation modification has been found involving fatty liver. However, the role of methyltransferase-like 14 (METTL14), the core component of m6A methylation, in the development of steatohepatitis is unknown. Herein, we aimed to explore the role of METTL14 on steatohepatitis and insulin resistance in mice with metabolic dysfunction-associated steatotic liver disease (MASLD). MethodsThe liver tissues of mice and patients with MASLD were collected to detect the expression of METTL14. METTL14 overexpression and METTL14 silence were used to investigate the effect of METTL14 on lipid metabolism disorder in vivo and in vitro. Knockout of METTL14 in primary hepatocytes was used to investigate the role of Sirtuin 1 (SIRT1) on lipid accumulation induced by METTL14. ResultsMETTL14 was dramatically up-regulated in the livers of db/db mice, high-fat diet (HFD)-fed mice, and patients with MASLD. METTL14 overexpression exacerbated MASLD and promoted lipid metabolism disorder and insulin resistance in mice. Conversely, METTL14 knockout ameliorated lipid deposition and insulin resistance in HFD-fed mice. Furthermore, METTL14 overexpression facilitated lipid accumulation, while METTL14 knockout reduced lipid accumulation in HepG2 cells and primary hepatocytes. In addition, METTL14 lost up-regulated SIRT1 expression in hepatocytes. SIRT1 deficiency abrogated the ameliorating effects of METTL14 downregulation in MASLD mice. ConclusionsThese findings suggest that dysfunction of the METTL14-SIRT1 pathway might promote hepatic steatosis and insulin resistance.

Neuroprotective potential for mitigating ischemia-reperfusion-induced damage.

Reperfusion following cerebral ischemia causes both structural and functional damage to brain tissue and could aggravate a patient's condition; this phenomenon is known as cerebral ischemia-reperfusion injury. Current studies have elucidated the neuroprotective role of the sirtuin protein family (Sirtuins) in modulating cerebral ischemia-reperfusion injury. However, the potential of utilizing it as a novel intervention target to influence the prognosis of cerebral ischemia-reperfusion injury requires additional exploration. In this review, the origin and research progress of Sirtuins are summarized, suggesting the involvement of Sirtuins in diverse mechanisms that affect cerebral ischemia-reperfusion injury, including inflammation, oxidative stress, blood-brain barrier damage, apoptosis, pyroptosis, and autophagy. The therapeutic avenues related to Sirtuins that may improve the prognosis of cerebral ischemia-reperfusion injury were also investigated by modulating Sirtuins expression and affecting representative pathways, such as nuclear factor-kappa B signaling, oxidative stress mediated by adenosine monophosphate-activated protein kinase, and the forkhead box O. This review also summarizes the potential of endogenous substances, such as RNA and hormones, drugs, dietary supplements, and emerging therapies that regulate Sirtuins expression. This review also reveals that regulating Sirtuins mitigates cerebral ischemia-reperfusion injury when combined with other risk factors. While Sirtuins show promise as a potential target for the treatment of cerebral ischemia-reperfusion injury, most recent studies are based on rodent models with circadian rhythms that are distinct from those of humans, potentially influencing the efficacy of Sirtuins-targeting drug therapies. Overall, this review provides new insights into the role of Sirtuins in the pathology and treatment of cerebral ischemia-reperfusion injury.

Roles of Sirtuins in Hearing Protection.

Hearing loss is a health crisis that affects more than 60 million Americans. Currently, sodium thiosulfate is the only drug approved by the Food and Drug Administration (FDA) to counter hearing loss. Sirtuins were proposed as therapeutic targets in the search for new compounds or drugs to prevent or cure age-, noise-, or drug-induced hearing loss. Sirtuins are proteins involved in metabolic regulation with the potential to ameliorate sensorineural hearing loss. The mammalian sirtuin family includes seven members, SIRT1-7. This paper is a literature review on the sirtuins and their protective roles in sensorineural hearing loss. Literature search on the NCBI PubMed database and NUsearch included the keywords 'sirtuin' and 'hearing'. Studies on sirtuins without relevance to hearing and studies on hearing without relevance to sirtuins were excluded. Only primary research articles with data on sirtuin expression and physiologic auditory tests were considered. The literature review identified 183 records on sirtuins and hearing. After removing duplicates, eighty-one records remained. After screening for eligibility criteria, there were forty-eight primary research articles with statistically significant data relevant to sirtuins and hearing. Overall, SIRT1 (n = 29) was the most studied sirtuin paralog. Over the last two decades, research on sirtuins and hearing has largely focused on age-, noise-, and drug-induced hearing loss. Past and current studies highlight the role of sirtuins as a mediator of redox homeostasis. However, more studies need to be conducted on the involvement of SIRT2 and SIRT4-7 in hearing protection.

