Midterm Distribution Mean = N = 68 Grade (%) Frequency (#)

Outline of Lectures on Ageing Evolutionary Tradeoffs: Evolution of Ageing Cancer: a Disease of Ageing Molecular Mechanisms of Ageing, and Mitigating its Effects (Sirtuins)

Evolutionary and Mechanistic Theories of Ageing

Questions from Reading: Hughes, K. A. and Reynolds, R. M Evolutionary and mechanistic theories of aging. Annual Review of Entomology. 50: Q: What are some proposed evolutionary causes of ageing? Q: What are some physiological mechanisms of ageing? Q: How might selection act on a population to increase lifespan?

Evolutionary Costs or Tradeoffs: Ageing is an example Adaptation is not perfect There is often a cost, and there are often tradeoffs One example of such a cost or tradeoff is Ageing

What is ageing? Senescence: decline in performance and fitness with advancing age

Basic Evolutionary Concepts Natural Selection Pleiotropy Antagonistic Pleiotropy Evolutionary Tradeoffs

Darwin’s Contribution: Natural Selection “Of course, long before you mature, most of you will be eaten” Too many offspring are produced Limited resources and competition Variation in a population Better adapted individuals survive Survivors leave more offspring (“fitness) Thus, the average composition of the population is altered Natural selection leads to adaptation

“Population speciation through Natural Selection”

Mutation

This mutation happens to be beneficial

Individuals with this mutation happen to leave more offspring (greater “fitness”)

Ageing is not Universal Bacteria do not age; they simply grow and divide Multicellular organisms tend to age and die Organisms that reproduce early in life are the ones that age faster

Outline Evolutionary causes (WHY did it evolve?) Mechanistic causes (HOW does it occur? What physiological changes occur?)

Outline Evolutionary causes (WHY) –Mutational Accumulation –Antagonistic Pleiotropy –Disposable Soma Mechanistic causes (HOW) –Oxidative Stress –Other types of Stress –Signal transduction pathways –Role of Diet

Causes of Ageing There might not be any adaptive reason for an individual to age –It could be a tragic by-product of natural selection weakening with age –Natural selection would act to reduce physiological damage Cellular ageing and death might occur to prevent excessive cell proliferation in multicellular organisms (discuss next time in lecture on evolution and cancer)

Evolutionary Causes: Senescence occurs because the force of natural selection declines with age in populations that have age structure (individuals of different ages) Selection acts differently on different age groups (more effective before reproduction, declines with age)

Why would the action of natural selection weaken with age? Because natural selection acts deterministically: individuals die for a reason… selection acts when more adapted individuals have a greater probability of surviving and leaving offspring

Why would the action of natural selection weaken with increasing age? With increasing age, extrinsic mortality increases, that is death from random causes (accidents, non-age specific diseases, etc). These random deaths weaken the effect of natural selection (as deaths need to be caused by nonrandom forces for selection to act) Natural selection is less efficient when deaths are random, and not due to particular genetically-determined traits

So, as Natural Selection weakens with age (due to extrinsic mortality), traits that are harmful later in life do not get weeded out of the population… Negative traits accumulate later in life

Evolutionary Mechanisms General Model: The ultimate evolutionary cause of aging is extrinsic mortality (WD Hamilton, 1966) The hypothesized mechanisms by which ageing could evolve include: –Mutational Accumulation –Antagonistic Pleiotropy –Disposable Soma

Evolutionary Mechanisms General Model: The ultimate evolutionary cause of aging is extrinsic mortality (WD Hamilton, 1966) The hypothesized mechanisms by which extrinsic mortality (i.e. ineffective selection) causes ageing to evolve include: –Mutational Accumulation –Due to ineffective selection later in life, deleterious mutations accumulate –Antagonistic Pleiotropy –Mutations that are favored by selection early in life, might be harmful later, but selection is ineffective later in life –Disposable Soma –Selection early in life favors reproduction, ineffective selection later in life will not favor maintenance and repair

The reduction in natural selection later in life (due to extrinsic mortality, i.e. random deaths) might result in aging due to: –Mutational accumulation –Antagonistic pleiotropy –Disposable Soma That is, ineffective selection later in life might lead to senescence (ageing) due to one of the mechanisms above.

(1) Mutational Accumulation Medawar (1952) Deleterious mutations expressed at a young age are severely selected against, due to their high negative impact on fitness (number of offspring produced). On the other hand, deleterious mutations expressed only later in life are neutral to selection, because their bearers have already transmitted their genes to the next generation. Because genes have already been passed on, selection is weaker later in life, and thus mutations accumulate, and the negative effects are manifested as ageing.

(2) Antagonistic Pleiotropy Williams (1957) Pleiotropy: phenomenon where a gene affects several different traits Antagonistic Pleiotropy: where a gene has a positive effect on one trait but a negative effect on another trait (example: a gene that increases heat tolerance but reduces cold tolerance) Antagonistic Pleiotropy Theory of Aging: Mutations that are beneficial early in life (before reproduction), but are deleterious later in life do not get selected out of a population because selection is less efficient later in life Antagonistic pleiotropy could leads to evolutionary “trade-offs” (sometimes between fecundity and longevity)

Conversely, a seemingly unbeneficial trait might get selected for because the gene that codes for it also enhances fitness Pleiotropy: when a gene affects many traits or functions Selection might not be able to act on trait if the gene that codes it also affects many other traits, and the change negatively affects the other traits Gene Network

Antagonistic Pleiotropy could lead to evolutionary tradeoffs such as: Degeneration during Aging: A trait that is beneficial early in life might be deleterious (bad) later in life Or Not….

