Altered synaptic currents,mitophagy,mitochondrial dynamics in Alzheimer's disease models and therapeutic potential of Dengzhan Shengmai capsules intervention

Emerging research suggests a potential association of progression of Alzheimer's disease(AD)with alterations in synaptic currents and mitochondrial dynamics.However,the specific associations between these pathological changes remain unclear.In this study,we utilized Aβ42-induced AD rats and primary neural cells as in vivo and in vitro models.The investigations included behavioural tests,brain magnetic resonance imaging(MRI),liquid chromatography-tandem mass spectrometry(UPLC-MS/MS)analysis,Nissl staining,thioflavin-S staining,enzyme-linked immunosorbent assay,Golgi-Cox staining,transmission electron microscopy(TEM),immunofluorescence staining,proteomics,adenosine triphosphate(ATP)detection,mitochondrial membrane potential(MMP)and reactive oxygen species(ROS)assessment,mitochondrial morphology analysis,electrophysiological studies,Western blotting,and molecular docking.The results revealed changes in synaptic currents,mitophagy,and mitochondrial dynamics in the AD models.Remarkably,intervention with Dengzhan Shengmai(DZSM)capsules emerged as a pivotal element in this investigation.Aβ42-induced synaptic dysfunction was significantly mitigated by DZSM intervention,which notably amplified the frequency and amplitude of synaptic transmission.The cognitive impairment observed in AD rats was ameliorated and accompanied by robust protection against structural damage in key brain regions,including the hippocampal CA3,primary cingular cortex,prelimbic system,and dysgranular insular cortex.DZSM intervention led to increased IDE levels,augmented long-term potential(LTP)amplitude,and enhanced dendritic spine density and length.Moreover,DZSM intervention led to favourable changes in mitochondrial parameters,including ROS expression,MMP and ATP contents,and mitochondrial morphology.In conclusion,our findings delved into the realm of altered synaptic currents,mitophagy,and mitochondrial dynamics in AD,concurrently highlighting the therapeutic potential of DZSM intervention.

Inflammatory markers,oxidative stress,and mitochondrial dynamics:Repercussions on coronary artery disease in diabetes

Inflammatory markers and mediators that affect the development of cardiovascular diseases have been the focus of recent scientific work.Thus,the purpose of this editorial is to promote a critical debate about the article titled“Nε-carboxymethyl-lysine and inflammatory cytokines,markers,and mediators of coronary artery disease progression in diabetes”,published in the World Journal of Diabetes in 2024.This work directs us to reflect on the role of advanced glycation end products,which are pro-inflammatory products arising from the metabolism of fatty acids and sugars whose main marker in tissues is Nε-carboxymethyllysine(NML).Recent studies have linked high levels of pro-inflammatory agents with the development of coronary artery disease(CAD),especially tumor necrosis factor alpha,interleukins,and C-reactive protein.These inflammatory agents increase the production of reactive oxygen species(ROS),of which people with diabetes are known to have an increased production.The increase in ROS promotes lipid peroxidation,which causes damage to myocytes,promoting myocardial damage.Furthermore,oxidative stress induces the binding of NML to its receptor RAGE,which in turn activates the nuclear factor-kB,and consequently,inflammatory cytokines.These inflammatory cytokines induce endothelial dysfunction,with increased expression of adhesion molecules,changes in endothelial permeability and changes in the expression of nitric oxide.In this sense,the therapeutic use of monoclonal antibodies(inflammatory reducers such as statins and sodium-glucose transport inhibitors)has demonstrated positive results in the regression of atherogenic plaques and consequently CAD.On the other hand,many studies have demonstrated a relationship between mitochondrial dynamics,diabetes,and cardiovascular diseases.This link occurs since ROS have their origin in the imbalance in glucose metabolism that occurs in the mitochondrial matrix,and this imbalance can have its origin in inadequate diet as well as some pathologies.Photobiomodulation(PBM)has recently been considered a possible therapeutic agent for cardiovascular diseases due to its effects on mitochondrial dynamics and oxidative stress.In this sense,therapies such as PBM that act on pro-inflammatory mediators and mitochondrial modulation could benefit those with cardiovascular diseases.

