Potential Therapeutic Targets to Modulate the Endocannabinoid System in Alzheimer's Disease.

Alzheimer's disease (AD), the most common neurodegenerative disease (NDD), is characterized by chronic neuronal cell death through progressive loss of cognitive function. Amyloid beta (Aß) deposition, neuroinflammation, oxidative stress, and hyperphosphorylated tau proteins are considered the hallmarks of AD pathology. Different therapeutic approaches approved by the Food and Drug Administration can only target a single altered pathway instead of various mechanisms that are involved in AD pathology, resulting in limited symptomatic relief and almost no effect in slowing down the disease progression. Growing evidence on modulating the components of the endocannabinoid system (ECS) proclaimed their neuroprotective effects by reducing neurochemical alterations and preventing cellular dysfunction. Recent studies on AD mouse models have reported that the inhibitors of the fatty acid amide hydrolase (FAAH) and monoacylglycerol (MAGL), hydrolytic enzymes for N-arachidonoyl ethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), respectively, might be promising candidates as therapeutical intervention. The FAAH and MAGL inhibitors alone or in combination seem to produce neuroprotection by reversing cognitive deficits along with Aß-induced neuroinflammation, oxidative responses, and neuronal death, delaying AD progression. Their exact signaling mechanisms need to be elucidated for understanding the brain intrinsic repair mechanism. The aim of this review was to shed light on physiology and pathophysiology of AD and to summarize the experimental data on neuroprotective roles of FAAH and MAGL inhibitors. In this review, we have also included CB1R and CB2R modulators with their diverse roles to modulate ECS mediated responses such as anti-nociceptive, anxiolytic, and anti-inflammatory actions in AD. Future research would provide the directions in understanding the molecular mechanisms and development of new therapeutic interventions for the treatment of AD.

Liver fat content assessed by conventional B-mode ultrasound and metabolic profile in non-diabetic patients: Implications for clinical practice.

Introduction: Several studies have demonstrated a positive correlation between severe hepatic steatosis and metabolic alterations; however, few studies have addressed the potential association between different grades of steatosis and clinical patterns in a non-diabetic population. Methods: We conducted a cross-sectional study of 223 non-diabetic individuals. The severity of steatosis was assessed using B-mode ultrasound. We analyzed lipid and glucose profiles according to the severity of hepatic steatosis. Estimated glomerular filtration rate (eGFR) values were also recorded to investigate the potential impact of steatosis on kidney function. Results: Patients with steatosis were found to have higher insulinemia and mean values of fasting plasma glucose compared to patients without steatosis. A significant decrease in high-density lipoprotein level was observed only in patients with severe or moderate steatosis. All grades of steatosis were associated with increased triglyceride levels, which were more significant in severe steatosis. Subgroup analysis by body mass index demonstrated a significant difference between lean patients with steatosis and lean patients without steatosis for triglycerides (p = 0.002) and high-density lipoprotein levels (p = 0.019). Finally, patients diagnosed with steatosis demonstrated a higher prevalence of estimated glomerular filtration rate < 90 ml/min. Conclusion: The degree of steatosis diagnosed at ultrasound may predict glucose or lipid metabolism disorders and a decline in kidney function in a non-diabetic population.

Liver Ultrasound Elastography in Non-Alcoholic Fatty Liver Disease: A State-of-the-Art Summary.

Non-alcoholic fatty liver disease (NAFLD) is a chronic disease which is currently the most common hepatic disorder affecting up to 38% of the general population with differences according to age, country, ethnicity and sex. Both genetic and acquired risk factors such as a high-calorie diet or high intake of saturated fats have been associated with obesity, diabetes and, finally, NAFLD. A liver biopsy has always been considered essential for the diagnosis of NAFLD; however, due to several limitations such as the potential occurrence of major complications, sampling variability and the poor repeatability in clinical practice, it is considered an imperfect option for the evaluation of liver fibrosis over time. For these reasons, a non-invasive assessment by serum biomarkers and the quantification of liver stiffness is becoming the new frontier in the management of patients with NAFLD and liver fibrosis. We present a state-of-the-art summary addressing the methods for the non-invasive evaluation of liver fibrosis in NAFLD patients, particularly the ultrasound-based techniques (transient elastography, ARFI techniques and strain elastography) and their optimal cut-off values for the staging of liver fibrosis.

