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Death: the Ultimate Phenotype

Death: the Ultimate Phenotype. Genomics of Aging. Studying Aging in Model Systems. yeast- caloric restriction slows aging living systems tend to delay reproduction until food is plentiful worms- 4 other signaling pathways that prolong life:

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Death: the Ultimate Phenotype

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  1. Death: the Ultimate Phenotype Genomics of Aging

  2. Studying Aging in Model Systems • yeast- caloric restriction slows aging living systems tend to delay reproduction until food is plentiful • worms- 4 other signaling pathways that prolong life: • hormonal signaling- Daf2 makes worms more resistant to stress • reproductive cells- gamete formation • mitochondrial signals slow metabolism • tyrosine kinase mutants live 60% longer

  3. More Model Systems • flies- methusela mutation can prolong life by 35% gene encodes a G-protein coupled integral membrane protein No orthologs of this protein have been found • mice- Ames dwarf mice live longer than normal These mice have altered hormonal levels Another mutation, in p66shc, changes the stress response

  4. Why Do We Age? • If the selection pressure is to produce as many offspring as possible- evolution should favor longer and longer lifespan • Two hypotheses have been put forth: • mutation accumulation- mutations accumulate gradually and become fixed by genetic drift (adaptation to 1 environment is not related to loss of adaptation in a different one) • antagonistic pleiotrophy- a mutation which produced a benefit in 1 environment may be detrimental in another

  5. Trade-offs for Longer Life • Age-1 is a mutation in C. elegans which affects a kinase involved in insulin signaling • Gordon Lithgow (Manchester) tested the survival of worms in populations with different proportions of age-1 mutants • The ratios of age-1 to wt were .9 (black), .5 (gray), or .1 (blue) • Worms were given unlimited amounts of food and were maintained at 20o C • The results supported the mutation accumulation hypothesis

  6. Another Interpretation • Lithgow realized that the experimental conditions did not mimic conditions in nature • Worms don’t usually have unlimited supplies of food • His lab repeated the experiments, this time feeding the worms a large amount of food and then starving them for four days • They started with a 50:50 mix of age-1 and wt • Only young adults laid eggs during starvation • Their results now supported the antagonistic pleiotrophy hypothesis

  7. Aging Studies Using Bacteria • Richard Lenski (MSU) has grown E. coli for 20,000 generations (since 1988) • His lab grows bacteria in glucose as its only C source and then switches to other C sources to test for the loss of catabolic function • Fitness = improved metabolism in glucose • If AP is correct- loss of catabolic function will be inversely proportional to gains in fitness • If MA is correct- loss of catabolic function will occur at an independent rate

  8. Antagonistic Pleiotrophy • A mutation which produces a selective advantage early in life may accumulate a cost that is exhibited late in life • In many cases, reduced fitness appears to be a trade-off for increased longevity • A genetically engineered mouse that was smarter than average mice was more sensitive to chronic pain • Animal models of the genomics of aging are not perfect since humans do not live in controlled environments

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