Neural stem cell-derived exosomes promote mitochondrial biogenesis and restore abnormal protein distribution in a mouse model of Alzheimer's disease

Mitochondrial dysfunction is a hallmark of Alzheimer’s disease.We previously showed that neural stem cell-derived extracellular vesicles improved mitochondrial function in the cortex of AP P/PS1 mice.Because Alzheimer’s disease affects the entire brain,further research is needed to elucidate alterations in mitochondrial metabolism in the brain as a whole.Here,we investigated the expression of several important mitochondrial biogenesis-related cytokines in multiple brain regions after treatment with neural stem cell-derived exosomes and used a combination of whole brain clearing,immunostaining,and lightsheet imaging to clarify their spatial distribution.Additionally,to clarify whether the sirtuin 1(SIRT1)-related pathway plays a regulatory role in neural stem cell-de rived exosomes interfering with mitochondrial functional changes,we generated a novel nervous system-SIRT1 conditional knoc kout AP P/PS1mouse model.Our findings demonstrate that neural stem cell-de rived exosomes significantly increase SIRT1 levels,enhance the production of mitochondrial biogenesis-related fa ctors,and inhibit astrocyte activation,but do not suppress amyloid-βproduction.Thus,neural stem cell-derived exosomes may be a useful therapeutic strategy for Alzheimer’s disease that activates the SIRT1-PGC1αsignaling pathway and increases NRF1 and COXIV synthesis to improve mitochondrial biogenesis.In addition,we showed that the spatial distribution of mitochondrial biogenesis-related factors is disrupted in Alzheimer’s disease,and that neural stem cell-derived exosome treatment can reverse this effect,indicating that neural stem cell-derived exosomes promote mitochondrial biogenesis.

Mitochondrial therapeutics and mitochondrial transfer for neurodegenerative diseases and aging

Mitochondrial dysfunction and neurodegeneration:Progressive neurodegenerative diseases affect a significant proportion of the population;in a single year,there are as many as 276 million disabilities and 9 million deaths as a result of neurological diseases.

Resveratrol combats chronic diseases through enhancing mitochondrial quality

Resveratrol(RSV),as a functional food component extracted from natural plants,has been widely studied and recognized in preventing and treating various diseases,with major mechanisms including executing anti-inflammation and anti-oxidation functions,and improving mitochondrial quality.Chronic diseases as non-communicable diseases are mainly caused by multiple factors,such as physiological decline and dysfunction in the body,and have become a significant challenge on public health worldwide.It is worth noting that chronic diseases such as Alzheimer's disease(AD),Parkinson's disease(PD),muscle atrophy,cardiovascular disease,obesity,and cancer are accompanied by abnormal mitochondrial function.Therefore,targeted regulation of mitochondria may be a meaningful way to prevent and treat chronic diseases.Increasing evidence has confirmed that RSV is actively involved in regulating mitochondria,and it has become an essential consideration to prevent and treat chronic diseases through targeting mitochondria and improving corresponding functions.In this article,current studies on RSV to optimize mitochondrial quality for preventing and alleviating chronic disease are systematically summarized,which can provide a theoretical reference for the development of functional foods or drugs to combat chronic diseases.

Low Selenium and Low Protein Exacerbate Myocardial Damage in Keshan Disease by Affecting the PINK1/Parkin-mediated Mitochondrial Autophagy Pathway

Objective Keshan disease(KD)is a myocardial mitochondrial disease closely related to insufficient selenium(Se)and protein intake.PTEN induced putative kinase 1(PINK1)/Parkin mediated mitochondrial autophagy regulates various physiological and pathological processes in the body.This study aimed to elucidate the relationship between PINK1/Parkin-regulated mitochondrial autophagy and KD-related myocardial injury.Methods A low Se and low protein animal model was established.One hundred Wistar rats were randomly divided into 5 groups(control group,low Se group,low protein group,low Se+low protein group,and corn from KD area group).The JC-1 method was used to detect the mitochondrial membrane potential(MMP).ELISA was used to detect serum creatine kinase MB(CK-MB),cardiac troponin I(cTnI),and mitochondrial-glutamicoxalacetic transaminase(M-GOT)levels.RT-PCR and Western blot analysis were used to detect the expression of PINK1,Parkin,sequestome 1(P62),and microtubule-associated proteins1A/1B light chain 3B(MAP1LC3B).Results The MMP was significantly decreased and the activity of CK-MB,cTnI,and M-GOT significantly increased in each experimental group(low Se group,low protein group,low Se+low protein group and corn from KD area group)compared with the control group(P<0.05 for all).The mRNA and protein expression levels of PINK1,Parkin and MAP1LC3B were profoundly increased,and those of P62 markedly decreased in the experimental groups compared with the control group(P<0.05 for all).Conclusion Low Se and low protein levels exacerbate myocardial damage in KD by affecting the PINK1/Parkin-mediated mitochondrial autophagy pathway.

