SIRT3 deficiency decreases oxidative metabolism capacity but increases lifespan in male mice under caloric restriction

Mitochondrial NAD⁺‐dependent protein deacetylase Sirtuin3 (SIRT3) has been proposed to mediate calorie restriction (CR)‐dependent metabolic regulation and lifespan extension. Here, we investigated the role of SIRT3 in CR‐mediated longevity, mitochondrial function, and aerobic fitness. We report that SIRT3 is required for whole‐body aerobic capacity but is dispensable for CR‐dependent lifespan extension. Under CR, loss of SIRT3 (Sirt3 ^−/− ) yielded a longer overall and maximum lifespan as compared to Sirt3 ^+/+ mice. This unexpected lifespan extension was associated with altered mitochondrial protein acetylation in oxidative metabolic pathways, reduced mitochondrial respiration, and reduced aerobic exercise capacity. Also, Sirt3 ^−/− CR mice exhibit lower spontaneous activity and a trend favoring fatty acid oxidation during the postprandial period. This study shows the uncoupling of lifespan and healthspan parameters (aerobic fitness and spontaneous activity) and provides new insights into SIRT3 function in CR adaptation, fuel utilization, and aging.     

Relative sensitivities of repair-deficient mammalian cells for clonogenic survival after alpha-particle irradiation

The clonogenic survival of cells of the radiation-sensitive hamster cell lines irs1, irs2, irs3 and xrs5, representing different DNA repair pathways, was compared to that of their parent lines after alpha-particle irradiation. Measurements of nuclear area were made to calculate the probability of surviving a single alpha-particle traversal, the average number of lethal lesions per track and per unit dose, along with the "intrinsic radiosensitivity" of these cells, allowing for the potential of multiple lethal lesions per traversal. For all cell lines studied, alpha particles were found to be more biologically effective per unit absorbed dose than X rays at inducing cell inactivation. The repair-deficient cells showed an enhanced sensitivity to alpha particles compared to their parent line, but the degree of enhancement was less than for X rays. The reduction in additional sensitivity for alpha-particle irradiation was shown not to be due predominantly to differences in cell geometry limiting the probability of a cell nucleus being traversed. The results suggest that both the nonhomologous end-joining pathway and to a lesser extent the homologous recombination repair pathway play a role in successful repair of alpha-particle-induced damage, although a large proportion of damage is not repaired by either pathway.     

Ethanol, fruit ripening, and the historical origins of human alcoholism in primate frugivory

Ethanol is a naturally occurring substance resulting from thefermentation by yeast of fruit sugars. The association betweenyeasts and angiosperms dates to the Cretaceous, and dietaryexposure of diverse frugivorous taxa to ethanol is similarlyancient. Ethanol plumes can potentially be used to localizeripe fruit, and consumption of low-concentration ethanol withinfruit may act as a feeding stimulant. Ripe and over-ripe fruitsof the Neotropical palm Astrocaryum standleyanum contained ethanolwithin the pulp at concentrations averaging 0.9% and 4.5%, respectively.Fruit ripening was associated with significant changes in color,puncture resistance, sugar, and ethanol content. Natural consumptionrates of ethanol via frugivory and associated blood levels arenot known for any animal taxon. However, behavioral responsesto ethanol may have been the target of natural selection forall frugivorous species, including many primates and the hominoidlineages ancestral to modern humans. Pre-existing sensory biasesassociating this ancient psychoactive compound with nutritionalreward might accordingly underlie contemporary patterns of alcoholconsumption and abuse.     

Solution structure of the novel dispersin protein of enteroaggregative Escherichia coli

Enteroaggregative Escherichia coli (EAEC), increasingly recognized as an important cause of infant and travelers' diarrhoea, exhibits an aggregative, stacked-brick pattern of adherence to epithelial cells. Adherence is mediated by aggregative adherence fimbriae (AAFs), which are encoded on the pAA virulence plasmid. We recently described a highly prevalent pAA plasmid-borne gene, aap, which encodes a protein (nicknamed dispersin) that is secreted to the bacterial cell surface. Dispersin-null mutants display a unique hyper-aggregating phenotype, accompanied by collapse of AAF pili onto the bacterial cell surface. To study the mechanism of this effect, we solved the structure of dispersin from EAEC strain 042 using solution NMR, revealing a stable beta-sandwich with a conserved net positive surface charge of +3 to +4 among 23 dispersin alleles. Experimental data suggest that dispersin binds non-covalently to lipopolysaccharide on the surface of the bacterium. We also show that the AAF organelles contribute positive charge to the bacterial surface, suggesting that dispersin's role in fimbrial function is to overcome electrostatic attraction between AAF and the bacterial surface.