biological theories of aging winter 08 lecture 5 – chapter 5

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  • Slide 1
  • Biological Theories of Aging Winter 08 Lecture 5 Chapter 5
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  • Many Theories Wear & tear Hayflick Telomere Rate of Living Caloric Restriction Free Radical Autoimmune Cross linkage Non Genetic Genetic Cellular Error Cascade Genetic
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  • 1882
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  • Wear & Tear Theory of Aging Ordinary insults and injuries of daily living accumulate, and over time decrease the organisms efficiency years of damage to cells, tissues and organs preprogrammed process: biological clock preprogrammed amount of energy used up Human body like your car engine
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  • Hans Selye: The Discovery of Stress (1936) General Adaptation Syndrome (G.A.S.) if the duration of stress is sufficiently long, the body eventually enters a stage of exhaustion, a sort of aging "due to wear and tear" Alarm reaction Resistance Exhaustion childhood adulthood senescence
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  • 1 week old fruit flies fly 110 minutes without landing 1 month-old fruit flies must land after 19 minutes
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  • Theory is weak Animals raised in a protective environment still age Wear and tear could easily be viewed as a result of aging and not a cause of it The theory is outdated because it does not deal with specific cellular and molecular mechanisms
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  • Hayflick Theory of Aging Cellular Theory (1960) there is a limit to the number of times cell can divide cells reach a predefined limit (Hayflick Limit) replicative senescence causes a nondividing state inability to divide represents aging cells from older organisms divide proportionately fewer times than cells from younger ones Debunked Carrel (1940): cultured cells were immortal (HeLa Cells)
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  • Hayflicks experiments In vitro cell culture Finite # of passages: Hayflick Limit~50 tissue trypsin Medium, temp confluent trypsin Passage population doubling Medium, temp confluent
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  • Hayflick Experiments: Male & Female Fetal Cells 40 th PD10 th PD Male conMale & Female mix Female con young old 20 PD Male con 30 PD Only female cells remain Female con
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  • Rats: PD ~ 10 3.5 Humans PD ~ 50 122 Galapagos tortoises PD ~110 200 Fibroblasts Cells in long-lived animals replicate longer in culture than animals with shorter life spans. Long-lived animals have a higher Hayflick Limit than short-lived ones.
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  • Normal human fibroblasts (left) and fibroblasts showing a senescent morphology (right). Notice the common elongated morphology of senescent cells.
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  • Extension of Wear & Tear: Why only 50 PDs? Answer: The Telomere Hypothesis of Aging Telomeres are sequences of nucleic acid End pieces of DNA (the tail of DNA) Every time cells divides, telomeres shorten Once the telomeres become too short, cell division slows and finally ceases and the cell will die A.M. Olovnikov, 1996 telomeres are lost with age in normal dividing cells, cancer cells escape mortality by activating the enzyme telomerase.
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  • Telomere becomes too short & cannot replicate Cell becomes old Apoptosis: The process by which a cell dies at a natural, "pre-programmed" time 1.Erosion 2.Addition: telomerase
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  • Dolly had DNA in her cells that is typical of an older animal Dolly was cloned from a mammary cell taken from a 6-year-old ewe Cloned in 1996 Died Feb 14, 2003: euthanized progressive lung diseasedied 6!!! years earlier
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  • The energy an animal burns in an hour Max Rubner (1908) discovered the relationship among metabolic rate, body size and survival rate Born with a limited amount of energy If we use energy slowly rate of aging is slowed If the energy is consumed quickly aging speeds up nearly all mammals expire after anywhere from 1 billion to 2 billion heartbeats Rate of Living Theory of Aging (1908)
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  • This theory explains why most larger animals live longer than most smaller animals rapid metabolism = shortest life spans slower metabolic rates = tend to have longer life spans 70 yrs 50 yrs 12 yrs 3 yrs
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  • Rate of Living Theory Updated & Refined: Caloric Restriction Theory of Longevity 1937 - Clive McCay, Cornell University - 33% CR (rats) 50% increase in max lifespan Yeast (increases by 25% when glucose level in culture reduced from 2% to 0.5%) Mosquitoes Flies Protozoans Roundworms Spiders fish late 1980s - start three studies with monkeys NIA - Baltimore - 160 monkeys (squirrel monkeys and rhesus monkeys) Univ. Maryland - Baltimore - 27 monkeys Univ. Wisconsin - 76 monkeys approx. 30% CR + supplements
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  • "To lengthen thy life, lessen thy meals." Benjamin Franklin
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  • Mice: 1 mo. = 2 yr old in human
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  • Adult-onset CR extends animal life only when phased in gradually (over a period equivalent to 2.5 yrs in humans) & when given a nutrient-enriched diet. 44% CR CR starting at: 12.5 mo. = 30 yrs. In human 27% CR 13.5 mo. = 40 yrs in humans
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  • George Roth, Ph.D Long-term study Began in 1987 "Until 1987, caloric restriction was never tried in a controlled way with animals that live longer than three years," says Roth. A decade later, we're finally accumulating information on how caloric restriction affects primates. currently a Guest Scientist at NIA, President and CEO of Gerotech Inc.