Altered O-GlcNAcylation and mitochondrial dysfunction,a molecular link between brain glucose dysregulation and sporadic Alzheimer's disease

Alzheimer’s disease is a neurodegenerative disease that affected over 6.5 million people in the United States in 2021,with this number expected to double in the next 40 years without any sort of treatment.Due to its heterogeneity and complexity,the etiology of Alzheimer’s disease,especially sporadic Alzheimer’s disease,remains largely unclear.Compelling evidence suggests that brain glucose hypometabolism,preceding Alzheimer’s disease hallmarks,is involved in the pathogenesis of Alzheimer’s disease.Herein,we discuss the potential causes of reduced glucose uptake and the mechanisms underlying glucose hypometabolism and Alzheimer’s disease pathology.Specifically,decreased O-Glc NAcylation levels by glucose deficiency alter mitochondrial functions and together contribute to Alzheimer’s disease pathogenesis.One major problem with Alzheimer’s disease research is that the disease progresses for several years before the onset of any symptoms,suggesting the critical need for appropriate models to study the molecular changes in the early phase of Alzheimer’s disease progression.Therefore,this review also discusses current available sporadic Alzheimer’s disease models induced by metabolic abnormalities and provides novel directions for establishing a human neuronal sporadic Alzheimer’s disease model that better represents human sporadic Alzheimer’s disease as a metabolic disease.

Neuroprotective effects of curculigoside against Alzheimer’s disease via regulation oxidative stress mediated mitochondrial dysfunction in L-Glu-exposed HT22 cells and APP/PS1 mice

Curculigoside(CCG)is a phenolic glycoside compound extracted from the root of a natural plant called Curculigo orchioides Gaertn.In this study,the neuroprotective effect of CCG through oxidative stress mediated mitochondrial dysfunction on L-glutamate(L-Glu)-damaged hippocampal neuron cell line(HT22)and APPswe/PSEN1dE9 transgenic(APP/PS1)mice were investigated.Observably,CCG in L-Glu-damaged HT22 cells suppressed apoptosis,reduced the accumulation of reactive oxygen species,balanced the mitochondrial membrane potential and prevented the over-influx of calcium.In APP/PS1 mice,4-week CCG administration significantly improved their memory and behavioral impairments,enhanced the function of cholinergic system,reduced the deposition of Aβand neurofibrillary fiber tangles caused by tau phosphorylation,and suppressed the development and progression of oxidative stress in brains of APP/PS1 mice.Based on the screening of proteomic analysis on hippocampus,CCG were confirmed that it could regulate the expression levels of proteins related to mitochondrial dysfunction,mainly through activating on AMPK/Nrf2 signaling,in APP/PS1 mice and L-Glu-exposed HT22 cells.CCG has a prominent neuroprotective effect on regulate the AMPK/Nrf2-mediated mitochondrial dysfunction in cells APP/PS1 mice support CCG is a potentially potent drug for AD treatment and merits further investigation.

Mitochondria in Huntington’s disease:implications in pathogenesis and mitochondrial-targeted therapeutic strategies

Huntington’s disease is a genetic disease caused by expanded CAG repeats on exon 1 of the huntingtin gene located on chromosome 4.Compelling evidence implicates impaired mitochondrial energetics,altered mitochondrial biogenesis and quality control,disturbed mitochondrial trafficking,oxidative stress and mitochondrial calcium dyshomeostasis in the pathogenesis of the disorder.Unfortunately,conventional mitochondrial-targeted molecules,such as cysteamine,creatine,coenzyme Q10,or triheptanoin,yielded negative or inconclusive results.However,future therapeutic strategies,aiming to restore mitochondrial biogenesis,improving the fission/fusion balance,and improving mitochondrial trafficking,could prove useful tools in improving the phenotype of Huntington’s disease and,used in combination with genome-editing methods,could lead to a cure for the disease.

