lecture 2 mechanisms of aging

Question 1

who started the concept of biology of aging?

Answer 1

August Weismann

Question 2

What did August Weismann propose?

Answer 2

he proposed the wear and tear hypothesis and argued that death was necessary for selection to occur

• there is not a specific mechanism –> cells and processes just slow down

death is adaptive and necessary for natural selection to occur

aging as a programmed trait

Question 3

wear and tear hypothesis: senescence

Answer 3

organismal aging analogous to aging of mechanical devices

Question 4

wear and tear hypothesis: Death

Answer 4

natural selection to eliminate the old and worn out

-turnover necessary for evolution

Question 5

wear and tear hypothesis: mechanism

Answer 5

unclear but argued it might involve limitation of a number of cell divisions

Question 6

Rate of living theory by Rubner and Paul

Answer 6

-higher metabolic rate –> shorter lifespan (this is not the complete answer)

-thought higher levels of damage occurred

-larger animals outlive smaller animals
-larger animals have lower metabolic rates
-organisms that metabolize oxygen more rapidly –> higher energy expenditure = shorter lifespan

-maximum lifespan inversely proportional to basal metabolic rate

Question 7

Has there been evidence found to support the rate of living theory?

Answer 7

A simple link between metabolic rates, oxidative damage and lifespan is NOT supported

-only recently been debunked

there is reduced extrinsic mortality as a consequence of larger size, which may alter the optimal investment in somatic maintenance. lower predation risk could lead to investment in somatic maintenance and repair being more profitable

essentially- if you are bigger then there is less stress on you, you will not get eaten and could put more energy into maintenance

Question 8

who considered aging the unsolved problem of biology?

Answer 8

Sir Peter Medewar - father of transplantation

-Senescence lowers fitness

Question 9

Mutation accumulation theory

Answer 9

• accumulation of DNA damage is not selected for or against because they are past reproductive age

-no selective pressures on an aging population

-mutations in genes expressed later in life would not be affected by natural selection
-beyond reproductive age, evolutionary benefit of a long lifespan is negligible

**antagonistic pleiotropy

Question 10

long-lived and short-lived species mutation frequency?

Answer 10

mutation frequency among cells from longer-lived species is more stable than those of shorter-lived species and therefore also points toward greater genome maintenance capacity

-suggests that long-lived species are capable of processing DNA damage in more accurate ways than short-lived species

Question 11

primary lung fibroblast isolated from young adults experiment

Answer 11

bleomycin treatment

frequency of mutation was higher in mice and lowest in humans and naked mole rats

Question 12

Cellular Senescnece

Answer 12

Cultured Cells have a limited number of cell divisions

Question 13

hayflick limit

Answer 13

cells give out after a certain number of divisions

hela cells can perpetuate for a long time

e.g 20-30x passed would be a hayflick limit

Question 14

what did leonard hayflick study?

Answer 14

cell replication

-hayflick limit

Question 15

telomere theory

Answer 15

telomeres
-protect ends of chromosomes
-progressively get shorter as cells divide

-ends of chromosomes lose parts of DNA, non-coding regions on the end
-gets to a point where the parts getting lost or affected have something to do with the loss of DNA or even cell division and this is bad

Question 16

Telomerase

Answer 16

enzyme that adds nucleotides to telomeres
-normal cells do not have telomerase
- if we could add telomerase you could essentially make a cell immortal
-germ cells are telomerase positive

Question 17

cells that are important to aging typically don’t _____?

Answer 17

differentiate/ replicate

e.g. nervous tissue, skeletal muscle, cardiac cells

-neurons, muscle fibers, and cardiac cells don’t replicate — telomerase only affects differentiating cells so we need a different mechanism to understand aging or senescence of these cells

Question 18

protein misfolding

Answer 18

proteins need to be folded in a proper way, there is a system in the cells that can identify and remove misfolded proteins –> but no system is perfect. As we age things escape and things accumulate

e.g. amyloid Alzheimer’s, and tao are all neurodegenerative disorders caused by misfolded proteins

Question 19

diseases and their matching misfolding proteins

Answer 19

Alzheimer’s disease -> amyloid-B-> abnormal protein misfolding->neurodegeneration

Parkinson’s disease -> a-synuclein-> abnormal protein misfolding->neurodegeneration

Huntington’s disease (HD, SCAs) -> huntingtin axis

Amyotrophic lateral sclerosis-> TDP-43 SOD1

Frontotemporal lobar degeneration-> Tau

Question 20

Free Radical theory of aging by Denham Harmon

Answer 20

-physiological iron (and other metals) cause reactive oxygen species (ros) to form in the cell

-ROS damaging nearby structures

free radicals
-atoms with unpaired electrons
-HIGHLY reactive

proposed that iron was a culprit–> during the metabolism of iron, ROS are being generated which interact with and damage lipids, DNA, etc.–> This creates aging
-electrons escape from metabolic processes

-oxygen free radicals are generated in the mitochondria

Question 21

oxidative stress theory of aging

Answer 21

oxygen radicals
-created during respiration
-oxidative damage to macromolecules
-can damage every cell constituent
-damage that increases with age
-causing senescence (0rganismal aging)

-generated during electron transport, results in cellular dysfunction and cellular senescence

