MCB 135K Section February 13, 2005 GSI: Laura Epstein

Today Evolutionary Theory of Lifespan Oxidants and Anti-oxidants Neurodegeneration, Repair, Plasticity

Evolutionary Theory of Life Span - Huntington’s Disease, a dominant lethal mutation How does Huntington’s stay in the population if it results in lethality? *JBS Haldane Hypothesis: Aging results from a decline in the force of natural selection. % age in years 100 Natural Selection Age of onset for Huntington’s = ~35yr

% Alive age in years 100 Aging in Nature - Most organisms do not age in a natural environment. Life Span in the Lab Life Span in Nature Aging Begins Natural Selection

Lifespan is proportional to extrinsic mortality! -If mortality is high an organism will die from predation or other hazards before it grows old. -Therefore, if extrinsic mortality limits survival there is no reason to evolve a life span that is longer than an organism would normally survive in nature.

Evolutionary Theories of Aging Disposable Soma - Somatic cells are maintained only to ensure continued reproductive success, following reproduction the soma is disposable. (life span theory) Antagonistic Pleiotropy - Genes that are beneficial at younger ages are deleterious at older ages. ( Pleiotropism = The control by a single gene of several distinct and seemingly unrelated phenotypic effects) Mutation Accumulation - Mutations that affect health at older ages are not selected against (no strong evidence).

Opossums and Life Span - ultimate prey, ~ 80% die from predation - typically reproduce once - age very rapidly -Hypothesis: The presence of predators limits life span, natural selection favors somatic maintenance for only as long as an average opossum can be expected to live. Steve Austad, U. of Idaho -How could you test this hypothesis?

Sapelo Island Opossums - no predators (out in daytime) - longer average life span - reproduce twice (fewer offspring/litter) -Are these changes due to a lack of predators, or a physiological change that delays the aging process? Physiological Change - Sapelo island opossums not only live longer, they age slower than mainland animals. -Sapelo Island opossums have less oxidative damage than mainland opossums. (collagen X-linking)

- Reproductive period extended - Stress resistant, -super flies - Early adult fecundity reduced * antagonistic pleiotropy Offspring of “old” flies are selected Normal old flies selected % Surviving Age in Days Selection at age of reproduction alters lifespan

Evolution in the Laboratory old flies selected young flies selected Normal % Surviving Age in Days - Early adult fecundity increased * antagonistic pleiotropy Offspring of “young” flies are selected

Summary of Drosophila Selection 1) Selection at age of reproduction can alter the lifespan of Drosophila (lifespan has been doubled by this technique). 2) Increase in lifespan has a cost, reduced fecundity (reproduction). - antagonistic pleiotropy - 3) Long-lived flies are stress resistant (heat shock, oxidants).

Exceptions to the Rule Some organisms evolve unique adaptations that allow the subsequent evolution of exceptional life span. Rats and Bats: Rats live for ~3 years, Bats live for ~30 years Bats evolved a mechanism (flight) that reduced extrinsic mortality and allowed for the subsequent evolution of a long life span. What other adaptations might lead to prolonged life span?

Exceptional Life Span in Eusocial Insects Queen Bees and Queen Ants have exceptional life spans! Small size Many offspring Why do they live so long? - Protected from the environment, therefore extrinsic mortality is low!

What does this tell us about aging? -Body size is correlated with lifespan, but is not necessarily a determinant of lifespan. -Reproduction / metabolism does not control life span. Some queen ants produce their body weight in offspring each day -Life Span results from selective pressures.

Stress Genome Stress DNA damage Oxidative Stress p53 Apoptosis Senescence Growth Inhibition The p53 Tumor Suppressor - Loss of p53 function results in an increased incidence of cancer - p53 is mutated in ~80% of all human tumors

p53 may promote aging… p53 CancerAging

Why did we evolve a system that limits our lifespan? -to protect against cancer! (Antagonistic Pleiotropy again!)

Life Span versus Aging Aging - can not be selected for, results from an absence of natural selection. Life Span - results from selection and extrinsic mortality Environmental Selection - predators, natural hazards Social Selection - parental investment, sexual behavior

Main Ideas 1. Life span results from selective pressure. 2. Life span is inversely proportional to extrinsic mortality. 3. Aging results from a lack of natural selection with age.

Questions What is the disposable soma theory? What is antagonistic pleiotropy? Is life span proportional to extrinsic mortality? Does natural selection cause aging?

Oxidants and Anti-Oxidants

Free Radicals Free radicals are unstableFree radicals are unstable React quickly with other compounds, doing cell and body damageReact quickly with other compounds, doing cell and body damage Once produced, they multiply unless neutralized by anti-oxidants or other free-radical scavengers.Once produced, they multiply unless neutralized by anti-oxidants or other free-radical scavengers. Free radicals rarely occur in natureFree radicals rarely occur in nature Oxygen can have several unpaired electron “pairs”Oxygen can have several unpaired electron “pairs”

The Free Radical Theory of Aging “Aging results from the deleterious effects of free radicals produced in the course of cellular metabolism” Harman D., Aging: A theory based on free radical and radiation chemistry, J. Gerontol. 11: 298, 1956 Harman D., Aging: A theory based on free radical and radiation chemistry, J. Gerontol. 11: 298, 1956