SIRT3 regulates mitochondrial biogenesis in aging-related diseases

Sirtuin 3(SIRT3),the main family member of mitochondrial deacetylase,targets the majority of substrates controlling mitochondrial biogenesis via lysine deacetylation and modulates important cellular functions such as energy metabolism,reactive oxygen species production and clearance,oxidative stress,and aging.Deletion of SIRT3 has a deleterious effect on mitochondrial biogenesis,thus leading to the defect in mitochondrial function and insufficient ATP production.Imbalance of mitochondrial dynamics leads to excessive mitochondrial biogenesis,dampening mitochondrial function.Mitochondrial dysfunction plays an important role in several diseases related to aging,such as cardiovascular disease,cancer and neurodegenerative diseases.Peroxisome proliferator-activated receptor gamma coactivator 1-alpha(PGC1α)launches mitochondrial biogenesis through activating nuclear respiratory factors.These factors act on genes,transcribing and translating mitochondrial DNA to generate new mitochondria.PGC1αbuilds a bridge between SIRT3 and mitochondrial biogenesis.This review described the involvement of SIRT3 and mitochondrial dynamics,particularly mitochondrial biogenesis in agingrelated diseases,and further illustrated the role of the signaling events between SIRT3 and mitochondrial biogenesis in the pathological process of aging-related diseases.

Mitochondrial carnitine palmitoyltransferase-Ⅱ dysfunction: A possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis

Nonalcoholic fatty liver disease(NAFLD)or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseases in the world.The complex mechanisms of NAFLD formation are still under identification.Carnitine palmitoyltransferase-Ⅱ(CPT-Ⅱ)on inner mitochondrial membrane(IMM)regulates long chain fatty acidβ-oxidation,and its abnormality has had more and more attention paid to it by basic and clinical research in NAFLD.The sequences of its peptide chain and DNA nucleotides have been identified,and the catalytic activity of CPT-Ⅱ is affected on its gene mutations,deficiency,enzymatic thermal instability,circulating carnitine level and so on.Recently,the CPT-Ⅱ dysfunction has been discovered in models of liver lipid accumulation.Meanwhile,the malignant transformation of hepatocyte-related CD44^(+) stem T cell activation,high levels of tumor-related biomarkers(AFP,GPC3)and abnormal activation of Wnt3a expression as a key signal molecule of the Wnt/β-catenin pathway run parallel to the alterations of hepatocyte pathology.This review focuses on some of the progress of CPT-Ⅱ inactivity on IMM with liver fatty accumulation as a possible novel pathogenesis for NAFLD in hepatocarcinogenesis.

Study on the mechanism of action of Lizhong Tang in ameliorating non-alcoholic fatty liver disease by regulating mitochondrial autophagy

Objective:To investigate the therapeutic efficacy and underlying mechanisms of LiZhong Tang in the context of non-alcoholic fatty liver disease(NAFLD).Methods:High-fat feed was used to induce NAFLD in rats,Blood and liver samples were collected to facilitate a comparative analysis of rat body mass and liver wet weight and calculate the liver index.Liver pathology was observed,while serum transaminase and blood lipid levels were measured.The protein expression levels of PINK1,Parkin,and LC-3II in rat liver were detected using Western Blot analysis.Results:Compared with the control group,the NAFLD rats exhibited a significant increase in body weight,liver wet weight,liver index,transaminase levels,and blood lipid levels.The expression levels of PINK1,Parkin,and LC3-II protein were significantly decreased(P<0.01).Following intervention with Lizhong Tang,rats in each herbal treatment group displayed a decrease in body weight,liver wet weight,liver index,se-rum transaminase,and blood lipid levels.The expression levels of PINK1,Parkin,and LC-3II rebounded(P<0.05),with the high-dose group demonstrating the most pronounced effects(P<0.01).Histopathological examination of liver tissue revealed that rats in the model group displayed disrupted hepatic lobule structure,swollen hepatocytes,disordered arrangement,and a multi-tude of varying-sized lipid vacuoles within the cytoplasm.Conversely,rats treated with different doses of the herbal remedy exhibited improvements in liver tissue pathology,with the high-dose group showing the most notable enhancement.Conclusion:Lizhong Tang can improve NAFLD disease by regulating mitochondrial autophagy.

