1. Life History Evolution I. Components of Fitness and Trade-Offs II. Aging

2. Life History Evolution I. Components of Fitness and Trade-Offs II. Aging Aging is a dirty little trick of nature. Oh sure, it's fun getting older when you are maturing from adolescence through young adulthood. But the fun stops as you begin to senesce... when your fertility and probability of survival decline later in life.

3. Life History Evolution I. Components of Fitness and Trade-Offs II. Aging Aging is a dirty little trick of nature. Oh sure, it's fun getting older when you are maturing from adolescence through young adulthood. But the fun stops as you begin to senesce... when your fertility and probability of survival decline later in life. If senescence reduced fitness, it should be selected against. What is counteracting the benefit of living forever?

4. Life History Evolution I. Components of Fitness and Trade-Offs II. Aging A. The Rate of Living Hypothesis 1. Assumptions

5. Life History Evolution I. Components of Fitness and Trade-Offs II. Aging A. The Rate of Living Hypothesis 1. Assumptions This makes one major assumption - that selection has already honed DNA and tissue repair to the maximum value. If there is no genetic variation for better repair, then selection cannot improve upon this trait, and we are doomed to our fate.

6. Life History Evolution I. Components of Fitness and Trade-Offs II. Aging A. The Rate of Living Hypothesis 1. Assumptions This makes one major assumption - that selection has already honed DNA and tissue repair to the maximum value. If there is no genetic variation for better repair, then selection cannot improve upon this trait, and we are doomed to our fate. The rate at which we age should be a function of metabolic rate. The faster the metabolic rate, the faster the production of toxic metabolites that will corrupt DNA replication and protein synthesis, and the shorter the generation time. Organisms with low metabolic rates will produce less toxic waste per unit time and will have longer lives.

7. Life History Evolution I. Components of Fitness and Trade-Offs II. Aging A. The Rate of Living Hypothesis 1. Assumptions This makes one major assumption - that selection has already honed DNA and tissue repair to the maximum value. If there is no genetic variation for better repair, then selection cannot improve upon this trait, and we are doomed to our fate. The rate at which we age should be a function of metabolic rate. The faster the metabolic rate, the faster the production of toxic metabolites that will corrupt DNA replication and protein synthesis, and the shorter the generation time. Organisms with low metabolic rates will produce less toxic waste per unit time and will have longer lives. Essentially, all organisms should expend the same amount of energy/unit body mass in their lifetime. Burn it fast, die young.

8. Should all be about equal, but there are 5 statistical outliers

10. Life History Evolution I. Components of Fitness and Trade-Offs II. Aging A. The Rate of Living Hypothesis 1. Assumptions 2. Tests Among quadrapedal mammals, there is a weak correlation between metabolic rate and lifespan. But include bats and the relationship fails… bats have a very high metabolic rate, but a long lifespan. Similar life span across a 1000x difference in body size.

11. Life History Evolution I. Components of Fitness and Trade-Offs II. Aging A. The Rate of Living Hypothesis 1. Assumptions 2. Tests Selection in fruit flies revealed that you COULD select for longer lifespan. This would only support the RL model if there was also a decline in metabolic rate (Assumption is no variation in repair enzymes). There was, but only in the first 15 days, in a lifespan that lasted over 60 days. (Correlated better with reproductive schedule, as shown)

12. A. The Rate of Living Hypothesis B. Cell Division Hypothesis

13. A. The Rate of Living Hypothesis B. Cell Division Hypothesis Maybe it's not metabolic rate, but the rate/amount of cell division.

14. A. The Rate of Living Hypothesis B. Cell Division Hypothesis Maybe it's not metabolic rate, but the rate/amount of cell division. The more divisional cycles, the more chance for a somatic mutation.

15. A. The Rate of Living Hypothesis B. Cell Division Hypothesis Maybe it's not metabolic rate, but the rate/amount of cell division. The more divisional cycles, the more chance for a somatic mutation. Also, most cells have a prescribed number of divisions that they can perform. After this, the cell dies. Longer cell life, and more divisional cycles, might correlate with longer organismal life. What influences the number of divisions a cell can perform?

16. A. The Rate of Living Hypothesis B. Cell Division Hypothesis Telomeres: - Telomeres have long repeat sequences. - With each replication cycle, a short sequence is lost from the end of the chromosome (except in stem cells and cancer cells, where the enzyme telomerase reconstructs these sequences).

