Evolution of Aging Flashcards
Overall Question in lecture
Why do individuals organisms age and die –> Organisms are young + healthy early –> Why change in phenotype to get less fit?
Senescence
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
Why study aging
Study because it is relevant to people BUT humans are not the only things that get old
Decline in age-specific survival probability
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
Senescence in evolutionary biology
Senescence is part of a broader subject in evolutionary biology – PART of “Life history evolution”
Life history evolution –
Life history
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
Senescence + NS
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
Senescence in nature
Senescence is ubiquitous in nature
Seen everywhere in nature – All animals = have age specific decrease in S/R successes = all organisms senesce through time
Variation in Senescence
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)
- 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
- 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
- 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 about variation
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
Aging across populations and time
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
Variation in aging + Environment
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
Life span vs. Life expectancy
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
Example LE
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
Low LE in humans + Lifespans
Low like expectancies in human history are not necessarily driven by low life spans
Why does our fitness decrease as we get older (overall)
Two classes of Explanations:
1. Purley physiological “rate of living thoery”
- Evolutionary perspective (NOT ME)
- Mutation accumalation
- Antagpnistic pleitropy
Rate of Living theory
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
Why do we age in Rate of Living theory
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
Two key predictions in the rate of living theory
- 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
- 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
Testing relationship between lifespan and metabolic rate (First prediction)
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
What type of trait is lifespan
Life span is likely a quantitative trait
Testing second prediction in rate of living theory
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
Physiology in aging
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
Telomeres + Telomerase in aging
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
Varaition in telemerase
There is varaition in telemerase activity = shows we can do better to live longer = against rate of living theory
Aging + Mitocondria
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
Somatic mutations + Mitcodnria
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 in evolution of aging
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?
Mutation accumaltion theory
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)
NS acting on alleles that act later in life
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
Reproductive success
Proxy for fitness
RS = Frequencey of indiviudal survivors X expected Reproductive success for individuals
Mutation Accumulation + Mutation selection balance
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
Other example for mutation accumation
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
Effect of inbreeding
- 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
What causes inbreeding depression
Inbreeding depression is caused by the
expression of deleterious recessive mutations that usually don’t occur as
homozygotes
Pleiotropy
Allelic variation influencing more than one
phenotype
- Allele at one locus has effect on more than one trait
Antoagonists pleitropy
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
Antoagonists pleitropy + Evolution
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
Antoagonists pleitropy + aging
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
Where is AP common
Might be common for traits that affect fitness at different points in life –> helps survive early but fitness cost later in life
Idea in AP
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
Example of Balance in AP
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
Example of Antagonostic pleitropy
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
What wins in AP
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
Lifespan evolving in nature Example
Look at Possums
Why are possums used in life history evolution
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
Extrinsinc mortality
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
Evolutionary models of aging + Extrinsic mortality
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
Why age fast if high extrinsic mortality in both models
If you are likely to die young from extrinsic causes:
- 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
- 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
Life history of possums on mainland vs. possums on predator free island
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)
Measuring physical effects on aging in possums
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
Result of possum study
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
Solving the problem of aging
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
Koch example + solving aging
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
