Mechanisms of Aging Angela Chen Biochem 118Q Bioinformatics Genomics Medicine Spring 2003 2004 Aging Time related deterioration of the physiological functions Outline n Major Theories Hypotheses on Aging n Premature Ageing Diseases n What s in the Future Major Theories Hypotheses of Aging Major Theories Hypotheses of Aging 1 Reactive Oxygen Species ROS 2 Genetic Programming of Aging 3 The Wear and Tear Theory n n n DNA Information Mitochondria Telomere Telomerase 1 Reactive Oxygen Species n n n No mutations required Senescence When oxygen atoms in the mitochondria are reduced to ROS ROS molecules that oxidize and damage cell membranes proteins nucleic acids Examples n P66shc protein in mice n Caloric restriction n Vitamins E C 2 Genetic Programming of Aging n Hutchinson Gilford Progeria syndrome n 2 examples of C elegans 3 Wear and Tear Theory n n Accumulated point mutations Senescence Examples n n n DNA Information Mitochondrial mutations Telomere Telomerase Telomere Telomerase http www web books com MoBio Free Ch7C htm However some suggested that n n n Telomere lengths are independent of life span There are no correlations between one s age and one s telomere lengths More research needed Who is Geron n n Biopharmaceutical company focusing on telomerase human embryonic stem cell and nuclear transfer researches Feb 18th 2003 Effects of telomerase transduction suggest differential impairment of lytic and cytokine functions in senescent HIV 1 specific cytotoxic T lymphocytes Premature Ageing Diseases Premature Aging Diseases 1 Down syndrome Early onset Alzheimer s Disease 2 Werner s Syndrome 3 Hutchinson Gilford Progeria syndrome Down Syndrome Early onset Alzheimer s Disease n n n Neurodegenerative disorder loss of memory language reasoning Autosomal dominant genetic disease on chromosome 21 Early onset 30 40 years Werner s Syndrome n n n n Autosomal recessive genetic disease on chromosome 8 Defective DNA metabolism Symptoms hair graying loss cataracts atherosclerosis osteoporosis but NO signs of nuerogeneration hypertension Average living age 47 years Hutchinson Gilford Progeria Syndrome n n n Single dominant mutation on exon 11 of chromosome 1 Lamin A gene Symptoms dwarfism arteriosclerosis myocardial infarction Average living age 13 5 years Database Results eMATRIX Lamin A Progeria Nuclear membrane structure 1824 C T 1819 1968del n n n Nodavirus coat precursor endopeptidase A6 Alpha 2C adrenergic receptor Metabotropic glutamate receptor 5 n EB module n Claudin 14 Exon 11 only eMATRIX Progeria n 3 16e 02 Keratin high sulfur B2 protein n 4 54e 01 Claudin 14 signature IV n 7 89e 01 EB module 3 MTCSITTTAPTAAARGTPLSTTCARAPCCAGPAG 36 3 MTCSITTTAPTAAARGTPLSTTCARAPCCAGPAG 36 14 AAARGTPLSTTCA 26 21 LSTTCARAPCC 31 Lamin A n 7 14e 02 Nodavirus coat precursor endopeptidase A6 aspartic protease signature VII 69 ATAVWGAVGVAASGT 83 n 8 88e 02 Keratin high sulfur B2 protein n 1 63e 01 Alpha 2C adrenergic receptor signature I n 9 05e 01 Metabotropic glutamate receptor 5 sig VII 3 MTCSITTTAPTAAARGTPLSTTCARAPCCAGPAG 36 3 MTCSITTTAPTAAARGTPLSTTCARAPCCAGPAG 36 75 AVGVAASGTIWSPAPTSW 92 50 RWADPSPLALLP 61 Telomerase Connections n Down syndrome n Werner s syndrome n Progeria n Diseased cell s telomere length no significant difference with normal cell s Diseased fibroblast s telomere length at senescence slightly longer than normal cell s at senescence Diseased fibroblast s telomere length shorter than normal cell s but not all progeric fibroblasts have reduced telomere lengths CONCLUSION No apparent connections there must be other factors besides telomerase Other Premature Aging Diseases Generalized n n ROTHMAN THOMSON SYNDROME cataracts thinning hair COCKAYNE SYNDROME degeneration of the brain cataracts Neurodegeneration n Eye n n n Skin n n HUNTINGTON S CHOREA RETINITIS PIGMENTOSA MACULAR DEGENERATION CATARACTS CUTIS LAXA early degeneration of elastin in the skin PSEUDOXANTHOMA ELASTICUM disorder of elastic tissues affecting skin eyes retinal tears and vasculature What is in the Future Technology RNA interference RNAi n n n Function forms RNA dimers that inhibit expression of specific genes Blocking certain protein production may cause a change such as an increase in lifespan Ex C elegans Main Social Issue As more and more people are living longer How do we better life quality of the elderly Population Pyramid of the US http www census go cgi bin ipc idbpyrs pl cty US out s ymax 250 The End
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