Mitochondrial dysfunction in metabolism and ageing: shared mechanisms and outcomes?

Mitochondria are key in the metabolism of aerobic organisms and in ageing progression and age-related diseases. Mitochondria are essential for obtaining ATP from glucose and fatty acids but also in many other essential functions in cells including aminoacids metabolism, pyridine synthesis, phospholipid modifications and calcium regulation. On the other hand, the activity of mitochondria is also the principal source of reactive oxygen species in cells. Ageing and chronic age-related diseases are associated with the deregulation of cell metabolism and dysfunction of mitochondria. Cell metabolism is controlled by three major nutritional sensors: mTOR, AMPK and Sirtuins. These factors control mitochondrial biogenesis and dynamics by regulating fusion, fission and turnover through mito- and autophagy. A complex interaction between the activity of these nutritional sensors, mitochondrial biogenesis rate and dynamics exists and affect ageing, age-related diseases including metabolic disease. Further, mitochondria maintain a constant communication with nucleus modulating gene expression and modifying epigenetics. In this review we highlight the importance of mitochondria in ageing and the repercussion in the progression of age-related diseases and metabolic disease.     

CypD−/− hearts have altered levels of proteins involved in Krebs cycle,branch chain amino acid degradation and pyruvate metabolism

Cyclophilin D (CypD) is a mitochondrial chaperone that has been shown to regulate the mitochondrial permeability transition pore (MPTP). MPTP opening is a major determinant of mitochondrial dysfunction and cardiomyocyte death during ischemia/reperfusion (I/R) injury. Mice lacking CypD have been widely used to study regulation of the MPTP, and it has been shown recently that genetic depletion of CypD correlates with elevated levels of mitochondrial Ca^2 +. The present study aimed to characterize the metabolic changes in CypD^−/− hearts. Initially, we used a proteomics approach to examine protein changes in CypD^−/− mice. Using pathway analysis, we found that CypD^−/− hearts have alterations in branched chain amino acid metabolism, pyruvate metabolism and the Krebs cycle. We tested whether these metabolic changes were due to inhibition of electron transfer from these metabolic pathways into the electron transport chain. As we found decreased levels of succinate dehydrogenase and electron transfer flavoprotein in the proteomics analysis, we examined whether activities of these enzymes might be altered. However, we found no alterations in their activities. The proteomics study also showed a 23% decrease in carnitine-palmitoyltransferase 1 (CPT1), which prompted us to perform a metabolomics analysis. Consistent with the decrease in CPT1, we found a significant decrease in C4/Ci4, C5-OH/C3-DC, C12:1, C14:1, C16:1, and C20:3 acyl carnitines in hearts from CypD^−/− mice. In summary, CypD^−/− hearts exhibit changes in many metabolic pathways and caution should be used when interpreting results from these mice as due solely to inhibition of the MPTP.     

Fibrosis of liver, pancreas and intestine: common mechanisms and clear targets?

Chronic diseases of the liver, pancreas, intestine, kidneys, skin and lungs are usually accompanied by scarring. Loss of organ function is often progressive despite the use of immunosuppressive, antiviral or antiinflammatory agents. Therefore, well tolerated antifibrotic therapies are urgently needed. The targets for such therapies are activated mesenchymal cells that synthesize an excess of matrix proteins and resemble the myofibroblasts of healing wounds. These cells derive from normally quiescent fibroblasts or smooth muscle cells and from stellate cells of liver and pancreas. Their activation is triggered and maintained by mechanical stress and several fibrogenic modulators and cytokines. Some agents inhibit myofibroblast proliferation and collagen synthesis in vitro, but only few of them are effective in vivo. Potential antifibrotic drugs have been tested mainly in models of liver fibrosis. In the suitable rat model of biliary fibrosis, an antifibrotic effect was demonstrated for silymarin, a defined mixture of flavonoids, and to a lesser degree for pentoxifylline. A spin-off of the large multicenter trials for hepatitis C is the finding that interferon-alpha given for 6-12 months may halt or reverse fibrosis, even in virological non-responders. This has to be proven in prospective randomized trials. Specific inhibitors of the endothelin-A-receptor which are orally available can suppress liver collagen accumulation by 40-60%. Other strategies aim at inhibition of the profibrogenic cytokines TGF-beta or connective tissue growth factor. Effective drug targeting to the fibrogenic liver cells is now possible by use of cyclic peptides that bind to receptors which are specifically upregulated on activated stellate cells. Blockade of such activation receptors can induce stress-relaxation which reverts the fibrogenic cells to a fibrolytic, collagen degrading phenotype. Fibrosis has been discovered as a novel target for the pharmaceutical industry. This implies the use of combinatorial chemistry and an automatized screening machinery, greatly speeding up the design and selection of specific antifibrotic agents. Combined with the rapidly evolving validation of serological markers of fibrogenesis and fibrolysis unforeseen progress in the treatment of organ fibrosis can be expected.     