PDIA3 Expression Is Altered in the Limbic Brain Regions of Triple-Transgenic Mouse Model of Alzheimer's Disease.

In the present study, we used a mouse model of Alzheimer's disease (AD) (3×Tg-AD mice) to longitudinally analyse the expression level of PDIA3, a protein disulfide isomerase and endoplasmic reticulum (ER) chaperone, in selected brain limbic areas strongly affected by AD-pathology (amygdala, entorhinal cortex, dorsal and ventral hippocampus). Our results suggest that, while in Non-Tg mice PDIA3 levels gradually reduce with aging in all brain regions analyzed, 3×Tg-AD mice showed an age-dependent increase in PDIA3 levels in the amygdala, entorhinal cortex, and ventral hippocampus. A significant reduction of PDIA3 was observed in 3×Tg-AD mice already at 6 months of age, as compared to age-matched Non-Tg mice. A comparative immunohistochemistry analysis performed on 3×Tg-AD mice at 6 (mild AD-like pathology) and 18 (severe AD-like pathology) months of age showed a direct correlation between the cellular level of Aß and PDIA3 proteins in all the brain regions analysed, even if with different magnitudes. Additionally, an immunohistochemistry analysis showed the presence of PDIA3 in all post-mitotic neurons and astrocytes. Overall, altered PDIA3 levels appear to be age- and/or pathology-dependent, corroborating the ER chaperone's involvement in AD pathology, and supporting the PDIA3 protein as a potential novel therapeutic target for the treatment of AD.

Prevalence and risk factors for hospital-acquired anemia in internal medicine patients: learning from the "less is more" perspective.

Hospital-acquired anemia is defined as a new-onset anemia in hospitalized patients who have a normal hemoglobin level at admission. Its prevalence is unknown and most studies published on this topic have been conducted in intensive care unit patients with limited applicability to less acute settings, such as internal medicine wards. We conducted a retrospective study and enrolled 129 patients who were admitted to an Internal Medicine Unit between October 2021 and February 2022. The median value of phlebotomy during hospitalization was 46 ml (IQR 30-72 ml), whereas the median length of hospital stay was 9 days (IQR 5-13 days). The median value of hemoglobin reduction was -0.63 g/dl (p < 0.001) and the maximum value of drop in hemoglobin value was -2.6 g/dl. All patients who experienced a phlebotomy > 85 ml had a hemoglobin reduction > 0.6 g/dl. 20.9% of patients developed anemia during the hospital stay (7% moderate and 13.9% mild). No cases of severe anemia were observed. The volume of blood drawn during the hospital stay and the Hb value on admission were the only two variables statistically associated with the development of anemia, whereas gender, age, and chronic diseases, such as diabetes, history of cancer, or heart failure, were not. Strategies, such as elimination of unnecessary laboratory tests and the use of smaller tubes for blood collection, are needed to reduce the volume of iatrogenic blood loss and avoid blood wastage occurring during hospitalization in internal medicine patients.

Exploring the Relationship between Epicardial Fat Thickness and Coronary Revascularization: Implications for Cardiovascular Health.