Antagonistic Pleiotropy Theory of Aging: Mutations that are beneficial early in life (before reproduction) will be selected for even if they are deleterious later in life BirthJuvenile Adult reproduction Post reproduction Death

Antagonistic Pleiotropy Theory of Aging: Mutations that are beneficial early in life (before reproduction) will be selected for even if they are deleterious later in life BirthJuvenile Adult reproduction Post reproduction Death Genes that affect reproduction early in life might have negative health effects later in life Example: high estrogen -> high fecundity when young, but increased chance of breast cancer later in life; tradeoffs between fecundity and ageing

(3) Disposable Soma (a special case of antagonist pleiotropy) Somatic maintenance and repair are metabolically costly Metabolic resources devoted to reproduction are not available for maintenance and repair (tradeoff between reproduction vs repair) Selective advantage to devote resources to reproduction and allocate just enough somatic maintenance to keep the organism alive and good enough condition for as long as needed (for fitness of offspring) Senescence results from accumulation of unrepaired somatic damage

Tests of Theories Effect of extrinsic mortality --> ineffective selection --> –Role of mutation accumulation –Role of Antagonistic Pleiotropy

Tests of Theories Effect of extrinsic mortality Prediction: if extrinsic mortality is reduced and natural selection could act on a population, the rate of aging should go down Evidence: –Organisms in low-risk environments age more slowly –Artificial experiments that selectively bred older individuals, allowing natural selection to act at later life stages, increased life span (cited in Hughes p. 426)

Tests of Theories –Role of Mutation Accumulation –Prediction: because of the accumulation of deleterious mutations (most of which will be recessive), inbreeding depression (due to homozygous recessive alleles coming together) should increase with age. Genetic variance and dominance variance should also increase (because of the new recessive mutations) –Evidence: see Hughes, p A few studies support this prediction. Further studies are needed to conclusively test this hypothesis.

Tests of Theories –Role of Antagonistic Pleiotropy –Prediction: selection on enhanced late life reproduction should select against early- life reproduction –Evidence: see Hughes, p Several studies support this prediction

Test of Theories Based on current evidence, it appears nearly certain that antagonist pleiotropy is a cause of senescence, while mutation accumulation likely contributes

Mechanistic Causes of Ageing: How does ageing occur (physiologically)? We talked about deleterious mutations accumulating-and not getting selected out (via MA and AP); what mutations are accumulating? Which traits are affected by mutations? Which traits are experiencing tradeoffs? Hundreds of theories Oxidative Stress Other types of Stress Signal transduction pathways Role of Diet

Mechanistic Causes: Oxidative Stress Other types of Stress Signal transduction pathways Role of Diet (not well understood) –dietary restriction and lifespan

Mechanistic Causes: Oxidative Stress Ageing is a consequence of cellular damage caused by reactive oxygen species (ROS) ROS generation in animals occurs mainly within mitochondria, where more than 90% of oxygen used by cells is consumed (as an electron acceptor during respiration)

Production of Free Radicals Electrons escape from the electron transport chain These electrons latch on to oxygens, creating superoxides and peroxides These free radicals causes cellular damage

Several enzymes (antioxidants) such as superoxide dismutase (SOD) and Catalase (CAT) will convert the free radicals into less harmful products

Evolution at genes that code for these enzymes have been found

Tests of the Oxidative Stress Theory: Artificial selection experiment: selection for late life reproduction in Drosophila resulted in populations with increased life span and increased resistance to oxidative stress. Selection acted to increase gene expression of SOD or CAT genes Transgenic experiment: overexpression of SOD genes resulted in lifespan increases (Table 1, next slide)

Transgenic and mutant studies that examined effects of over-expression of single genes on Lifespan

Evolutionary changes that would mitigate Oxidative Stress Evolution of genes that mitigate oxidative stress (SOD, CAT) Reduce damage by reducing amount of ROS (free radical) production –Increase respiration efficiency Repair of oxidative damage (Example: methionine sulfoxide reductase--increased gene expression led to longer lifespan)

Mechanistic Causes: Oxidative Stress Other types of Stress Signal transduction pathways Dietary restriction and lifespan

Mutations in signal transduction pathways were found to extend lifespan in yeast, C. elegans, and D. melanogaster Insulin signaling pathway: mutations that decrease signaling through this pathway lead to increased longevity (and sometimes nonreproductive-- tradeoff)

Mechanistic Causes: Oxidative Stress Other types of Stress Signal transduction pathways Dietary restriction and lifespan (talk about this in the next lecture when I discuss sirtuins)

Role of Diet Dietary restriction (DR) has been found to increase life span in many organisms Caloric Reduction by 30% greatly increases lifespan Mechanism is not fully understood HYPOTHESIS: DR affects insulin/IGF pathway that regulates a trade-off between fecundity and longevity