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