The role of sirtuins in intervertebral disc degeneration: Mechanisms and therapeutic potential.

Intervertebral disc degeneration (IDD) is one of the main causes of low back pain, which affects the patients' quality of life and health and imposes a significant socioeconomic burden. Despite great efforts made by researchers to understand the pathogenesis of IDD, effective strategies for preventing and treating this disease remain very limited. Sirtuins are a highly conserved family of (NAD+)-dependent deacetylases in mammals that are involved in a variety of metabolic processes in vivo. In recent years, sirtuins have attracted much attention owing to their regulatory roles in IDD on physiological activities such as inflammation, apoptosis, autophagy, aging, oxidative stress, and mitochondrial function. At the same time, many studies have explored the therapeutic effects of sirtuins-targeting activators or micro-RNA in IDD. This review summarizes the molecular pathways of sirtuins involved in IDD, and summarizes the therapeutic role of activators or micro-RNA targeting Sirtuins in IDD, as well as the current limitations and challenges, with a view to provide possible solutions for the treatment of IDD.

The dual role of sirtuins in cancer: biological functions and implications.

Sirtuins are pivotal in orchestrating numerous cellular pathways, critically influencing cell metabolism, DNA repair, aging processes, and oxidative stress. In recent years, the involvement of sirtuins in tumor biology has garnered substantial attention, with a growing body of evidence underscoring their regulatory roles in various aberrant cellular processes within tumor environments. This article delves into the sirtuin family and its biological functions, shedding light on their dual roles-either as promoters or inhibitors-in various cancers including oral, breast, hepatocellular, lung, and gastric cancers. It further explores potential anti-tumor agents targeting sirtuins, unraveling the complex interplay between sirtuins, miRNAs, and chemotherapeutic drugs. The dual roles of sirtuins in cancer biology reflect the complexity of targeting these enzymes but also highlight the immense therapeutic potential. These advancements hold significant promise for enhancing clinical outcomes, marking a pivotal step forward in the ongoing battle against cancer.

A role for sirtuin 1 in FGF23 activation following β-glycerophosphate treatment

Phosphate homeostasis is vital for many biological processes and disruptions in circulating levels can be detrimental. While the mechanisms behind FGF23 regulation have been regularly studied, the role of extracellular phosphate sensing and its impact on fibroblast growth factor 23 (FGF23) expression remains unclear. This study aimed to investigate the involvement of reactive oxygen species (ROS), silent information regulator 1 (SIRT1), and Hairy and Enhancer of Split-1 (HES1) in regulating FGF23 in FGF23 expressing MC3T3-E1 cells. MC3T3-E1 cells treated with β-glycerophosphate (BGP) resulted in increased Fgf23 expression. Inhibition of ROS formation by inhibition of NADPH oxidase, which is essential for ROS production, did not affect this response to BGP, suggesting ROS is not involved in this process. Moreover, treatment with tert-butyl hydroperoxide (TBHP), a ROS-inducing agent, did not increase Fgf23 expression. This suggests that ROS machinery is not involved in FGF23 stimulation as previously suggested. Nonetheless, inhibition of SIRT1 using Ex527 eliminated the Fgf23 response to BGP, indicating its involvement in FGF23 regulation after BGP treatment. Indeed, activation of SIRT1 using SRT1720 increased Fgf23 expression. Moreover, transcription factor Hes1 was upregulated by BGP treatment, which was diminished when cells were treated with Ex527 implying it is also regulated through SIRT1. These findings suggest the existence of an upstream SIRT1-HES1 axis in the regulation of FGF23 by phosphate, though we were unable to find a role for ROS in this process. Further research should provide insights into phosphate homeostasis and potential therapeutic targets for phosphate-related disorders.

Context-dependent role of sirtuin 2 in inflammation.

