De Biase, Davide (2017) New perspectives in the mechanisms of aging in animals. [Tesi di dottorato]

Preview

Text Davide_DeBiase_30.pdf Download (2MB) | Preview

Collection description

In recent years, the study of aging process in humans and animals has progressed rapidly, mainly due to the advent of new research instruments and our increasing liability to assemble large, complex data sets acquired across several approaches into an integrated representation of neural and muscular function at the molecular, cellular, and systemic levels. The overall aim of my Ph.D. thesis was to describe the age-related morphological changes in brain and skeletal muscle of cattle and to investigate some of the mechanisms and pathways underlying the aging process of Central Nervous System. First, I describe morphological changes of brain tissue and skeletal muscle associated with old age. Second, I report our studies on autophagy, a highly regulated process involving the bulk degradation of cytoplasmic macromolecules and the possible consequences of the intraneuronal accumulation of lipofuscin, amyloid precursor protein (APP) and increased reactive oxygen species (ROS) on autophagy machinery. Finally, I present the results of our researches concerning one on the most recognized effects of aging: the “immunosenescence”, the dysregulation of the immune system as a result of defects in both initiation and resolution of immune responses. Specifically, we investigated the expression of one of the major “culprits” of neuroinflammation, the NALP3 inflammasome and its association with autophagy and increased ROS production. Our results indicate that changes such as satellitosis, lipofuscin accumulation and central chromatolysis are quite consistent in bovine brains, although it is still debatable whether call them pathologic lesions or simply physiologic age-related alteration. Moreover, we confirm the presence of age-related morphologic changes in skeletal muscle of cows similar to human sarcopenia and underline the possible role of amyloid deposition and subsequent inflammation in muscle senescence. In aged bovine, autophagy is significantly impaired if compared to young animals. In our opinion, this data suggest that the increased age-related intraneuronal deposition of APP and lipofuscin may have an important role on the age-related autophagy impairment. Consistent with the recent scientific literature, our findings showed an increased expression of NLRP3 inflammasome in neurons and microglial cells of aged brains when compared with younger, indicating that the NLRP3 inflammasome is up-regulated in the brain as a result of aging. We also report a direct association between NLRP3 inflammasome, Superoxide Dismutase 1 (SOD1) and autophagy marker Beclin 1. The consequences of the autophagy and inflammasomes interplay are still poorly understood. Our results led us to hypothesize that the increased ROS production may activate inflammasomes provoking a low‐grade inflammation thus accelerating the aging process. Furthermore, the activation of inflammasomes may lead to an induction of autophagy that work to limit inflammasome activity by physical engulfment. This Ph.D thesis is the outcome of several experiments, all aimed to elucidate the molecular mechanisms resulting in morphologic and/or clinical age-related alterations of brain and skeletal muscle in cows. Our ultimate goal is to improve our understanding of aging with more detailed studies and, possibly, include bovine as a valuable animal model for the study of brain aging, sarcopenia and other age-related alterations.

Downloads

Actions (login required)

View Item