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  • Findings in NIA Primate CR StudyMatches Rodent Data (-) Body weightyes (-) Fat and lean massyes (-) Time to sexual maturationyes (-) Time to skeletal maturationyes (-) Fasting glucose/insulinyes (-) Metabolic rate (short-term)yes (*) Metabolic rate (long-term)yes (-) Body temperatureyes (*) or (+) Locomotionyes (-) Triglyceridesyes (+) IGF-1/growth hormoneyes (*) Wound closure rateyes (*) B-gal senescent cells? (-) = decrease, (+) = increase, (*) = no change 30% CR 10 yr study diabetes: greatly reduced fewer signs of spinal arthritis less decline in melatonin levels increase in HDL
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  • Compared to Americans, Okinawan elders get 80% fewer breast and prostate cancers get 50% fewer ovarian and colon cancers have 50% fewer hip fractures have 80% fewer heart attacks 40% fewer calories than Americans and 17% fewer calories than the Japanese average http://www7.nationalgeographic.com/ngm/0511/sights_n_sounds/index.html Okinawan Elders Greatest # centenarians
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  • CR reduces the amount of fuel available for cells and the amount of oxygen needed by the mitochondria to convert the existing fuel into energy, and it makes the existing metabolic process more efficient
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  • Free Radical Theory of Aging (1954) Aging is a result of oxidative damage caused by free radicals generated by the metabolic system Free radicals are unstable organic molecules that appear as a by- product of oxygen metabolism in cells Free radicals are any number of chemical species that are highly reactive because they possess an odd number of electrons and seek to combine with other molecules to pair off their free electron Damage: lipids, protein, carbohydrates, nucleic acids, various other cell components Supported by caloric restriction studies: caloric restriction extends life expectancy by Denham Harman, Ph.D, M.D,
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  • ROS Oxygen-derived radicals are generated constantly as part of normal aerobic life (1 5 % of 0 2 ) formed in mitochondria as oxygen is reduced along the electron transport chain ROSs: are also formed as necessary intermediates in a variety of enzyme reactions
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  • Table 02 Leading Causes of Death in the U.S.
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  • Table 1. Rates of Auto-Oxidation and Life Spans of Mammalian Species 14 Species Oxidation Rate Life Span (yrs) Man2490 Orangutan2550 Baboon3537 Green monkey 4134 Squirrel monkey 7418 Rat1044 Mouse1823.5
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  • Melatonin All found to decrease free radical damage
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  • Induced overexpression of mitochondrial Mn-superoxide dismutase extends the life span of adult Drosophila melanogaster. Sun J; Folk D; Bradley TJ; Tower J Molecular and Computational Biology Program, Department of Biological Sciences, University of Southern California, University Park, Los Angeles, California 90089-1340, USA Genetics. 2002; 161(2):661-72 (ISSN: 0016-6731) Superoxide dismutase An enzyme that converts the superoxide ion (O2) into hydrogen peroxide. This enzyme is part of the cellular antioxidant defense system.
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  • Error Cascade Theory
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  • Autoimmune Theory: immune system begins to decline after adolescence vulnerability to disease and a sluggish response to some tumor cells system so weakened that it can no longer distinguish between the bodys own and foreign tissues, i.e. the body may begin to attack itself. Cross-Linkage Theory: C

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