BACKGROUND: this study aimed to assess the complex relationship between EAT thickness, as measured with echocardiography, and the severity of coronary artery disease (CAD). We investigated whether individuals with higher EAT thickness underwent coronary revascularization. Subsequently, we conducted a three-year follow-up to explore any potential modifications in EAT depots post-angioplasty. METHODS: we conducted a prospective and retrospective cross-sectional observational study involving 150 patients consecutively referred for acute coronary syndrome, including ST-elevation myocardial infarction (STEMI), non-ST elevation myocardial infarction (NSTEMI), and unstable angina. Upon admission (T0), all patients underwent coronary angiography to assess the number of pathologic coronary vessels. Percutaneous transluminal coronary angioplasty (PTCA) was performed based on angiogram results if indicated. The sample was categorized into two groups: non-revascularized (no-PTCA) and revascularized (PTCA). Transthoracic echocardiograms to measure epicardial fat thickness were conducted at admission (T0) and after a 3-year follow-up (T1). RESULTS AND CONCLUSIONS: findings revealed a positive correlation between EAT thickness and the severity of coronary artery disease (CAD), with patients undergoing PTCA showing decreased EAT thickness after three years. Echocardiography demonstrated reliability in assessing EAT, offering potential for risk stratification. The study introduces a cut-off value of 0.65 cm as a diagnostic tool for cardiovascular risk. Incorporating EAT measurements into clinical practice may lead to more precise risk stratification and tailored treatment strategies, ultimately reducing the burden of cardiovascular disease.

Pseudocirrhosis and portal hypertension in patients with metastatic cancers: a systematic review and meta-analysis.

Pseudocirrhosis is a clinical and radiological entity mimicking liver cirrhosis in patients without a history of chronic liver disease. We performed a systematic review and meta-analysis of the current literature to evaluate the state-of-the-art and investigate the epidemiology and clinical features of pseudocirrhosis. We searched PubMed, Web of Science and Scopus for literature published until February 28, 2022. We included in the final analysis 62 articles (N = 389 patients): 51 case reports (N = 64 patients), 5 case series (N = 35 patients) and 6 observational studies (N = 290 patients). About 80% of patients included in the case reports and case series had breast cancer. Most patients had at least one clinical sign of portal hypertension and ascites was the most common clinical manifestation of portal hypertension. The median time from pseudocirrhosis to death was 2 months (IQR 1-7 months). Alkylating agents and antimitotics were the most common classes of anticancer drugs reported in our study population. Notably, about 70% of patients received three or more anticancer drugs. Finally, pseudocirrhosis is a condition that occurs in patients with hepatic metastases and may have a negative impact on survival and clinical management of patients because of the potential development of portal hypertension and its complications.

Genetic Polymorphisms and Clinical Features in Diabetic Patients With Fatty Liver: Results From a Single-Center Experience in Southern Italy.

Genetic background may be involved in the promotion and progression of non-alcoholic fatty liver disease (NAFLD). Previous studies have suggested that the single nucleotide polymorphisms (SNPs) may be associated with the specific clinical features in the patients with hepatic steatosis; however, data on the patients with diabetes from Southern Italy are lacking. We enrolled 454 patients and 260 of them had type 2 diabetes. We studied the PNPLA3 rs738409, LPIN1 rs13412852, KLF6 rs3750861, SOD2 rs4880, TM6SF2 rs58542926, and ZNF624 rs12603226 SNPs and their distribution in the study population. Lipid profile, liver stiffness, and kidney function were also studied to understand the potential role of the SNPs in the development of clinical phenotypes. No differences were observed in the distribution of polymorphisms between the diabetic and non-diabetic subjects. Carriers of risk allele G for PNPLA3 rs738409 SNP showed a lower mean value of serum triglycerides and a higher liver stiffness. Risk allele for KLF6 rs3750861 and SOD2 rs4880 polymorphism had a lower estimated glomerular filtration rate (eGFR) value, whereas no differences in the glucose and glycated hemoglobin level were observed in the subgroups by the different genotypes. Genetic polymorphisms are useful to identify the patients at higher risk of development of liver fibrosis and lower eGFR values in the patients with diabetes and NAFLD. Their use in clinical practice may help the clinicians to identify the patients who require a more strict follow-up program.