17. A. The Rate of Living Hypothesis B. Cell Division Hypothesis Telomeres: - Telomeres have long repeat sequences. - With each replication cycle, a short sequence is lost from the end of the chromosome (except in stem cells and cancer cells, where the enzyme telomerase reconstructs these sequences). - The shortening of telomeres correlates with aging... and organisms may live longer if their telomeres are longer and their cells are capable of more cell divisions. But in comparisons of wild organisms, no consistent relationship between telomere length and survivorship. Genetically engineered to over-express telomere binding protein

18. Relationship between mean telomere length (± SEM, measured by T/S ratio using qPCR) and age at measurement in 99 zebra finches. Heidinger B J et al. PNAS 2012;109:1743-1748 ©2012 by National Academy of Sciences

19. (A) Mean change in telomere length (measured using qPCR) between 25 d and 1 y (± SEM) for zebra finches in each reproductive treatment group. Heidinger B J et al. PNAS 2012;109:1743-1748 ©2012 by National Academy of Sciences

20. Relationship between natural log-transformed relative telomere length (T/S ratio from qPCR) at 25 d and lifespan in zebra finches (n = 99). Heidinger B J et al. PNAS 2012;109:1743-1748 ©2012 by National Academy of Sciences

21. Relationship between mean (± SEM) telomere length (T/S ratio from qPCR) and age at measurement (first sample, shown as year = 0, was collected at 25 d) in zebra finches in three lifespan categories. Heidinger B J et al. PNAS 2012;109:1743-1748 ©2012 by National Academy of Sciences Green = mean lifespan of 1.6 yrs Red = mean lifespan of 3.6 yrs Black = mean lifespan of 6.3 yrs

24. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis Telomeres: - p53 is a tumor suppressor. - Tyner (et al. 2002): - mice who were deficient in p53 were susceptible to cancer (no repair). - They also isolated a strain that had overproduction of p53. These mutants had a reduce susceptibility to cancer, but they aged more rapidly than normal mice.

25. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis Telomeres: - p53 is a tumor suppressor. - Tyner (et al. 2002): - mice who were deficient in p53 were susceptible to cancer (no repair). - They also isolated a strain that had overproduction of p53. These mutants had a reduce susceptibility to cancer, but they aged more rapidly than normal mice. - Tyner explained this as a function of the effect of p53 on stem cells. Stem cells continually produce new cells that can repair damaged tissues. If they are shut down by overproductive p53, they stop dividing. - Then, tissue damage or even simple cell death goes unrepaired or uncompensated. So, normal mice have longer life spans and intermediate levels of p53 - enough to reduce cancer rates while not shortening the rate of cell division too much... So, aging is the result of a balance: You need new cells, but cell divisions allow for mutations...

26. Telomere shortening activates p53 and drives formation of epithelial cancers through gene amplification and deletion. Artandi S E, and DePinho R A Carcinogenesis 2009;31:9- 18 © The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

27. END OF MATERIAL FOR EXAM

28. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis C. Evolutionary Theory of Aging 1. Ideas variation in lifespan exists and can be selected for Why isn't it selected for in natural populations? The Evolutionary Theory: - aging isn't caused by the direct effects of cell and tissue damage - rather it's the failure to repair the damage completely - this might be caused by deleterious mutations, or trade-offs with reproduction

29. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis C. Evolutionary Theory of Aging 1. Ideas 2. The Mutation Accumulation Hypothesis Mutations that exert their effects early in life impose a very significant cost to reproductive success (fitness) However, if the expression of the same mutation can be delayed, it's effect will wane; if the effect is delayed to after reproduction, the mutation is invisible to selection and can drift to fixation. Medewar (1952) hypothesized that aging was the cumulative effects of these delayed mutations, which cripple cell function in the end. Experiments show that one type of mutation, a mutation in repair enzymes that fix base mismatches, are only expressed post-reproductively.

30. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis C. Evolutionary Theory of Aging 1. Ideas 2. The Mutation Accumulation Hypothesis Hughes et al.(2002) use a clever approach involving inbreeding depression. If deleterious alleles are expressed later in life, then the severity of inbreeding depression should be more dramatic later in life - even though the frequency of homozygosity should be the same. Created 10 inbred lines. Then conducted all 100 possible crosses, including self-crosses (continued inbreeding). Measured reproductive success of offspring at various ages. The difference in reproductive success between outbred and inbred lines did increase with age.

31. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis C. Evolutionary Theory of Aging 1. Ideas 2. The Mutation Accumulation Hypothesis 3. Trade Offs - the Antagonistic Pleiotropy Hypothesis - If a gene exerted a positive effect on early reproduction, it would be selected for even if it also led to negative consequences later in life. - In C. elegans, the age-1 gene has two effects. - 1) It increases reproductive output at a young age, and - 2) it causes senescence. Mutations in the gene increase lifespan by 80%.

32. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis C. Evolutionary Theory of Aging 1. Ideas 2. The Mutation Accumulation Hypothesis 3. Trade Offs - the Antagonistic Pleiotropy Hypothesis - If a gene exerted a positive effect on early reproduction, it would be selected for even if it also led to negative consequences later in life. Early reproduction creates the ‘compound interest effect’ on lifetime fitness

33. Reproduce at Age 3, live to 14:

34. Reproduce at Age 3, live to 16 – increase lifespan: Live to 14 = 2.340

35. So, all other things being equal, there is stronger selection for early reproduction than extending lifespan. … Remember? Reproduce at Age 2, live to 10 – reproduce earlier, die younger: Live to 14 = 2.340 Live to 16 = 2.419

36. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis C. Evolutionary Theory of Aging 1. Ideas 2. The Mutation Accumulation Hypothesis 3. Trade Offs - the Antagonistic Pleiotropy Hypothesis - If a gene exerted a positive effect on early reproduction, it would be selected for even if it also led to negative consequences later in life. - In C. elegans, the age-1 gene has two effects. - 1) It increases reproductive output at a young age, and - 2) it causes senescence. Mutations in the gene increase lifespan by 80%. Again, early reproduction really has a disproportionate affect on lifetime reproductive success. Even if a later effect is negative, even if the later effect causes DEATH, it's tough to outweigh the positive effect on fitness of early reproduction. Once you are old, if you've reproduced, then your descendents are copying your genes faster than you could by reproducing yourself....

37. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis C. Evolutionary Theory of Aging 1. Ideas 2. The Mutation Accumulation Hypothesis 3. Trade Offs - the Antagonistic Pleiotropy Hypothesis 4. Why such a long post-reproductive period in human females?

38. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis C. Evolutionary Theory of Aging 1. Ideas 2. The Mutation Accumulation Hypothesis 3. Trade Offs - the Antagonistic Pleiotropy Hypothesis 4. Why such a long post-reproductive period in human females? - most animals reproduce until they die... not humans.

39. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis C. Evolutionary Theory of Aging 1. Ideas 2. The Mutation Accumulation Hypothesis 3. Trade Offs - the Antagonistic Pleiotropy Hypothesis 4. Why such a long post-reproductive period in human females? - most animals reproduce until they die... not humans. - why, and how could this be adaptive? (think Kin Selection)

40. A. The Rate of Living Hypothesis B. Cell Division Rate Hypothesis C. Evolutionary Theory of Aging 1. Ideas 2. The Mutation Accumulation Hypothesis 3. Trade Offs - the Antagonistic Pleiotropy Hypothesis 4. Why such a long post-reproductive period in human females? - most animals reproduce until they die... not humans. - why, and how could this be adaptive? (think Kin Selection) - If a woman increases the reproductive success of her offspring (which may be numerous), she can increase her fitness more than by having one more offspring, herself.

41. Lahdenpera et al. 2004. Nature 428:178-181. - study of Finnish and Canadian women in 17-1800's, using demographic records. - women with longer life had more grandchildren. (Not producing them later, though.) Finland Canada

42. Lahdenpera et al. 2004. Nature 428:178-181. - study of Finnish and Canadian women in 17-1800's, using demographic records. - women with longer life period had more grandchildren. - the presence of a mother increased a daughters fecundity and earlier age of rep.

43. Lahdenpera et al. 2004. Nature 428:178-181. - grandmothers increase probability of grandchildren survival.

44. Lahdenpera et al. 2004. Nature 428:178-181. - grandmothers increase probability of grandchildren survival. - once children stop reproducing, and grandchildren's survival is assured, the mortality rate of grandparents increases dramatically. So, in 17-1800's, the presence of grandparents increased reproductive rate of daughters and survival of grandchildren, and thus increased their own post-reproductive fitness.