Free Radical Chemistry Reactive radicals attack indiscriminatelyReactive radicals attack indiscriminately Can add to unsaturated bondsCan add to unsaturated bonds Can abstract electrons or hydrogen atomsCan abstract electrons or hydrogen atoms Propagate chain reactionsPropagate chain reactions Can cause bond scissionCan cause bond scission Can cause crosslinkingCan cause crosslinking –Crosslinking - Formation of bonds among polymeric chains Produce secondary toxic agentsProduce secondary toxic agents

Implications for Aging Some free radical-induced chemical modifications may have unique impactsSome free radical-induced chemical modifications may have unique impacts Crosslinked products may not be degradableCrosslinked products may not be degradable Scission of bonds in DNA, particularly multiple events may erase vital informationScission of bonds in DNA, particularly multiple events may erase vital information

What are the Major Oxidants? Hydroxyl radical (OH. )Hydroxyl radical (OH. ) Hypochlorite (HOCl)Hypochlorite (HOCl) Singlet oxygen 1 O 2Singlet oxygen 1 O 2 Peroxynitrite (OONO - )Peroxynitrite (OONO - ) Hydrogen peroxide (H 2 O 2 )Hydrogen peroxide (H 2 O 2 ) Free or loosely-bound iron, copper or hemeFree or loosely-bound iron, copper or heme Superoxide radical (O 2. - )Superoxide radical (O 2. - ) Nitric oxide (NO. )Nitric oxide (NO. )

Lipid Peroxidation PUFAs* contain weakly bonded hydrogen atoms between double bondsPUFAs* contain weakly bonded hydrogen atoms between double bonds Chain reactions are probable because of high local concentrations of double bondsChain reactions are probable because of high local concentrations of double bonds *PUFAs means fatty acids *PUFAs means polyunsaturated fatty acids

Oxidant Sources Table 5.1 Enzymes involved in cell signalingEnzymes involved in cell signaling Immune cellsImmune cells “Leaky” electron transport“Leaky” electron transport Damaged proteins and lipidsDamaged proteins and lipids Toxins (food, water)Toxins (food, water) SmokeSmoke Irradiation (UV)Irradiation (UV) Regulated Unregulated

Major Antioxidants Table 5.2 Vitamins E and CVitamins E and C Thiols, particularly glutathioneThiols, particularly glutathione Uric acidUric acid Superoxide dismutases (Cu/Zn or Mn SOD)Superoxide dismutases (Cu/Zn or Mn SOD) Catalase and glutathione peroxidaseCatalase and glutathione peroxidase Heme oxygenasesHeme oxygenases Protein surface groups (Msr)Protein surface groups (Msr)

Glucose and Oxidants In cell culture models high glucose correlates with oxidant productionIn cell culture models high glucose correlates with oxidant production Diabetes implicationsDiabetes implications

Are Oxidants the Cause of Aging? (Table 5.8) ProCon Caloric restriction may reduce oxidative stressCaloric restriction may reduce oxidative stress Life span extension in mutants may be associated with stress resistanceLife span extension in mutants may be associated with stress resistance Knockout mice lacking MnSOD have restricted survivalKnockout mice lacking MnSOD have restricted survival Enzyme mimetics extend life span in some aging models.Enzyme mimetics extend life span in some aging models. Some drugs, probably acting as antioxidants, have been claimed to extend lifespan.Some drugs, probably acting as antioxidants, have been claimed to extend lifespan. Vitamin C, a superb free radical scavenger, is not synthesized by long-lived primates.Vitamin C, a superb free radical scavenger, is not synthesized by long-lived primates. Chronic radiation in low doses does not shorten life span (may increase it).Chronic radiation in low doses does not shorten life span (may increase it). Dietary supplementation with Vitamin E and C does not extend life span.Dietary supplementation with Vitamin E and C does not extend life span. Tissue comparison (brain vs. muscle) seems incompatible with oxidant/antioxidant models of aging.Tissue comparison (brain vs. muscle) seems incompatible with oxidant/antioxidant models of aging. Exercise, that increases oxidant stress, improves life span.Exercise, that increases oxidant stress, improves life span.

Questions Name 3 oxidants and 3 antioxidants What are sources of oxidants? How do free radicals cause damage? What does high levels of glucose have to do with oxidants?

Neurodegeneration, Repair, and Plasticity Neuroendocrine theory of aging: Alterations in either the number or the sensitivity of various neuroendocrine receptors gives rise to homeostatic or homeodynamic changes that result in senescence.

Neuron regeneration? How is that possible? While until the 1990s we thought neurons couldn’t regenerate, now we’ve seen that certain neurons have the potential to regenerate under specific circumstances. –Neurons in lining of cerebral ventricles –Hippocampus –Neuroglia (astrocytes and oligodendrocytes) –Microglia (“macrophages” of nervous system)

What conditions favor regeneration? Whole body: –Exercise –Nutrition –Some stress –Education –Good circulation Neural microenvironment –Brain metabolism –Hormonal changes

Education and death rates Higher education, lower death rates Higher education, lower disability Higher income, lower death rates Comments?

Why would education decrease death rates? Access to medical care Access to exercise Better nutrition Higher income Responsibility to health behaviors Lower rates of smoking and alcohol

Brain reserve capacity When these things (listed in previous slide) happen in young life, brain reserve capacity built This means more neuronal branches and more axonal/dendritic connections, better brain blood supply Evidence: a person with more education has longer dendritic branching length and more connections With old age there is denudation of neurons—less branching

Questions What is the neuroendocrine theory of aging? What is the relationship between education and death rates? And why is it hypothesized to be this way? What is brain reserve capacity? How might it help you in old age?