Evolution of Aging

Question 1

Overall Question in lecture

Answer 1

Why do individuals organisms age and die –> Organisms are young + healthy early –> Why change in phenotype to get less fit?

Question 2

Senescence

Answer 2

Deteriorative changes that occur in an individuals with increasing age

Decline in age specific survival probability AND decline in age-specific reproductive rates
- Survival/reproduction sucess decreases in individual as lifespan plays out

Question 3

Why study aging

Answer 3

Study because it is relevant to people BUT humans are not the only things that get old

Question 4

Decline in age-specific survival probability

Answer 4

Means that the probability of surviving to the next year decreases as you get old

NOT fixed probability and die because go through rounds of probability – it is that the probability decreases over time

Question 5

Senescence in evolutionary biology

Answer 5

Senescence is part of a broader subject in evolutionary biology – PART of “Life history evolution”

Life history evolution –

Question 6

Life history

Answer 6

Life History phenomena relate to the pattern of investment an organism makes in growth and reproduction
- Deals with life cycle timing + investment of development

Example – Including age at first reproduction,
the duration of reproductive
periods, number and size and offspring, seasonal timing of life cycle, and life span

Question 7

Senescence + NS

Answer 7

Senescence inhertiley involves decrease in survival and or reproduction –> S/R is a key part of our fitness –> Should NS work against aging since aging decreases fitness over time = shouldn’t get old

Question 8

Senescence in nature

Answer 8

Senescence is ubiquitous in nature

Seen everywhere in nature – All animals = have age specific decrease in S/R successes = all organisms senesce through time

Question 9

Variation in Senescence

Answer 9

There is a lot of variation among species (Senescence is everywhere but have lots of variation)
- Evolutionary biology = looks at causes and consequence of varaition

Example:
1. Plants have lots of varaition – Flower that ages fast (2 week Cycle) VS. Pine tree (can be over 400,000 YO)

2. Arthropods – Many flies are short lived organisms (Adults live one day but total egg and adult live one year) Vs. Dropsphilla (lives 40 days total)
   
   • Secadas = live for 17 years
3. Mammals have varaition – mice live less than a year Vs. Boehead whale can live over 200 years Vs. greenlung sharks = oldest living vertabtrey (700 years based on growth rates)
   
   • In whale they dound harpoon that was made a long time ago = know how old they are
4. Spiders – some live 25 years and others can live 40 years

Overall: Have huge variation (weeks/days - years) – variation in aging needs to account fir the diversity we see

Question 10

Question about variation

Answer 10

Why do some people live longer than others – BIG interest in biomedical researchers

Example – Oldest person died at 122 and she smoked everyday until 117

Question 11

Aging across populations and time

Answer 11

Image: Life expetetcy in humans in different countires across time periods – have varaition across popultioms amd varaition across time
- 1950 = lots of varaition but have countries catching up
- See big change over time (<30 in 1800s –> 60 in 2012) – The change is NOT genetic it is change in conditions – expect genetic and environmental effects

Question 12

Variation in aging + Environment

Answer 12

How much varaition is due to envirnment – know a lot of varaition is environmental (expect genetic and environmental effects)

Example – GDP vs. Life expectancy has a strong relationship – once reach certain level of economic stability Life expectancy increases

Question 13

Life span vs. Life expectancy

Answer 13

NOT the same things

Life span = How long individuals survive

Life expectancy = it’s a statistically derived demographic measure of the amount of time you likely have left at a given age
- Look at demography of popultion and see average amount of life indiviual has left (often look at since brith)

Variation in LE does not always follow varaition in Lifespan

Question 14

Example LE

Answer 14

If LE ar birth = 30 –> that does NOT mean that 30 was elderly and aging

Means that you are likely to die by 30 for any cause (many ways to die that doesn’t involve aging/deteriorating)
- Know that if you are not killed by other things = you are likley to live to 60 before deteriorate and die

LE of 30 = just means that early mortality was higher – in most cases if you made if you adulthood you were still expected to live well into 60s

Question 15

Low LE in humans + Lifespans

Answer 15

Low like expectancies in human history are not necessarily driven by low life spans

Question 16

Why does our fitness decrease as we get older (overall)

Answer 16

Two classes of Explanations:
1. Purley physiological “rate of living thoery”

2. Evolutionary perspective (NOT ME)
   
   • Mutation accumalation
   • Antagpnistic pleitropy

Question 17

Rate of Living theory

Answer 17

Overall: Contends that senescence is simply the result of wear and tear at the metabolic level
- Aging = accumulation of byproduct of metabolism needed to survive
- If biochemistry is not perfect = increase in entropy and problems over time = decrease fitness = die
- Process creates harmful byproducts or build errors in DNA or proteins = explains aging