Serum lipid profile in HCV patients treated with direct-acting antivirals: a systematic review and meta-analysis.

Although direct-acting antivirals are very effective and safe drugs, several authors have reported the alteration of lipid profile during and after anti-HCV therapy suggesting a potential impact on the risk of cardiovascular events. We performed a systematic review and meta-analysis of observational studies to investigate the magnitude and temporal trend of lipid profile changes in DAA treated patients. All selected studies included data on lipid profile before starting therapy and at least one follow-up assessment during or after antiviral treatment. We identified 14 studies (N = 1537 patients) after removing duplicates. Pooled data showed an increase in total cholesterol 4 weeks after starting therapy (+ 15.86 mg/dl; 95% CI + 9.68 to 22.05; p < 0.001) and 12 weeks after treatment completion (+ 17.05 mg/dl; 95% CI + 11.24 to 22.85; p < 0.001). LDL trend was similar to the total cholesterol change in overall analysis. A mean increase in HDL-cholesterol of 3.36 mg/dl (95% CI + 0.92 to 5.79; p = 0.07) was observed after 12 weeks of treatment, whereas at SVR24 HDL difference was + 4.34 mg/dl (95% CI + 1.40 to 7.28; p = 0.004).Triglycerides did not show significant changes during treatment and after treatment completion. DAAs induce mild lipid changes in chronic hepatitis C patients treated with DAAs, which may persist after treatment completion.

A Novel Nutraceuticals Mixture Improves Liver Steatosis by Preventing Oxidative Stress and Mitochondrial Dysfunction in a NAFLD Model.

Non-alcoholic fatty liver disease (NAFLD) is the leading cause of liver disease globally, and represents a health care burden as treatment options are very scarce. The reason behind the NAFLD progression to non-alcoholic steatohepatitis (NASH) is not completely understood. Recently, the deficiency of micronutrients (e.g., vitamins, minerals, and other elements) has been suggested as crucial in NAFLD progression, such that recent studies reported the potential hepatic antioxidant properties of micronutrients supplementation. However, very little is known. Here we have explored the potential beneficial effects of dietary supplementation with FLINAX, a novel mixture of nutraceuticals (i.e., vitamin E, vitamin D3, olive dry-extract, cinnamon dry-extract and fish oil) in a NAFLD model characterized by oxidative stress and mitochondrial function impairment. Steatosis was firstly induced in Wistar rats by feeding with a high-fat/high-cholesterol diet for 4 weeks, and following this the rats were divided into two groups. One group (n = 8) was treated for 2 weeks with a normal chow-diet, while a second group (n = 8) was fed with a chow-diet supplemented with 2% FLINAX. Along with the entire experiment (6 weeks), a third group of rats was fed with a chow-diet only as control. Statistical analysis was performed with Student's T test or one-way ANOVA followed by post-hoc Bonferroni test when appropriate. Steatosis, oxidative stress and mitochondrial respiratory chain (RC) complexes activity were analyzed in liver tissues. The dietary supplementation with FLINAX significantly improved hepatic steatosis and lipid accumulation compared to untreated rats. The mRNA and protein levels analysis showed that CPT1A and CPT2 were up-regulated by FLINAX, suggesting the enhancement of fatty acids oxidation (FAO). Important lipoperoxidation markers (i.e., HNE- and MDA-protein adducts) and the quantity of total mitochondrial oxidized proteins were significantly lower in FLINAX-treated rats. Intriguingly, FLINAX restored the mitochondrial function, stimulating the activity of mitochondrial RC complexes (i.e., I, II, III and ATP-synthase) and counteracting the peroxide production from pyruvate/malate (complex I) and succinate (complex II). Therefore, the supplementation with FLINAX reprogrammed the cellular energy homeostasis by restoring the efficiency of mitochondrial function, with a consequent improvement in steatosis.

Direct-acting antivirals improve kidney function in diabetic patients with HCV infection and chronic kidney disease.