Question 22

free radicals and ROS

Answer 22

free radicals unpaired electron, metals, oxygen, highly reactive

-the unpaired electron makes it highly reactive to other molecules

oxygen radical
-result of respiration (ETC)
-unpaired electron

superoxide

Question 23

generation of free radicals

Answer 23

occurs during the generation of ATP
- ETC
-SOD and GPX are enzymes that combat the oxygen radicals –> enzymes convert to free radicals to water

creates a lot of ATP but also free radicals

Question 24

lipid peroxidation

Answer 24

increases with age
-4-hydroxy-2-nonenol (4-HNE)

-oxidative degradation of lipids, free radicals steal electrons from the lipids in the cell membrane = cell damage

Question 25

protein oxidation

Answer 25

increases with age

-carbonyl derivatives on lysine, arginine, proline, histidine, cysteine, threonine residues

Question 26

nucleic oxidation

Answer 26

increases with age
8-oxo-2-deoxyguanosine (oxo8dG)

oxo8dG makes up approximately 5% of the total oxidized bases known to occur in DNA

Question 27

where are reactive oxygen species produced?

Answer 27

in the mitochondria

Question 28

Antioxidant defense mechanisms

Answer 28

Superoxide Reductases and Dismutases (SOD)

-SOD converts superoxide anions into hydrogen peroxide

-Cu/ZnSOD cytoplasmic form
-MnSOD mitochondrial form

-catalase

superoxide anions–> SOD–>H2o2 –>catalase–>H20

Question 29

oxidative damage, ros generation and mitochondria

Answer 29

mitochondrial function
I
Ros generation
I
Oxidative damage
(DNA, proteins, lipids)
I
Mitochondrial dysfunction
I
aging

** This is a vicious cycle between mitochondrial function and dysfunction

Question 30

transgenic manipulation of antioxidant defense mechanisms

Answer 30

make transgenics that will upregulate SOD, would they live longer?

overexpression of antioxidant lifespans: prediction is that lifespan would increase

under-expression of antioxidant enzymes
-prediction lifespan would shorten

Question 31

what is glutathione peroxidase?

Answer 31

enzyme family with peroxidase activity with the role of protecting from oxidative damage

Question 32

Drosophila melanogaster experiment by William. C. Orr and Rajhindar Sohal

Answer 32

extension of life span by over-expression of superoxide dismutase and catalase

-they lived longer than non-transgenics, however, they were not able to repeat these findings –> concluded that the living longer had nothing to do with the upregulation of SOD and catalase

Question 33

transgenic mouse models

Answer 33

performed knockouts in mice with a deficiency in various enzymes

-found no effect, the systems of the enzymes that impact this don’t have much effect

-only one of the 18 genetic manipulations had an effect on lifespan, so we question whether oxidative damage or stress plays a huge role in longevity of mice

Question 34

A mitochondrial superoxide signal triggers increases longevity in Caenorhabditis elegans

Answer 34

study on C. elegans
-worm
-decreased or downregulated it and the worms actually lived longer

-worms with more free radicals lived longer

-some worms were given n acetyl cysteine (NAC) as an antioxidant

Question 35

What are the pros and cons of oxidative stress theory?

Answer 35

pros
-logical
-metabolic theory -> high metabolism - shorter lifespan

-oxidative damage accrues with age

anti-oxidant enzyme system

cons
-genetic interventions that modulate antioxidant enzyme pathways do not consistently delay disease progression or extend lifespan

Question 36

Redox stress

Answer 36

-free radicals are deleterious yet essential for signaling molecules
-mediating stress response
-ROS could be important for signal transduction, gene regulation, redox regulation

-if you are over or under expressed this is not good

Question 37

Redox signaling

Answer 37

ROS involved in cellular regulation by acting as redox signals

-harmful effects of ROS- not due to direct damage, compromised redox signaling

Question 38

absence of a program for aging- Kirkwood continued work

Answer 38

contrary to widely held belief, the body is not programmed to age and die

-animals in the wild rarely live long enough to display signs of old age

-natural selection will oppose any programmed for death

-animals in the wild have a much shorter lifespan

Question 39

genetically inbred mice vs human lifespan curve

Answer 39

• the curves are not that different, but in humans there is so much genetic variability. mice are inbred and have no variability –> yet similar graph

this suggests that there is a lot more than genetics to lifespan

Question 40

chance, development, and aging?

Answer 40

genes, chance and environment

e.g. gene mutations in mid-life are linked to cancer, but if that gene does not get targeted you likely wont get cancer

Question 41

factors that influence health trajectories in old age

Answer 41

genes, nutrition, physical activity, lifestyle, environment, socioeconomic status, attitude, chance

Question 42

Chance

Answer 42

longevity variability due to progressive accumulation of defects

defects caused by random damage that is stochastic (randomly determined)

possible stochastic mechanisms
-oxidative damage
-mitochondrial DNA deletion mutations (DNA replication errors)
-methylation
-protein damage/aggregation

Question 43

epigenetics

Answer 43

DNA modifications that do not change the DNA sequence yet affect gene activity

-changes to DNA that are not directly changing amino acids
-we modify other things

Question 44

DNA methylation and aging

Answer 44

-DNA methylation increases with age
-biomarker of chronological age, physiological age?

-Major changes in DNA methylation occur with age

-what do changes in methylation contribute to physiological and molecular aging

Question 45

general aging diagram

Answer 45

prion disease, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, lewy-body dementia , fronto-temporal dementia