Question 18

Why do we age in Rate of Living theory

Answer 18

Aging occurs as the inevitable by product of physiological processes

Metabolic processes can’t be perfect, so the damage done by things like replication errors, misfolded proteins, toxic metabolic intermediates, production of free radicals, etc. just build up through time and eventually overwhelm the organism

Question 19

Two key predictions in the rate of living theory

Answer 19

1. If lifespan is a by-product of metabolism, we should expect strong relationships between lifespan and metabolic rate –within and among species – organisms should die after a given amount of “metabolizing”
   
   • Inevitable limit to metabolism that organisms can do
   • Means that the lifespan is set by the metabolism rate
2. If lifespan is set by physiological constraints, organisms should be doing “the best the can,” and we should expect no genetic variance in populations for lifespan
   
   • If inevitable problem that can’t get rid = should NOT have variation for improving aging – doing the best we can reapring and removing byproduct = no variation in life span
   • All varaition is environmental

Question 20

Testing relationship between lifespan and metabolic rate (First prediction)

Answer 20

Looking at metabolism rate vs. maximum lifespan

There are definitely some relationship between metabolic rate and lifespan BUT only explains 20-40% of variation in lifespan
- Lower metabolism rate = higher max lifespan
- Not enough to explain variation in lifespan

IF look at the metabolism across entire lifespan – if consistent with prediction then expect to metabolize a certain amount and die BUT see overall energy expenditure is different in difefrent mamalian orders = not just reaching a ceratin amount of metabolism = other things explain varaition

Question 21

What type of trait is lifespan

Answer 21

Life span is likely a quantitative trait

Question 22

Testing second prediction in rate of living theory

Answer 22

Looking to see if variation in lifespan can be selected for

Overall: Do a selection experiment –> Do breeders (because quanatative trait) to see if have narrow sense heretibility (additive varaition) –> THEN select for life span

Results: Get strong response – Popultions contain additive genetic variance for lifespan
- Responds readliy to selection = means lots of varaution in genetics in lifespan = NOT at fixation
- IF aging was due to rate of lving theory then means we can’t do better with the alleles that we have and there is no varaition –> Clearly this is NOT the case

Question 23

Physiology in aging

Answer 23

Results = doesn’t mean that physiological processes and accumulated metabolic problems don’t affect aging BUT they tell us that the rate of living is NOT enough to explain the patterns of lifespan variation that we see in nature
- Physiological mechanisms are still important and the subject of a lot of important research

Example mechanisms:
1. Telomerase + telomerase

Question 24

Telomeres + Telomerase in aging

Answer 24

Background: DNA replication has to anchor onto something at end of chromosome before falls off – telemoerase keeps adding telemerase back on

Idea = maybe the length of telemeres that creates different lifespans – if have less telermerase = get shorter = lose coding regions = deteriorate

Telemerse = may play a role – places a limit on ceratin cell types BUT not likley effects span of organisms

In some species incerase in telemere length = plays role in aging provess but relationship is complicated
- May work work the oppersite way in some – some have longer lifespans that have shorter telemeres

Question 25

Varaition in telemerase

Answer 25

There is varaition in telemerase activity = shows we can do better to live longer = against rate of living theory

Question 26

Aging + Mitocondria

Answer 26

Other proposed mechanism of aging = mitocondrial damage
- Mitocondria = critical BUT does oxidataive phosphorylation

Mitocondria mutation rates = 10-20X higher in mtDNA –> have somatic mutations in mitocondria that cause them to do worse = worse cell respiration = age + die

Mitocondria= have high metabolic activity in an oxygen rich setting

Question 27

Somatic mutations + Mitcodnria

Answer 27

When old = have somatic mutations in mitocondria –> set scientisits on hunt to have expliantion of breakdown of mitochondrial genomes
- mtDNA mutations accumalate in humans with age

Test in experiment AND see than hypothesis falls apart
- When looking if mutation rate of mitocondira –> if decrease oxidative stress it doesn’t afefct life span
- Some mutations build in body that cause issues but mitcodnira are not more prone than somatic that cause probelms

END – Causative link is weak – increase oxidative stress and mtDNA mutations does not yeild faster aging

Question 28

Question in evolution of aging

Answer 28

organisms are clearly capable of repairing or preventing molecular and cell damage – why do they stop doing it
- Why stop repairing in 60s but not stoping in younger?

If can do better why don’t we do better?

