Presentation of the classical evolutionary theories of aging: antagonistic pleiotropism and disposable soma. Demographic aging, physiology of human aging and physiological predictors of lifespan.
The discovery of adult neurogenesis. Demonstration of adult neurogenesis in the human brain. Organization of the neurogenetic niches in hippocampus and lateral ventricle. Functional maturation of new-born neurons and integration in the existing circuits. Role of newborn neurons in LTP. Relevance of neurogenesis for pattern separation.
Decay of adult neurogenesis with age. Modulation of adult neurogenesis by learning and physical activity. Role of morphogens in the regulation of adult neurogenesis GABAergic control of adult neurogenesis.
Molecular organization of the circadian clock. The central clock and the SCN. Deterioration of circadian rhythms with aging and effects of circadian entrainment. EEG correlates of human sleep. The Moruzzi.Magoun experiment and the role of the ascending projections from the reticular formation. Sleep as homeostatic process. Decay of sleep during aging and its consequences on cognition.
Brain aging is associated to shrinkage but not over cellular loss. Synaptic changes during aging. Neuroinflamation and the role of microglia. Lysosomal dysfunction and accumulation of lipofuscin.
Aging of the sensory systems. Compensatory changes. Aging is associated to loss of specific cognitive function. Excitatory/inhibitory imbalance. Acute recovery of neurochemical phenotypes in the aging primate cortex. Aging of place cells and navigational system.
Transcriptomics studies of aging. Mitochondrial dysfucntions and aging. Aging and DNA damage. Continuity between developmental processes and aging. Evolutionary conservation of the aging signature.
Proteomics. Aging and DNA damage. Trascriptional noise and somatic mutations.
9. Conserved genetic mechanism of life-extension: IGF1 and dietary interventions
Use of the nematode work C. elegans as a genetic model for aging. Discovery of the daf-2 mutant. Identification of daf-2 as ortholog of the IGF/Insulin receptor. The dwarf mutant mice as a genetic model of life extension. Transgenic manipulations of IGF signalling in fruit fly and the mouse. IGF1R, FOXO3a and human centenarians. TOR as central hub at the intersection between nutrient sensing pathways and insulin/IGF pathways. Transgenic manipulations of TOR pathway in fruit fly and the mouse. Calorie restriction in rodents as a life-extending strategy. Contrasting results in primate calorie restriction studies. Calorie restriction in humans. Intermittent fasting and fasting-mimicking diets.
10. Pharmacology of aging
Sirtuins and aging. Resveratrol as a sirtuin activator: initial discoveries and later reconsiderations. Resveratrol prevents the development of age-related conditions. Are resveratrol effects really mediated by sirtuins? Rapamycin as a highly effective inhibitor of the TOR pathway. Rapamycin prevents ageing and prolongs lifespan in a reproducible way. Metformin and AMPK pathway. Are metformin effects mediated by complex I? Cellular senescence and senolytic drugs.
Aim of the course is to convey the basic knowledge of the biological phenomena that control aging ranging from the molecular to the level of integrative functions
Adult Neurogenesis II, G. Kempermann