After direct-acting antiviral (DAA) approval, a larger number of diabetic patients with chronic HCV infection have been treated. Cardiovascular risk and insulin resistance significantly change after successful clearance of HCV. Therefore, HCV therapy could potentially improve diabetes microvascular complications including nephropathy. We assessed kidney function after antiviral treatment completion in diabetic (N = 96) and non-diabetic patients (N = 187). Assessment of renal function was performed by serum creatinine and estimated glomerular filtration rate (eGFR) at baseline, at treatment completion and 12 weeks after treatment. Subgroup analysis by age, DAA regimen and eGFR stage at baseline was performed. Serum creatinine did not change significantly at any time whereas eGFR significantly improved during time in diabetic patients (baseline 83.7 ml/min/1.73 m2 vs 102.6 ml/min/1.73 m2 at 12 weeks after treatment completion; p = 0.028). Subgroup analysis showed that the improvement was observed particularly in old people with eGFR < 60 ml/min/1.73 m2. Antiviral regimens did not impact the eGFR values. Sixteen percent of diabetic patients improved their kidney function during treatment (vs 14.4% of non-diabetic patients) showing a one category change in eGFR. No acute kidney injury events were recorded in our cohort. Our study suggests that DAAs improve renal function in HCV diabetic patients with eGFR < 60 ml/min/1.73 m2 or aged ≥ 65 years independently from antiviral regimen.

Immunity as Cornerstone of Non-Alcoholic Fatty Liver Disease: The Contribution of Oxidative Stress in the Disease Progression.

Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic manifestation of metabolic syndrome and has become the major cause of chronic liver disease, especially in western countries. NAFLD encompasses a wide spectrum of hepatic histological alterations, from simple steatosis to steatohepatitis and cirrhosis with a potential development of hepatocellular carcinoma. Non-alcoholic steatohepatitis (NASH) is characterized by lobular inflammation and fibrosis. Several studies reported that insulin resistance, redox unbalance, inflammation, and lipid metabolism dysregulation are involved in NAFLD progression. However, the mechanisms beyond the evolution of simple steatosis to NASH are not clearly understood yet. Recent findings suggest that different oxidized products, such as lipids, cholesterol, aldehydes and other macromolecules could drive the inflammation onset. On the other hand, new evidence indicates innate and adaptive immunity activation as the driving force in establishing liver inflammation and fibrosis. In this review, we discuss how immunity, triggered by oxidative products and promoting in turn oxidative stress in a vicious cycle, fuels NAFLD progression. Furthermore, we explored the emerging importance of immune cell metabolism in determining inflammation, describing the potential application of trained immune discoveries in the NASH pathological context.

Management of intermediate-stage hepatocellular carcinoma in the elderly with transcatheter arterial chemoembolization failure: Retreatment or switching to systemic therapy?

BACKGROUND: Transcatheter Arterial chemoembolization (TACE) is the first-line option for the intermediate-stage hepatocellular carcinoma. Guidelines do not define the number of TACE sessions to be repeated before stopping treatment and switching to sorafenib. METHODS: We retrospectively analysed 76 patients aged ≥65 years who were treated by multiple TACE sessions (re-TACE group; N = 36 patients) or one TACE session followed by sorafenib (TACE/Sorafenib group; N = 40 patients). The primary outcome was the overall survival (Kaplan-Meier analysis and log-rank test). RESULTS: Median overall survival was 320 days (range: 70-420 days) in re-TACE subgroup and 285 days (range: 50-368 days) in TACE/Sorafenib subgroup without significant differences between the two groups (log-rank test P = .72; HR = 0.87; 95% IC 0.41-1.87). The survival rate at one year was 43.6% and 32% in the re-TACE and in the TACE/sorafenib groups (P = .12), respectively. Subgroup analysis by gender, number of nodules at baseline and etiology of liver cirrhosis was performed but no differences were found. No statistical difference was observed in the frequency of side effects, but sorafenib was associated with severe diarrhoea in most patients requiring dose reduction. CONCLUSION: In our study including HCC patients aged ≥65 years, no differences in survival rate and side effects were found between patients Retreated with further TACE sessions and patients with treatment stage migration to sorafenib after first TACE failure. We included in our analysis a small study population; therefore, larger prospective studies are needed to confirm these findings.