Question 29

Mutation accumaltion theory

Answer 29

Evolutionary accumulation in popultions - not somatic accumalation within individuals (like mtDNA)
- At population level

OVERALL – NS acts weakly on deleterious alleles that act later in life

IDEA = have increase in deleterious alleles that act later in life because NS is weak to get rid of alelles if act later in life (especially after the 1st round of reproduction – THEN strength of NS decreases)

Question 30

NS acting on alleles that act later in life

Answer 30

Example:

Have individuals that start reproducing at 3 and die at 15
- Probability of survival is the same over time = no age specific decline –> Have less indiviuals at age 15 than 4 but only because 80% Survival rate in each generation

IF add a lethal mutation that kills between 14 and 15 –> Leathal but later in life = NOW can’t live past 14 (all die at 14 not 15) and still start at 3 – 80% probability that all live to 14

NOW – RS = 2.34 –> Kills earlier BUT barley effects fitness (2.4 vs. 2.34)

IF convert to Selection coefficient
Before S = 1
New Fitness = 0.96 –> S = 0.04 (Small S)

S = 0.04 –> NOT string selection against lethal if occurs later in life = NS ability to get rid of deleetrious with affect later in life = weaker = get increase in deleterious alelles when affect later in life

Question 31

Reproductive success

Answer 31

Proxy for fitness

RS = Frequencey of indiviudal survivors X expected Reproductive success for individuals

Question 32

Mutation Accumulation + Mutation selection balance

Answer 32

Mutation accumalation theroy – comes down to muation selection balance

q> = Square root of (u/S)

Overall: The later a deleterious alelle the lower S will be = Higher q>
- If after maturity = S decreases EVEN if it is lethal –> THEN q (freq of deleterious) = increases for mutation that acts late
- Higher q for mutation that acts late than mutation that acts early –> Early can accumalate at higher frequnecey and manifest themselves
- Late acting alelles may be essentially neurtal

Question 33

Other example for mutation accumation

Answer 33

Plot – Inbreeding depression at different ages
- Can see where fitness problems come into play

Results: Over time the strength of inbvreeding issues increases
- Inbreeding – increases the probability of producing deleterious recessive phenotype

Plots shows that the frequencey of deleterious is hgigher in popultion if late than the frequnecey of deleterious earlier in life
- In breeding effects that show up later on life are more common and stronger

Question 34

Effect of inbreeding

Answer 34

• Inbreeding – increases the probability of producing deleterious recessive phenotype (if have rare allele at q frequnecey –> THEN q^2 is even lower –> with random mating then q^2 is low – BUT if mate related individuaks then q increases –> so q^2 increases )
  
  • If mate with siblings = siblings are likley to have the same allele = probability of deleterious homozygous phenotyoe increases

***Late acting allles with stringer affects are mianatined at higher frequncies

Question 35

What causes inbreeding depression

Answer 35

Inbreeding depression is caused by the
expression of deleterious recessive mutations that usually don’t occur as
homozygotes

Question 36

Pleiotropy

Answer 36

Allelic variation influencing more than one
phenotype
- Allele at one locus has effect on more than one trait

Question 37

Antoagonists pleitropy

Answer 37

Occurs when the fitness consequences of the affected traits run in opposite directions
- Poses a major constraint on evolution
- implies effects have antagonies for fitness –> increase of one compoennet of fitness and decreases another component of fitness

Question 38

Antoagonists pleitropy + Evolution

Answer 38

Poses a constraint on evolution –> Can’t optimize for all things at once
- gene affects trait in both ways

Example – Gall size –> select for opposite directions

Question 39

Antoagonists pleitropy + aging

Answer 39

There is good reason to believe that some allelic variation maybe beneficial early in life but deleterious later in life
- Much of this might have to do with
energy allocation - “disposable soma hypothesis”

***You can put your effort into reproduction or maintenance, but you can’t optimize both at the same time

Question 40

Where is AP common

Answer 40

Might be common for traits that affect fitness at different points in life –> helps survive early but fitness cost later in life

Question 41

Idea in AP

Answer 41

Idea of balancing self repair and reproductive output

Idea that you can put effort into reproduction early OR you can put in effort to marinating self in the long term but you can’t do both
- Cost to maintain longevity through time

***When allelic variation like this exists the early acting part of the tradeoff likley to win out –> benfit of early outweigh negitive affect late in life

Question 42

Example of Balance in AP

Answer 42

Example – mature at 3; 80% SR; Due at 15

Expected RS = 2.42

Look at allele that causes you to die at 10 (now have 2/3 lifespan) BUT you reprduce 1 year earlier = reproduce at 2 Years Old BUT die at 10

NOW lifetime Reproductive sucess = 2.60 –> you are killed earlier BUT little benefit in reproduction = This is selectively favored