Sirtuin 2 is a member of the sirtuin family nicotinamide adenine dinucleotide (NAD+)-dependent deacetylases, known for its regulatory role in different processes, including inflammation. In this context, sirtuin 2 has been involved in the modulation of key inflammatory signaling pathways and transcription factors by deacetylating specific targets, such as nuclear factor κB and nucleotide-binding oligomerization domain-leucine-rich-repeat and pyrin domain-containing protein 3 (NLRP3). However, whether sirtuin 2-mediated pathways induce a pro- or an anti-inflammatory response remains controversial. Sirtuin 2 has been implicated in promoting inflammation in conditions such as asthma and neurodegenerative diseases, suggesting that its inhibition in these conditions could be a potential therapeutic strategy. Conversely, arthritis and type 2 diabetes mellitus studies suggest that sirtuin 2 is essential at the peripheral level and, thus, its inhibition in these pathologies would not be recommended. Overall, the precise role of sirtuin 2 in inflammation appears to be context-dependent, and further investigation is needed to determine the specific molecular mechanisms and downstream targets through which sirtuin 2 influences inflammatory processes in various tissues and pathological conditions. The present review explores the involvement of sirtuin 2 in the inflammation associated with different pathologies to elucidate whether its pharmacological modulation could serve as an effective strategy for treating this prevalent symptom across various diseases.

Role of SIRT3 in Compensatory Flow-Induced Dilation Following High Pressure Stress in the Human Microcirculation

Reductions in flow-induced dilation (FID; vasodilation in response to increased blood flow from shear stress) is predictive of future adverse cardiac events. Vasodilatory capacity to flow is maintained in arterioles from healthy adults following exposure to high intraluminal pressure (150mmHg, 30min) by utilizing hydrogen peroxide (H2O2) to compensate for decreased bioavailability of nitric oxide (NO). Here, we tested the hypothesis that knockdown of NAD-dependent deacetylase sirtuin-3 (SIRT3), a mitochondrial protein activated during stress and known to stimulate cellular survival pathways, would prevent compensatory signaling during FID and reduce overall vasodilatory capacity following high intraluminal pressure. Adipose arterioles (100-200μm) from otherwise healthy adults (0-1 risk factor for cardiovascular disease) were treated intraluminally with siSIRT3 or negative control siRNA for 16-20hrs and cannulated for videomicroscopy prior to pre-constriction with endothelin-1. Changes in internal microvessel diameter in response to graded increases in flow were measured. Maximal dilation to flow was maintained both pre- and post-pressure in arterioles treated with negative control siRNA (93.3%±2.3 of maximal dilator capacity±SEM, n=3 versus 69.9%±11.5, n=3, respectively), however, vasodilatory capacity was significantly reduced post-pressure in arterioles treated with siSIRT3 (19.8%±5.7, n=3) compared to pre-pressure (76.0%±10.6, n=3, p<0.01, one-way ANOVA). These data suggest that SIRT3 plays a key mechanistic component in compensatory signaling during flow in human arterioles following stress. We conclude that SIRT3 may be a potential therapeutic target to increase vascular resilience and protect from stress in the human microcirculation thereby preventing microvascular dysfunction and future cardiovascular disease. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sirtuins and Cellular Senescence in Patients with Idiopathic Pulmonary Fibrosis and Systemic Autoimmune Disorders.

The sirtuin family is a heterogeneous group of proteins that play a critical role in many cellular activities. Several degenerative diseases have recently been linked to aberrant sirtuin expression and activity because of the involvement of sirtuins in maintaining cell longevity and their putative antiaging function. Idiopathic pulmonary fibrosis and progressive pulmonary fibrosis associated with systemic autoimmune disorders are severe diseases characterized by premature and accelerated exhaustion and failure of alveolar type II cells combined with aberrant activation of fibroblast proliferative pathways leading to dramatic destruction of lung architecture. The mechanisms underlying alveolar type II cell exhaustion in these disorders are not fully understood. In this review, we have focused on the role of sirtuins in the pathogenesis of idiopathic and secondary pulmonary fibrosis and their potential as biomarkers in the diagnosis and management of fibrotic interstitial lung diseases.

Aspartame Causes Developmental Defects and Teratogenicity in Zebra Fish Embryo: Role of Impaired SIRT1/FOXO3a Axis in Neuron Cells.

