Death: the Ultimate Phenotype Genomics of Aging

Studying Aging in Model Systems yeast- caloric restriction slows aging yeast- caloric restriction slows aging living systems tend to delay reproduction until food is plentiful worms- 4 other signaling pathways that prolong life: worms- 4 other signaling pathways that prolong life: 1) hormonal signaling- Daf2 makes worms more resistant to stress 2) reproductive cells- gamete formation 3) mitochondrial signals slow metabolism 4) tyrosine kinase mutants live 60% longer

More Model Systems flies- 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- mice- Ames dwarf mice live longer than normal These mice have altered hormonal levels Another mutation, in p66 shc, changes the stress response

Why Do We Age? If the selection pressure is to produce as many offspring as possible- evolution should favor longer and longer lifespan 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: Two hypotheses have been put forth: 1) 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) 2) antagonistic pleiotrophy- a mutation which produced a benefit in 1 environment may be detrimental in another

Trade-offs for Longer Life Age-1 is a mutation in C. elegans which affects a kinase involved in insulin signaling 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 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) 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 20 o C Worms were given unlimited amounts of food and were maintained at 20 o C The results supported the mutation accumulation hypothesis The results supported the mutation accumulation hypothesis

Another Interpretation Lithgow realized that the experimental conditions did not mimic conditions in nature Lithgow realized that the experimental conditions did not mimic conditions in nature Worms don’t usually have unlimited supplies of food 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 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 They started with a 50:50 mix of age-1 and wt Only young adults laid eggs during starvation Only young adults laid eggs during starvation Their results now supported the antagonistic pleiotrophy hypothesis Their results now supported the antagonistic pleiotrophy hypothesis

Aging Studies Using Bacteria Richard Lenski (MSU) has grown E. coli for 20,000 generations (since 1988) 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 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 Fitness = improved metabolism in glucose If AP is correct- loss of catabolic function will be inversely proportional to gains in fitness 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 If MA is correct- loss of catabolic function will occur at an independent rate

Antagonistic Pleiotrophy A mutation which produces a selective advantage early in life may accumulate a cost that is exhibited late in life 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 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 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 Animal models of the genomics of aging are not perfect since humans do not live in controlled environments