Correlation between the gut microbiome and neurodegenerative diseases:a review of metagenomics evidence

A growing body of evidence suggests that the gut microbiota contributes to the development of neurodegenerative diseases via the microbiota-gut-brain axis.As a contributing factor,microbiota dysbiosis always occurs in pathological changes of neurodegenerative diseases,such as Alzheimer’s disease,Parkinson’s disease,and amyotrophic lateral sclerosis.High-throughput sequencing technology has helped to reveal that the bidirectional communication between the central nervous system and the enteric nervous system is facilitated by the microbiota’s diverse microorganisms,and for both neuroimmune and neuroendocrine systems.Here,we summarize the bioinformatics analysis and wet-biology validation for the gut metagenomics in neurodegenerative diseases,with an emphasis on multi-omics studies and the gut virome.The pathogen-associated signaling biomarkers for identifying brain disorders and potential therapeutic targets are also elucidated.Finally,we discuss the role of diet,prebiotics,probiotics,postbiotics and exercise interventions in remodeling the microbiome and reducing the symptoms of neurodegenerative diseases.

NADPH oxidase 4(NOX4)as a biomarker and therapeutic target in neurodegenerative diseases

Diseases like Alzheimer’s and Parkinson’s diseases are defined by inflammation and the damage neurons undergo due to oxidative stress. A primary reactive oxygen species contributor in the central nervous system, NADPH oxidase 4, is viewed as a potential therapeutic touchstone and indicative marker for these ailments. This in-depth review brings to light distinct features of NADPH oxidase 4, responsible for generating superoxide and hydrogen peroxide, emphasizing its pivotal role in activating glial cells, inciting inflammation, and disturbing neuronal functions. Significantly, malfunctioning astrocytes, forming the majority in the central nervous system, play a part in advancing neurodegenerative diseases, due to their reactive oxygen species and inflammatory factor secretion. Our study reveals that aiming at NADPH oxidase 4 within astrocytes could be a viable treatment pathway to reduce oxidative damage and halt neurodegenerative processes. Adjusting NADPH oxidase 4 activity might influence the neuroinflammatory cytokine levels, including myeloperoxidase and osteopontin, offering better prospects for conditions like Alzheimer’s disease and Parkinson’s disease. This review sheds light on the role of NADPH oxidase 4 in neural degeneration, emphasizing its drug target potential, and paving the path for novel treatment approaches to combat these severe conditions.

Rethinking neurodegenerative diseases:neurometabolic concept linking lipid oxidation to diseases in the central nervous system

Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzheimer s disease.Given the unmet medical need,it is necessary to reevaluate the existing para digms of how to to rget these diseases.When considering neurodegenerative diseases from a systemic neurometabolic perspective,it becomes possible to explain the shared pathological features.This innovative approach presented in this paper draws upon exte nsive research conducted by the authors and researchers worldwide.In this review,we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases.We provide an overview of the risk factors associated with developing neurodegenerative disorders,including genetic,epigenetic,and environmental fa ctors.Additionally,we examine pathological mechanisms implicated in these diseases such as oxidative stress,accumulation of misfolded proteins,inflammation,demyelination,death of neurons,insulin resistance,dysbiosis,and neurotransmitter disturbances.Finally,we outline a proposal for the restoration of mitochondrial metabolism,a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.

The pathogenesis of Parkinson’s disease and crosstalk with other diseases

In China,Parkinson’s disease(PD)is the second most prevalent central nervous system(CNS)degenerative illness affecting middle-aged and older persons.Movement disorders including resting tremor,bradykinesia,myotonia,postural instability,and gait instability are the predominant clinical symptoms.The two main types of PD are sporadic and familial,with sporadic PD being the more prevalent of the two.The environment,genetics,mitochondrial dysfunction,oxidative stress,inflammation,protein aggregation and misfolding,loss of trophic factors,cell death,and gut microbiota may all have a role in the etiology of PD.PD is inversely connected with other cancers and positively correlated with COVID-19,diabetes mellitus(DM),melanoma,and ischemic heart disease(IHD)risk.Delaying disease progression,managing motor and non-motor symptoms,and avoiding and controlling dysfunction in the middle and later phases of the disease are the key areas of research and development for its therapy.Presently,the development and progression of PD can be slowed down by using conventional pharmacology,natural items,and innovative technology.This article reviews the pathogenesis of PD,its correlations with other non-genetic diseases,and the research progress of drugs and technologies for alleviating PD.