Aspartame, a widely used artificial sweetener, is present in many food products and beverages worldwide. It has been linked to potential neurotoxicity and developmental defects. However, its teratogenic effect on embryonic development and the underlying potential mechanisms need to be elucidated. We investigated the concentration- and time-dependent effects of aspartame on zebrafish development and teratogenicity. We focused on the role of sirtuin 1 (SIRT1) and Forkhead-box transcription factor (FOXO), two proteins that play key roles in neurodevelopment. It was found that aspartame exposure reduced the formation of larvae and the development of cartilage in zebrafish. It also delayed post-fertilization development by altering the head length and locomotor behavior of zebrafish. RNA-sequencing-based DEG analysis showed that SIRT1 and FOXO3a are involved in neurodevelopment. In silico and in vitro analyses showed that aspartame could target and reduce the expression of SIRT1 and FOXO3a proteins in neuron cells. Additionally, aspartame triggered the reduction of autophagy flux by inhibiting the nuclear translocation of SIRT1 in neuronal cells. The findings suggest that aspartame can cause developmental defects and teratogenicity in zebrafish embryos and reduce autophagy by impairing the SIRT1/FOXO3a axis in neuron cells.

Role of sirtuins in epigenetic regulation and aging control.

Advances in modern healthcare in developed countries make it possible to extend the human lifespan, which is why maintaining active longevity is becoming increasingly important. After the sirtuin (SIRT) protein family was discovered, it started to be considered as a significant regulator of the physiological processes associated with aging. SIRT has deacetylase, deacylase, and ADP-ribosyltransferase activity and modifies a variety of protein substrates, including chromatin components and regulatory proteins. This multifactorial regulatory system affects many processes: cellular metabolism, mitochondrial functions, epigenetic regulation, DNA repair and more. As is expected, the activity of sirtuin proteins affects the manifestation of classic signs of aging in the body, such as cellular senescence, metabolic disorders, mitochondrial dysfunction, genomic instability, and the disruption of epigenetic regulation. Changes in the SIRT activity in human cells can also be considered a marker of aging and are involved in the genesis of various age-dependent disorders. Additionally, experimental data obtained in animal models, as well as data from population genomic studies, suggest a SIRT effect on life expectancy. At the same time, the diversity of sirtuin functions and biochemical substrates makes it extremely complicated to identify cause-and-effect relationships and the direct role of SIRT in controlling the functional state of the body. However, the SIRT influence on the epigenetic regulation of gene expression during the aging process and the development of disorders is one of the most important aspects of maintaining the homeostasis of organs and tissues. The presented review centers on the diversity of SIRT in humans and model animals. In addition to a brief description of the main SIRT enzymatic and biological activity, the review discusses its role in the epigenetic regulation of chromatin structure, including the context of the development of genome instability associated with aging. Studies on the functional connection between SIRT and longevity, as well as its effect on pathological processes associated with aging, such as chronic inflammation, fibrosis, and neuroinflammation, have been critically analyzed.

Biomedical significance of the therapeutic use of autophagy (literature review)

Autophagy, or is an intracellular degradation pathway for improperly functioning aggre-gation-prone proteins, damaged organelles, unwanted macromolecules, and invading patho-gens. The process is necessary for maintaining cell and tissue homeostasis, which contributes to the survival of the organism, and is actively studied. The purpose of this work was the search, selection and analysis of the literature on autophagy as one of the main mechanisms of maintaining cellular homeostasis under conditions of oxidative stress; cellular aging; calo-rie restriction; as well as about the targeted effect on autophagy in the conditions of various diseases. The following generalizations were made: 1) the ability to be directly activated in response to the intense formation of reactive oxygen species in cells allows us to consider autophagy as an important element of antioxidant protection, therefore, the study of ways and means of effective autophagy management is becoming relevant today; 2) dietary con-sumption of autophagy activators may promote health and extend lifespan through multiple mechanisms, including reduction of oxidative stress, induction of autophagy, and suppression of inflammation; 3) studies aimed at elucidating the role of sirtuins, which are key regulators of cellular metabolism and oxidative stress, are gaining relevance in the initiation of autoph-agy. Currently, sirtuin-dependent mechanisms of autophagy require research in experimental models using mammalian cells; 4) continuing the study of autophagy processes will allow a better understanding of physiological aspects and help ensure progress in the development of new strategies for the prevention and treatment of human diseases (including those related to age); 5) autophagy is crucial for cellular physiology, autophagy dysfunction is in-volved in the pathogenesis of various human diseases, and therefore the therapeutic use of autophagy has potential biomedical significance. Keywords: cell death, cellular homeostasis, oxidative stress, cellular aging, calorie restriction, targeted effect on autophagy.