Mechanisms of ageing and development
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A balanced diet reduces the risk of life-threatening diseases such as diabetes and cancer. A reduced supply of energy at the cellular level leads to an increased concentration of AMP, which, in turn, results in LKB1-mediated activation of the AMPK kinase. The activation of the p53 tumor suppressor protein by metabolic stress has been shown to be mediated by AMPK. ⋯ Furthermore, p53 activation by AICAR was blocked by rapamycin, a specific inhibitor of the mTOR kinase, which is a crucial regulator of cell growth. Rapamycin did not block p53 activation by resveratrol, which, in contrast to AICAR, induced the DNA damage response, senescence-like growth inhibition, a high level of post-translational modification of p53, and weak upregulation of MDM2 (the negative regulator of p53). Thus, ATM and mTOR participate in the activation of p53 in response to a compound mimicking metabolic stress.
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Selenium (Se) is an essential trace mineral mediating its biological function primarily through selenoproteins. Accumulated lines of evidence indicate important roles of selenoproteins in the maintenance of optimal brain functions via redox regulation. ⋯ Recent advances using genetically manipulated mouse models demonstrate that selenoproteins offer protection against neurodegeneration primarily through redox regulation. Therapies targeting specific selenoproteins influencing redox regulation could delay the onset of neurodisorders, improve quality of life of patients already affected, and perhaps rescue patients with certain diseases by using novel gene therapies.
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Calorie restriction (CR) resets circadian rhythms and extends life span. Intermittent fasting (IF) also extends life span, but its affect on circadian rhythms has not been studied. To study the effect of IF alongside CR, we imposed IF in FVB/N mice or IF combined with CR using the transgenic FVB/N alphaMUPA mice that, when fed ad libitum, exhibit spontaneously reduced eating and extended life span. ⋯ However, IF restored the amplitudes of clock gene expression under disruptive light condition regardless whether the animals were calorically restricted or not. Unlike daytime feeding, nighttime feeding yielded rhythms similar to those generated during ad libitum feeding. Taken together, our results show that IF can affect circadian rhythms differently depending on the timing of food availability, and suggest that this regimen induces a metabolic state that affects the suprachiasmatic nuclei (SCN) clock.
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Associations between telomere length and various chronic diseases associated with ageing have led to the suggestion that telomere length may be an ageing biomarker. At the clinical level, the suggestion of using measurements of frailty as a measure of biological ageing has also been suggested. This study examines the hypothesis that telomere shortening may form the biological basis for frailty, using data obtained from a health survey of 2000 men and women aged 65 years and over, living in the community, and followed up for 4 years to determine survival. ⋯ In men only, there was a negative association between telomere length and age and a positive association between frailty index and mortality after adjusting for age. There was no correlation between telomere length and frailty index in either sex. While telomere length may be a biomarker of cellular senescence, this relationship may not be extrapolated to the functional level represented by the frailty phenotype.
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Accumulation of beta-amyloid (Abeta) peptide in the brain is a major hallmark of Alzheimer's disease (AD). Hypercholesterolemia is a risk factor for AD and has been shown by laboratory studies to cause Abeta accumulation. Abeta levels in the brain are governed by its generation from amyloid precursor protein by beta-secretase (BACE1), degradation by the insulin degrading enzyme (IDE), clearance from the brain by the low density lipoprotein receptor-related protein (LRP-1), and transport from circulation into the brain by receptor for advanced glycation end products (RAGE). ⋯ In the present study, we determined the extent to which hypercholesterolemia-induced Abeta accumulation is associated with alterations in BACE1, IDE, LRP-1, and RAGE expression levels. We show that hypercholesterolemia increases Abeta production, an effect that is associated with increased levels of BACE1 and RAGE and reduced levels of IDE and LRP-1. These results suggest that reducing Abeta accumulation in the brain may require strategies that combine reduction of generation and transport of Abeta in addition to acceleration of degradation and clearance of this peptide.