Bio 575 chapter 09 revised

Bio 575 chapter 09 revised - Chapter 9 Robert Arking...

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Chapter 9 Robert Arking Biology of Aging, 3e Oxford University Press Wayne State University
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1-7 In Chapter 1, we presented this sketch of a theory of aging. The time has come to add the details.
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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
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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
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These are the large effect Mendelian genes – note that they mostly cause disease syndromes.
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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
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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
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Let us start with the evidence for hsp involvement in longevity Both HSF & ISP are required for extended longevity
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hsf in muscle tissue extends life span hsf in neural or intestinal tissue also extends life span
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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 OK, so the  hsps are  involved. What are  they doing?
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These Q mutations are present from birth. But normal animals have a gradual buildup of abnormal proteins during their health phase that serve to initiate the senescent phase (e.g., AD).
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Abnormal Protein Accumulation in Fly Brain Causes Progressive Neuropathology & leads to an Accelerated Onset of Senescence from Marsh & Thompson, Bioessays 26:485 (2004)
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ts Mutations With Low Effect Act As Significant Modifiers of PolyQ Genes in Caenorhabiditis From Gidalevitz et al. Science 311:1471, 2006 Ex. 2 Pre-existing abnormal proteins synergistically enhance the effects of other abnormal proteins, & accelerate onset of senescence
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NNT is postulated to modify the effects of MnSOD deficiency due to NNT’s ability to decrease the internal ROS levels in the mitochondria, and thus decrease the rate of increase of mt ROS.
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