The Dual Role of Glutamatergic Neurotransmission in Alzheimer's Disease: From Pathophysiology to Pharmacotherapy.

Alzheimer's disease (AD) is an age-related dementia and neurodegenerative disorder, characterized by Aß and tau protein deposition impairing learning, memory and suppressing synaptic plasticity of neurons. Increasing evidence suggests that there is a link between the glucose and glutamate alterations with age that down-regulates glucose utilization reducing glutamate levels in AD patients. Deviations in brain energy metabolism reinforce the development of AD by hampering glutamate levels in the brain. Glutamate is a nonessential amino acid and the major excitatory neurotransmitter synthesized from glucose. Alterations in cerebral glucose and glutamate levels precede the deposition of Aß plaques. In the brain, over 40% of neuronal synapses are glutamatergic and disturbances in glutamatergic function have been implicated in pathophysiology of AD. Nevertheless, targeting the glutamatergic system seems to be a promising strategy to develop novel, improved therapeutics for AD. Here, we review data supporting the involvement of the glutamatergic system in AD pathophysiology as well as the efficacy of glutamatergic agents in this neurodegenerative disorder. We also discuss exciting new prospects for the development of improved therapeutics for this devastating disorder.

Molecular Aspects and Treatment of Iron Deficiency in the Elderly.

Iron deficiency (ID) is the most frequent nutritional deficiency in the whole population worldwide, and the second most common cause of anemia in the elderly. The prevalence of anemia is expecting to rise shortly, because of an ageing population. Even though WHO criteria define anemia as a hemoglobin serum concentration <12 g/dL in women and <13 g/dL in men, several authors propose different and specific cut-off values for the elderly. Anemia in aged subjects impacts health and quality of life, and it is associated with several negative outcomes, such as longer time of hospitalization and a higher risk of disability. Furthermore, it is an independent risk factor of increased morbidity and mortality. Even though iron deficiency anemia is a common disorder in older adults, it should be not considered as a normal ageing consequence, but a sign of underlying dysfunction. Relating to the molecular mechanism in Iron Deficiency Anemia (IDA), hepcidin has a key role in iron homeostasis. It downregulates the iron exporter ferroportin, inhibiting both iron absorption and release. IDA is frequently dependent on blood loss, especially caused by gastrointestinal lesions. Thus, a diagnostic algorithm for IDA should include invasive investigation such as endoscopic procedures. The treatment choice is influenced by the severity of anemia, underlying conditions, comorbidities, and the clinical state of the patient. Correction of anemia and iron supplementation should be associated with the treatment of the causal disease.

Two-Dimensional Shear Wave Elastography versus Transient Elastography: A Non-Invasive Comparison for the Assessment of Liver Fibrosis in Patients with Chronic Hepatitis C.

In recent years, several non-invasive methods have been developed for staging liver fibrosis in patients with chronic hepatitis C. A 2D-Shear wave elastography (SWE) technique has been recently introduced on the EPIQ 7 US system (ElastQ), but its accuracy has not been validated in patients with chronic hepatitis C virus (HCV) infection. We enrolled 178 HCV patients to assess their liver fibrosis stage with ElastQ software using transient elastography as a reference standard. The best cut-off values to diagnose ³ F2, ³ F3, and F4 were 8.15, 10.31, and 12.65 KPa, respectively. Liver stiffness values had a positive correlation with transient elastography (r = 0.57; p < 0.001). The area under the receiver operating characteristics (AUROC) was 0.899 for ³ F2 (moderate fibrosis), 0.900 for ³ F3 (severe fibrosis), and 0.899 for cirrhosis. 2D-SWE has excellent accuracy in assessing liver fibrosis in patients with chronic hepatitis C and an excellent correlation with transient elastography.

