Human brain aging is associated with robust normal functional, structural, and molecular changes that underlie changes in cognition, memory, mood and motor function, amongst other processes. Normal aging is also a requirement for onset of many neurological diseases, ranging from later onset neurodegenerative diseases such as Alzheimers(AD) and Parkinsons diseases(PD), to earlier onset psychiatric disorders such as bipolar disorder(BPD) and schizophrenia(SCHZ). Understanding the molecular mechanisms and genetic underpinnings of normal age-related brain changes would have profound consequences for prevention and treatment of age-related impairments and disease. Here I introduce current knowledge of these functional changes, their structural and molecular underpinnings, their genetic modulators, and the contribution of normal aging to age-related neurological disease. I then present my contribution to this field in the form of three papers on genetic modulation of mammalian brain molecular aging. These studies demonstrate and investigate mechanisms underlying the causal modulation of molecular brain aging rates by Brain Derived Neurotrophic Factor (BDNF) and Serotonin (5-HT) in knock-out (KO) mice, and associative modulation by the putative longevity gene, Sirtuin 5, in humans (novel low-expressing promoter polymorphism (Sirt5prom2)). In humans we additionally investigate the potential mechanism(s) underlying neurological disease gating by normal aging, providing supporting evidence for molecular aging being a genetically controlled transcriptional program that progressively promotes age-regulated neurological diseases. In the discussion, I place these studies in a broader context within the field, detailing their implications and future directions.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04012010-142303 |
| Date | 20 April 2010 |
| Creators | Glorioso, Christin Ann |
| Contributors | Stuart Kim, Ph.D., Pete Gianaros, Ph.D., Gonzalo Torres, Ph.D., Etienne Sibille, Ph.D., Michael Zigmond, Ph.D., Charles Bradberry, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04012010-142303/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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