Here a mutation that cuts your life in half is selectivley favored because of an increase in early reproductive

SHOWS that beneficial alelles that affect early win outweigh neg that effect late –> Early acting part of the tradeoff is likeley to win

Question 43

Example of Antagonostic pleitropy

Answer 43

Example – Gene in drosphilla –> lifespan expanding gene

Overall: Reproductive sucess vs. Longevity is commonly found in nature

Reason that the allele has not swept through the popultion is because carrying gene in homozygous that decreases fecundity/Reproductive sucess – Number of offspring for each female is small when you have the lifespan expanding gene = hasn’t swept through
- Have tradeoff with fecundity

Expalins how/why have allelic variation

Question 44

What wins in AP

Answer 44

Early acting part of the tradeoff is likely to win – if beneficial is early and deleterious is late then selectively favored
- NS can’t work to get rid of problem alleles late –> favors increase if benefit is early even if allele kills you earlier

Question 45

Lifespan evolving in nature Example

Answer 45

Look at Possums

Question 46

Why are possums used in life history evolution

Answer 46

Opposums have been of interst in life history evolution because they are very short-lived for mammals of their size – they don’t live much longer than two years
- Small lifespan + make many babies in short life

***High mortality BUT they reproduce early and have large litters

Question 47

Extrinsinc mortality

Answer 47

Things that make you die other than your own genetic and physiological issues – predators, pathogenic disease, exposure, cars, etc
- Anything making you die other than your own body

Question 48

Evolutionary models of aging + Extrinsic mortality

Answer 48

Both of the evolutionary models of aging that senescence should be faster in populations with high extrinsic mortality (the book calls it ecological mortality)

Why – Both models = high extrinsic mortality = ability fo NS to fight against aging decreaes
- Effect of NS decreases = constraint = expect to age faster

Question 49

Why age fast if high extrinsic mortality in both models

Answer 49

If you are likely to die young from extrinsic causes:

1. Selection against late-acting mutations is even weaker because fewer individuals even get the chance to express them
   
   • Because almost no one lives long enough to express them –> if don’t live = won’t manifest
2. Early investment in reproduction become even more strongly favored – you better have babies before you get eaten
   
   • Tips the balance between early vs late selection even more –> more benefical to reproduce early if likey to be killed early = invest in reproduction earlier because increase fitness

Question 50

Life history of possums on mainland vs. possums on predator free island

Answer 50

Experiment – Have possums living on island without natural predators

Background: Possums have high extrinsic mortality because they are killed by predators

Without predators = decrease extrinsic mortality = can affect lifespan

Follows posums on island vs. mainland to look at lifehistory + aging

Results: Found that the possums on island live X2 l;onger
- NOT kust because not getting killed but they age more slowley on the island – have difference in reproduction stradegy + investment in reproduction evolved
- Mainland = invest in developing early in 1st round because don’t live to second round
- Island = reproduce the same amount in both rounds –> even resource allocation (repduce more consistently in later years)

Question 51

Measuring physical effects on aging in possums

Answer 51

Looked at the brittlness of tendons

Found:
Mainland decrease in felxibility increases at faster rate in time Vs. slower rate in the island
- Possums live longer on island because are slower to age based on change in NS
- The island possum bodies have fewer signs of physical aging

Question 52

Result of possum study

Answer 52

The results of the island opossum study are strongly consistent with evolutionary predictions for aging

Senescence is a quanative trait that can evolve just like any other
- Explaining constraint in aging = explaining constraint on NS

We get old and die not because of absolute physical or biochemical constraints, but rather because of evolutionary constraints
- Not physical – gene can do better but because of evolutionary constraint on genes increases over time

Question 53

Solving the problem of aging

Answer 53

The problem of aging is biologically solved BUT not yet medically solved
- Know why we get old (because of mutation accumulation + antagonistic pleiotropy) BUT not medically solved
- medical solution needs to come out of biologic explanation

Question 54

Koch example + solving aging

Answer 54

Koch biologically solved the question of contagious diseases with the Germ Theory of Disease- and the medical solutions developed explicitly from that understanding
- Explained diease by explaining how pathogens work –> couldn’t solve until knew germ theory (clinical solution comes out of understanding)

The same is going to be true of medical solution to aging – nuanced, multidimensional approaches that recognize that any one cell or molecular level mechanism for senescence is not going to offer a panacea
- Understanding of clinical for aging comes from causes –> There is no one reason (not one gene) – not one small fix have a lot of reasons for aging
- We can see constraints on what we can do to increase lifespan (not one clincal fix) = clincal needs to be nuanced to handle multi faceted causes of aging