Recent advances in age-related metabolic dysfunction-associated steatotic liver disease

Metabolic dysfunction-associated steatotic liver disease(MASLD)affects approximately 25%of the world's population and has become a leading cause of chronic liver disease.In recent years,an increasing amount of data suggests that MASLD is associated with aging.As the population ages,age-related MASLD will become a major global health problem.Targeting an aging will become a new approach to the treatment of MASLD.This paper reviews the current studies on the role of aging-related factors and therapeutic targets in MASLD,including:Oxidative stress,autophagy,mitochondrial homeostasis,bile acid metabolism homeostasis,and dysbiosis.The aim is to identify effective therapeutic targets for age-related MASLD and its progression.

CHCHD2 Thr61Ile mutation impairs F1F0-ATPase assembly in in vitro and in vivo models of Parkinson's disease

Mitochondrial dysfunction is a significant pathological alte ration that occurs in Parkinson's disease(PD),and the Thr61lle(T61I)mutation in coiled-coil helix coiled-coil helix domain containing 2(CHCHD2),a crucial mitochondrial protein,has been reported to cause Parkinson's disease.FIFO-ATPase participates in the synthesis of cellular adenosine triphosphate(ATP)and plays a central role in mitochondrial energy metabolism.However,the specific roles of wild-type(WT)CHCHD2 and T611-mutant CHCHD2 in regulating F1FO-ATPase activity in Parkinson's disease,as well as whether CHCHD2 or CHCHD2 T61I affects mitochondrial function through regulating F1FO-ATPase activity,remain unclea r.Therefore,in this study,we expressed WT CHCHD2 and T61l-mutant CHCHD2 in an MPP^(+)-induced SH-SY5Y cell model of PD.We found that CHCHD2 protected mitochondria from developing MPP^(+)-induced dysfunction.Under normal conditions,ove rexpression of WT CHCHD2 promoted F1FO-ATPase assembly,while T61I-mutant CHCHD2 appeared to have lost the ability to regulate F1FO-ATPase assembly.In addition,mass spectrometry and immunoprecipitation showed that there was an interaction between CHCHD2 and F1FO-ATPase.Three weeks after transfection with AAV-CHCHD2 T61I,we intraperitoneally injected 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine into mice to establish an animal model of chronic Parkinson's disease and found that exogenous expression of the mutant protein worsened the behavioral deficits and dopaminergic neurodegeneration seen in this model.These findings suggest that WT CHCHD2 can alleviate mitochondrial dysfunction in PD by maintaining F1F0-ATPase structure and function.

Research Progress on Neuroprotective Effects of Salvianolic Acid B in an Animal Model of Parkinson's Disease

As an active ingredient extracted from Salvia miltiorrhiza,the neuroprotective effects of salvianolic acid B in Parkinson's disease include antioxidation,improvement of mitochondrial function,modulation of neuroinflammation,inhibition of apoptosis,promotion of neuronal differentiation and proliferation,and influence on intestinal flora.As an adjuvant drug,salbutamol B can be used in combination with conventional therapeutic drugs to enhance the efficacy and minimize the side effects,which provides a method and basis for the early diagnosis and treatment of Parkinson's disease in clinical practice.

Sodium-glucose cotransporter-2 inhibitors protect tissues via cellular and mitochondrial pathways:Experimental and clinical evidence

Mitochondrial dysfunction is a key driver of cardiovascular disease(CVD)in metabolic syndrome and diabetes.This dysfunction promotes the production of reactive oxygen species(ROS),which cause oxidative stress and inflammation.Angiotensin II,the main mediator of the renin-angiotensin-aldosterone system,also contributes to CVD by promoting ROS production.Reduced activity of sirtuins(SIRTs),a family of proteins that regulate cellular metabolism,also worsens oxidative stress.Reduction of energy production by mitochondria is a common feature of all metabolic disorders.High SIRT levels and 5’adenosine monophosphate-activated protein kinase signaling stimulate hypoxia-inducible factor 1 beta,which promotes ketosis.Ketosis,in turn,increases autophagy and mitophagy,processes that clear cells of debris and protect against damage.Sodiumglucose cotransporter-2 inhibitors(SGLT2i),a class of drugs used to treat type 2 diabetes,have a beneficial effect on these mechanisms.Randomized clinical trials have shown that SGLT2i improves cardiac function and reduces the rate of cardiovascular and renal events.SGLT2i also increase mitochondrial efficiency,reduce oxidative stress and inflammation,and strengthen tissues.These findings suggest that SGLT2i hold great potential for the treatment of CVD.Furthermore,they are proposed as anti-aging drugs;however,rigorous research is needed to validate these preliminary findings.