Glycation and insulin resistance: novel mechanisms and unique targets?

Multiple biochemical, metabolic, and signal transduction pathways contribute to insulin resistance. In this review, we present evidence that the posttranslational process of protein glycation may play a role in insulin resistance. The posttranslational modifications, the advanced glycation end products (AGEs), are formed and accumulated by endogenous and exogenous mechanisms. AGEs may contribute to insulin resistance by a variety of mechanisms, including generation of tumor necrosis factor-α direct modification of the insulin molecule, thereby leading to its impaired action, generation of oxidative stress, and impairment of mitochondrial function, as examples. AGEs may stimulate signal transduction via engagement of cellular receptors, such as receptor for AGEs. AGE-receptor for AGE interaction perpetuates AGE formation and cellular stress via induction of inflammation, oxidative stress, and reduction in the expression and activity of the enzyme glyoxalase I that detoxifies the AGE precursor, methylglyoxal. Once set in motion, glycation-promoting mechanisms may stimulate ongoing AGE production and target tissue stresses that reduce insulin responsiveness. Strategies to limit AGE accumulation and action may contribute to the prevention of insulin resistance and its consequences.     

Optimizing cardiac energy metabolism: how can fatty acid and carbohydrate metabolism be manipulated?

Optimizing energy metabolism in the heart is a novel approach for the management of ischaemic heart disease, especially in conjunction with optimizing or restoring coronary flow. In particular, promoting myocardial glucose metabolism can enhance heart function, lessen injury to tissue, or both. Several pharmacological agents that directly stimulate myocardial glucose oxidation or indirectly stimulate glucose oxidation secondary to inhibition of oxidation of fatty acids are now available. Trimetazidine is the first compound in the class of 3-ketoacyl-coenzyme A thiolase inhibitors to see wide-spread clinical use. This agent increases glucose metabolism in the heart secondary to a direct inhibition of fatty acid metabolism. Considering results of experimental and clinical studies on other agents, it is clear that metabolic agents may provide a new approach to treating cardiovascular disease that should complement and improve existing therapies.     

AGES in brain ageing: AGE-inhibitors as neuroprotective and anti-dementia drugs?

In Alzheimer's disease, age-related cellular changes such ascompromised energy production and increased radical formation areworsened by the presence of AGEs as additional, AD specificstress factors. Intracellular AGEs (most likely derived frommethylglyoxal) crosslink cytoskeletal proteins and render theminsoluble. These aggregates inhibit cellular functions includingtransport processes and contribute to neuronal dysfunction anddeath. Extracellular AGEs, which accumulate in ageing tissue (butmost prominently on long-lived protein deposits like the senileplaques) exert chronic oxidative stress on neurons. In addition,they activate glial cells to produce free radicals (superoxideand NO) and neurotoxic cytokines such as TNF-. Drugs, whichinhibit the formation of AGEs by specific chemical mechanisms(AGE-inhibitors), including aminoguanidine, carnosine,tenilsetam, OPB-9195 and pyridoxamine, attenuate the developmentof (AGE-mediated) diabetic complications. Assuming that `carbonylstress' contributes significantly to the progression ofAlzheimer's disease, AGE-inhibitors might also becomeinteresting novel therapeutic drugs for treatment of AD.     

Health and ageing in Australia: Is there culture after sixty?

