lecture 2 mechanisms of aging Flashcards
who started the concept of biology of aging?
August Weismann
What did August Weismann propose?
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
wear and tear hypothesis: senescence
organismal aging analogous to aging of mechanical devices
wear and tear hypothesis: Death
natural selection to eliminate the old and worn out
-turnover necessary for evolution
wear and tear hypothesis: mechanism
unclear but argued it might involve limitation of a number of cell divisions
Rate of living theory by Rubner and Paul
-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
Has there been evidence found to support the rate of living theory?
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
who considered aging the unsolved problem of biology?
Sir Peter Medewar - father of transplantation
-Senescence lowers fitness
Mutation accumulation theory
- 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
long-lived and short-lived species mutation frequency?
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
primary lung fibroblast isolated from young adults experiment
bleomycin treatment
frequency of mutation was higher in mice and lowest in humans and naked mole rats
Cellular Senescnece
Cultured Cells have a limited number of cell divisions
hayflick limit
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
what did leonard hayflick study?
cell replication
-hayflick limit
telomere theory
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
Telomerase
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
cells that are important to aging typically don’t _____?
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
protein misfolding
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
diseases and their matching misfolding proteins
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
Free Radical theory of aging by Denham Harmon
-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
oxidative stress theory of aging
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
free radicals and ROS
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
generation of free radicals
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
lipid peroxidation
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
protein oxidation
increases with age
-carbonyl derivatives on lysine, arginine, proline, histidine, cysteine, threonine residues
nucleic oxidation
increases with age
8-oxo-2-deoxyguanosine (oxo8dG)
oxo8dG makes up approximately 5% of the total oxidized bases known to occur in DNA
where are reactive oxygen species produced?
in the mitochondria
Antioxidant defense mechanisms
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
oxidative damage, ros generation and mitochondria
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
transgenic manipulation of antioxidant defense mechanisms
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
what is glutathione peroxidase?
enzyme family with peroxidase activity with the role of protecting from oxidative damage
Drosophila melanogaster experiment by William. C. Orr and Rajhindar Sohal
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
transgenic mouse models
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
A mitochondrial superoxide signal triggers increases longevity in Caenorhabditis elegans
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
What are the pros and cons of oxidative stress theory?
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
Redox stress
-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
Redox signaling
ROS involved in cellular regulation by acting as redox signals
-harmful effects of ROS- not due to direct damage, compromised redox signaling
absence of a program for aging- Kirkwood continued work
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
genetically inbred mice vs human lifespan curve
- 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
chance, development, and aging?
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
factors that influence health trajectories in old age
genes, nutrition, physical activity, lifestyle, environment, socioeconomic status, attitude, chance
Chance
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
epigenetics
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
DNA methylation and aging
-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
general aging diagram
prion disease, Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, amyotrophic lateral sclerosis, lewy-body dementia , fronto-temporal dementia
