Stress and oxidative stress (OS) might act synergistically to exacerbate the neuronal decay associated with aging. Recent evidence has shown a redox regulation of the function of the glucocorticoid... Show moreStress and oxidative stress (OS) might act synergistically to exacerbate the neuronal decay associated with aging. Recent evidence has shown a redox regulation of the function of the glucocorticoid receptors as nuclear transcription factors. The lack of the p66Shc gene reduces OS and increases lifespan in mice. Main aim of the study was to elucidate whether the interactions linking OS and the neuroendocrine system represent a crucial determinant of aging in p66Shc-/- mice. Thus, the contribution of p66Shc to behaviour and neuroendocrine regulations was assessed from early post-natal life to senescence. Mutant old mice were characterized by a slow-down in physical and emotional aging; adult subjects showed increased behavioural plasticity and lower emotionality associated to increased central levels of Brain-derived neurotrophic factor, reduced oxidative stress markers and greater resilience to stress-induced changes in the internal milieu. A role has been recently described for p66Shc in regulating energetic metabolism. Intriguingly, we found metabolic and emotional aspects to be strictly related and possibly mediated by maternal behaviour in these mutants. Our results shed light on the role played by OS and metabolism in longevity and emotionality/mood disorders and point to p66Shc as a candidate gene in the trade-off between fertility and lifespan. Show less
The lifespan of an organism is determined by a complex network of environmental-, genetic- and stochastic factors. Each of these components contributes to the wide variability in lifespan between... Show moreThe lifespan of an organism is determined by a complex network of environmental-, genetic- and stochastic factors. Each of these components contributes to the wide variability in lifespan between and within species. In recent years, it has been shown that 20-30 % of human lifespan is under genetic control. Furthermore, a number of longevity candidate genes have been identified. The majority of candidate genes have emerged from studies with model organisms, but also from the biology of human ageing. The objective of this thesis was to test the impact of the most prominent longevity candidate genes on the prevalence of age-related diseases and lifespan in humans. All studies presented in this thesis were performed within the Leiden 85-plus Study, which is a population-based prospective study of the oldest old. The results revealed that genetic variations in most of the candidate genes influence metabolism, prevalence of age-related diseases, cognitive functioning and lifespan. Therefore, the approach of analyzing the most prominent longevity candidate genes in humans, contributes to the identification of biological mechanisms that influence the prevalence of disease in old age and lifespan. Show less
