Bio 575 chapter 09 extra 07

Bio 575 chapter 09 extra 07 - Chapter 9 Robert Arking...

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Unformatted text preview: Chapter 9 Robert Arking Biology of Aging, 3e Oxford University Press Wayne State University 1-7 In Chapter 1, we presented this sketch of a theory of aging. The time has come to add the details. We will first examine the genetic architecture of two common physiological functions to see if tnere are any common features. Any models we build must be based on data. The systems we will investigate are: 1. Hypertension 2. Cardiac Function 3. Obesity 4. Metabolic Syndrome Genetic Architecture of Hypertension As A Model of Genomic Organization: Large Effect Genes that yield Mendelian phenotypes . N = 8 genes yielding hypertension + 9 genes yielding hypotension Accounts for ~5% of the population variance in blood pressure Small Effect Genes (QTLs) that individually have a small effect and whose effects are only seen when homozygous (i.e., inbreeding). N=~300-~600 yielding both hyper- & hypo-tension The 8-16 QTLs with the largest effect collectively account for ~25% of the population variance, while all the others account for the remaining 70% of the variance These are the large effect Mendelian genes note that they mostly cause disease syndromes. Both large & small effect genes probably affect these mechanisms so as to bring about blood pressure changes Small effect genes can act at any other point Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Simplified structures of different types of hearts, showing schematic diagrams of hearts and directions of blood flow Drosophila also Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Heart Development Genetic Aspects Heart of the fruitfly Evo-Devo of the Heart Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Fig. 1. Evolution of the heart and the core cardiac transcription factors Published by AAAS E. N. Olson Science 313, 1922 -1927 (2006) Schematic of transcriptional networks involved in mammalian heart development RV Absence of Major Gene Gives Rise to Major Mutant Effect So both Hypertension & Cardiac Function Depend On So both Hypertension & Cardiac Function Depend on both Major and Minor Genes Major genes = Mendelian mutations Minor genes = Modifier genes Any Model of Gene Action in Senescence Must Show the Different Roles that Major and Minor Genes Have. The Transition from Health to Senescence is Regulated by Major & Minor Genes Acting at the Cell Level from Arking, 2005, based on work from the Morimoto lab JH ---------l Prediction: Abnormal proteins or low antioxidant defense or high ISP activity will reduce longevity DR seems to activate these same major genes Let us start with the evidence for hsp involvement in longevity Both HSF & ISP are required for extended longevity hsf in muscle tissue extends life span hsf in neural or intestinal tissue also extends life span Hormesis Does Not Occur in the Long-lived La Fly (Keuther and Arking, 1999)...
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Bio 575 chapter 09 extra 07 - Chapter 9 Robert Arking...

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