This paper examines health and ageing in Australia using the concept of culture as a constitutive human process through which people create specific and different ways of life. Beliefs about and attitudes towards frailty and ill health among the old, and their associated practices, form the unifying theme. The ways in which such beliefs and practices are necessarily connected with material social structures and processes (especially class and gender relations) are emphasised.     

Healthy ageing, but what is health?

Ageing occurs in spite of complex pathways of maintenance and repair. There is no “enemy within”, which has the specific evolution-selected function to cause ageing and death. This understanding of ageing should transform our approach towards interventions from therapeutic “anti-ageing” to maintaining health. But what is health? Ideally, health is a state of complete physical and mental independence in activities of daily living. But in pragmatic terms, health is a state of adequate physical and mental independence in activities of daily living. In order to identify a set of measurable, evidence-based and demonstratable parameters of health, robustness and resilience at various levels, the concept of homeodynamic space can be a useful one. Age-related health problems for which there are no clear-cut causative agents, except the complex process of ageing, may be better tackled by focusing on health mechanisms and their maintenance, rather than disease management and treatment. Continuing the disease-oriented research approaches are economically, socially and psychologically unsustainable as compared with health-oriented and preventive strategies, such as hormesis. Supporting health-oriented research is the urgency of our time.     

Environmental stress,ageing and glial cell senescence: a novel mechanistic link to Parkinson's disease?

Exposure to environmental toxins is associated with a variety of age‐related diseases including cancer and neurodegeneration. For example, in Parkinson's disease (PD), chronic environmental exposure to certain toxins has been linked to the age‐related development of neuropathology. Neuronal damage is believed to involve the induction of neuroinflammatory events as a consequence of glial cell activation. Cellular senescence is a potent anti‐cancer mechanism that occurs in a number of proliferative cell types and causes the arrest of proliferation of cells at risk of malignant transformation following exposure to potentially oncogenic stimuli. With age, senescent cells accumulate and express a senescence‐associated secretory phenotype (SASP; that is the robust secretion of many inflammatory cytokines, growth factors and proteases). Whereas cell senescence in peripheral tissues has been causally linked to a number of age‐related pathologies, little is known about the induction of cellular senescence and the SASP in the brain. On the basis of recently reported findings, we propose that environmental stressors associated with PD may act in part by eliciting senescence and the SASP within non neuronal glial cells in the ageing brain, thus contributing to the characteristic decline in neuronal integrity that occurs in this disorder.     

Increased frequency of temporal acoustic window failure in rheumatoid arthritis: a manifestation of altered bone metabolism?

Assessment of intracranial vessels includes transcranial Doppler (TCD). TCD performance requires intact temporal acoustic windows (TAW). Failure of TAW (TAWF) is present in 8–20% of people. There have been no reports on TAWF in rheumatoid arthritis (RA). Altogether, 62 female RA patients were included. Among them, 20 were MTX-treated and biologic-free, 20 received infliximab, and 22 tocilizumab. The controls included 60 non-RA women. TAWF, temporal bone thickness, and texture were determined by ultrasound and CT. BMD and T-scores of multiple bones were determined by DEXA. Several bone biomarkers were assessed by ELISA. In RA, 54.8% of the patients had TAWF on at least one side. Neither TAW could be identified in 34% of RA subjects. In contrast, only 20.0% of control subjects had TAWF on either or both sides (p?<?0.001). In RA vs controls, 53.0 vs 2.9% of subjects exerted the trilayer, “sandwich-like” structure of TAW (p?<?0.001). Finally, in RA vs controls, the mean temporal bone thickness values of the right TAW were 3.58?±?1.43 vs 2.92?±?1.22 mm (p?=?NS), while those of the left TAW were 4.16?±?1.56 vs 2.90?±?1.16 mm (p?=?0.001). There was close association between TAWF, bone thickness, and texture (p?<?0.05). These TAW parameters all correlated with age; however, TAW failure and texture also correlated with serum osteoprotegerin. TAW bone thickness inversely correlated with hip BMD (p?<?0.05). TAWF, thicker, and heterogeneous temporal bones were associated with RA. These features have been associated with bone loss and OPG production. Bone loss seen in RA may result in OPG release and stimulation of bone formation around TAW.