This thesis discusses the metabolic and endocrine characteristics of long-lived Dutch families. We found that familial longevity is marked by low thyroid function and preserved insulin senitivity.... Show moreThis thesis discusses the metabolic and endocrine characteristics of long-lived Dutch families. We found that familial longevity is marked by low thyroid function and preserved insulin senitivity. The second part of this thesis adresses the Gompertz law of mortality as an estimate of the rate of senescence Show less
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
Lifespan in under genetic control. In this thesis we translated genes regulating lifespan in model organisms to humans. First we identified DAF-12 as a critical gene for lifespan regulation in the... Show moreLifespan in under genetic control. In this thesis we translated genes regulating lifespan in model organisms to humans. First we identified DAF-12 as a critical gene for lifespan regulation in the nematode worm C. elegans. Then we found that the Liver X Receptors and the Vitamin D Receptor are the most similar human proteins. We tested these genetic variation in these human genes in the Leiden 85-plus Study and found them to associate with with lifespan and cognitive decline respectively. Apolipoprotein E is a target gene of the Liver X Receptor. We found that plasma levels of apolipoprotein E associated with increased risk of cardiovascular mortality, cognitive decline and stroke in a manner independent of classical cardiovascular risk factors. Finally we reviewed the evidence from human candidate gene studies. We conclude that the use of model organisms provides useful directions for research into the genetics of human longevity. However, as the human signalling systems are more complex and our environment is different from that of model organisms, it is unclear to what extent results obtained in model organisms can be extrapolated to humans. Show less
In this thesis the reproducibility of new methods using MRI for measuring total cerebral blood flow and cerebrovascular reserve capacity was assessed. We used these methods to show that NO is an... Show moreIn this thesis the reproducibility of new methods using MRI for measuring total cerebral blood flow and cerebrovascular reserve capacity was assessed. We used these methods to show that NO is an important factor in the hypoxia induced vasodilatation of vessels in the brain. It was shown that basal total cerebral blood flow in the elderly, in contrary to the young, is dependent on the NO pathway. White matter hyperintensities are seen in almost every elderly subject. We showed that besides the white matter hyperintensities there are also change because of aging in the normal appearing white matter. This was demonstrated with the use of magnetization transfer imaging. The appearance of the white matter hyperintensities seems to be independent of the changes in the normal appearing white matter which gives rise to the idea that both entities have different aetiologies. Using this technique we also showed that not all white matter hyperintensities are the same but that differences exists between white matter hyperintensities periventricular and in the deep white matter. Also, differences between frontal and occipital located periventricular white matter hyperintensities exists. Finally, we found that cognitive decline in the elderly is associated with a diminished total cerebral blood flow. Show less
