The subject of this Thesis is the role of the immune system in age-related eye diseases, such as glaucoma. Glaucoma is a disease that afflicts nearly 70 million people worldwide. Little is known... Show moreThe subject of this Thesis is the role of the immune system in age-related eye diseases, such as glaucoma. Glaucoma is a disease that afflicts nearly 70 million people worldwide. Little is known about the origins of the disease, which damages the retina and optic nerve and can lead to blindness. One of the biggest risk factors for glaucoma is elevated eye pressure. Our study found that glaucoma may in fact be an autoimmune disorder. We found that the body’s own T cells are responsible for the progressive retinal degeneration seen in glaucoma. Furthermore these T cells appear to be primed to attack retinal neurons as the result of previous interactions with bacteria that normally live in our body. This opens a new approach to prevent and treat glaucoma. Currently most treatments focus on lowering eye pressure. However, in many patients, the disease worsens even after intraocular pressure returns to normal. We showed that when we blocked these autoreactive T cells in the eye, not only does it diminish the loss of retinal ganglion cells and axons, but it also preserves retinal function. Show less
Many organisms have developed an internal clock to cope with the daily and seasonal cycles in the environment. In mammals, suprachiasmatic nuclei (SCN) of the hypothalamus control circadian rhythms... Show moreMany organisms have developed an internal clock to cope with the daily and seasonal cycles in the environment. In mammals, suprachiasmatic nuclei (SCN) of the hypothalamus control circadian rhythms in behavior and physiology. Evidence links the proper function of circadian clock to mental and physical health. Aging disturbs the accurate function of the SCN and impairs many rhythms such as sleep-wake cycle. Hence improvement of clock function can aid healthy aging. In chapters 3 and 4 I show the ensemble output of the SCN neuronal network is more robust than individual cells__ output suggesting a compensatory role of the network in aging. Seasonal changes affect the physiology and reproduction success of many organisms. The SCN encodes for day-length by adjusting the pattern of its electrical activity rhythm.. In chapters 5 and 6 I reveal that plasticity in interneuronal and cell-intrinsic functions in the SCN helps the organism to adjust to yearly natural changes in photoperiod. These results imply that extensive artificial light in modern society may alter neurotransmitters action in the SCN. A better understanding of SCN network function and cellular properties facilitate alleviation of modern life-related diseases caused by circadian disturbances and aging. 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
