Ageing: mice and mitochondria.

Nature (Impact Factor: 38.6). 06/2004; 429(6990):357-9. DOI: 10.1038/429357a
Source: PubMed
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    ABSTRACT: The notion of a mobile pool of coenzyme Q (CoQ) in the lipid bilayer has changed with the discovery of respiratory supramolecular units, in particular the supercomplex comprising complexes I and III; in this model, the electron transfer is thought to be mediated by tunneling or microdiffusion, with a clear kinetic advantage on the transfer based on random collisions. The CoQ pool, however, has a fundamental function in establishing a dissociation equilibrium with bound quinone, besides being required for electron transfer from other dehydrogenases to complex III. The mechanism of CoQ reduction by complex I is analyzed regarding recent developments on the crystallographic structure of the enzyme, also in relation to the capacity of complex I to generate superoxide. Although the mechanism of the Q-cycle is well established for complex III, involvement of CoQ in proton translocation by complex I is still debated. Some additional roles of CoQ are also examined, such as the antioxidant effect of its reduced form and the capacity to bind the permeability transition pore and the mitochondrial uncoupling proteins. Finally, a working hypothesis is advanced on the establishment of a vicious circle of oxidative stress and supercomplex disorganization in pathological states, as in neurodegeneration and cancer.
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    ABSTRACT: This study was aimed at defining the reference ranges for biomarkers of oxidized guanine in (2'-deoxy)ribonucleotides and nucleic acids from a large Italian sample. We recruited 300 healthy subjects (150 males; mean age 44.1±13.6years; 26% smokers) without any known exposure to occupational oxidizing agents. They were asked to provide a spot urine sample, on which the following markers were determined by liquid chromatography-tandem mass spectrometry: 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodGuo), 8-oxo-7,8-dihydroguanosine (8-oxoGuo), 8-oxo-7,8-dihydroguanine (8-oxoGua), and cotinine. The reference ranges, estimated as the 5th-95th percentiles of creatinine-normalized values (pmol/μmol(creat)) were 0.7-4.2, 0.9-4.7, and 5.6-120.7 for 8-oxodGuo, 8-oxoGuo, and 8-oxoGua, respectively. Oxidation biomarkers were correlated with one another (p<0.005) and with urinary creatinine (p<0.0001). Males excreted significantly higher concentrations of 8-oxoGua than females (p<0.0001). 8-OxoGua and 8-oxoGuo showed a positive association with age (p<0.001), also after stratification by gender. Multiple linear regression models including urinary creatinine concentration, age, and smoking habit as independent variables showed a significant effect of age, but not of smoking, on the levels of 8-oxoGuo in males (p<0.0001) and of both 8-oxoGuo and 8-oxoGua in females (p<0.0001). A preliminary assessment in a small group (n=25) of patients affected by advanced non-small-cell lung cancer and receiving platinum-based chemotherapy showed significantly higher values of both 8-oxoGuo and 8-oxodGuo (p<0.0001 for both) compared to the referent population.
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    ABSTRACT: The fundamental questions of what represents a macronutritionally balanced diet and how this maintains health and longevity remain unanswered. Here, the Geometric Framework, a state-space nutritional modeling method, was used to measure interactive effects of dietary energy, protein, fat, and carbohydrate on food intake, cardiometabolic phenotype, and longevity in mice fed one of 25 diets ad libitum. Food intake was regulated primarily by protein and carbohydrate content. Longevity and health were optimized when protein was replaced with carbohydrate to limit compensatory feeding for protein and suppress protein intake. These consequences are associated with hepatic mammalian target of rapamycin (mTOR) activation and mitochondrial function and, in turn, related to circulating branched-chain amino acids and glucose. Calorie restriction achieved by high-protein diets or dietary dilution had no beneficial effects on lifespan. The results suggest that longevity can be extended in ad libitum-fed animals by manipulating the ratio of macronutrients to inhibit mTOR activation.
    Cell metabolism 03/2014; 19(3):418-430. · 17.35 Impact Factor

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