Diagnostic reliability of the procalcitonin serum marker in septic frail patient.

AIM: Aging is associated with increased inflammation, particularly in frailty. Indeed, such patient presents increased serum inflammatory markers, such as C-reactive protein and interleukin-6. Interleukin-6 is an important stimulating factor for the production of procalcitonin. The aim of this study is to evaluate the diagnostic reliability of serum PCT in the diagnosis of sepsis in frail elderly patients. METHODS: Using Fried's criteria for frailty, 140 older patients hospitalized for any cause were consecutively enrolled and divided in two groups: no-frail (60 patients) and frail (80 patients). Patients were further categorized on the basis of the presence/absence of sepsis. Interleukin-6, procalcitonin and inflammatory indices were sampled at hospital admission. RESULTS: Septic patients from frail and no-frail groups showed higher values of interleukin-6 and procalcitonin. However, focusing on groups without sepsis, a statistically significant difference of interleukin-6 and procalcitonin values among frail and no-frail groups was seen at the post-hoc analysis. In frail group, procalcitonin cut-off of 0.5 ng/ml had a sensibility and specificity, respectively, of 100 and 22%. Through receiver operating characteristic curve (ROC) analysis, we found that procalcitonin serum value of 1.4 ng/ml had better sensibility and specificity (respectively, 93.8 and 84.4%, AUC 0.965). CONCLUSIONS: In our study, we confirm the diagnostic reliability of procalcitonin in frail elderly patients for the diagnosis of sepsis. We found that 1.4 ng/ml was the best cut-off in this population.

Bioenergetics and mitochondrial dysfunction in aging: recent insights for a therapeutical approach.

The present review points out the role of oxidative stress in aging and the potential therapeutic targets of modern antioxidant therapies. Mitochondria are essential for several biological processes including energy production by generating ATP through the electron transport chain (ETC) located on the inner mitochondrial membrane. Due to their relevance in cellular physiology, defects in mitochondria are associated with various human diseases. Moreover, several years of research have demonstrated that mitochondria have a pivotal role in aging. The oxidative stress theory of aging suggests that mitochondria play a key role in aging as they are the main cellular source of reactive oxygen species (ROS), which indiscriminately damage macromolecules leading to an age-dependent decline in biological function. In this review we will discuss the mitochondrial dysfunction occurring in aging. In particular, we will focus on the novel mitochondria targeted therapies and the new selective molecules and nanocarriers technology as potentially effective in targeting mitochondrial dysfunction and diseases involving oxidative stress and metabolic failure.

Many faces of mitochondrial uncoupling during age: damage or defense?

An increased mitochondrial proton leak occurs in aging, but the origin of such modification remains unclear. This study defined the cause of mitochondrial uncoupling in mitotic (liver) and postmitotic (heart) rat tissues during aging and its effects on energy homeostasis and free radical production. Proton leak in old heart mitochondria was dependent on uncoupling proteins' upregulation, whereas it was caused by alterations in the mitochondrial membrane composition in old liver. ATP homeostasis was impaired in both tissues from old animals and was associated to disrupted F0F1-ATPase activity. H2O2 production rate and 4-hydroxy-2-nonenalprotein adducts were higher in old liver mitochondria compared with young liver mitochondria, but they were similar in heart mitochondria from both groups. Moreover, key mitochondrial biogenesis regulators were upregulated in old liver but downregulated in old heart. In conclusion, uncoupling proteins mediate proton leak and avoid oxidative damage in heart, acting as a protective mechanism. This does not occur in liver, where ATP depletion and oxidative stress may stimulate mitochondrial biogenesis and eliminate damaged cells.