10.1 Aging Flashcards
Young vs. Old
Old:
- Frail organs
- Decreased Tissue TON
- Increased Inflammation
- Wounds heal slowly
- More scaring of tissues
Young:
- Robust organs
- Increased Tissue TON
- less Inflammation
- Wounds heal fast
- Less scaring of tissues
4 Major players in aging that affect various differentiated cells as well as stem cell are as follows
- DNA repair enzymes
- Members of Insulin-signaling pathway
- Members of mTOR (mammalian target of rapamycin) signaling pathway
- Chroma’n remodeling
With aging point muta’ons increase as a result there is increased expression of faulty proteins. 3 Sources of mutations
- Reactive oxygen species: Damage the cell membranes, proteins, nucleic acids.
- Expression of enzymes that destroy ROS increases longevity.
- Telomerase and p53:
Telomerase, p53 and aging
• p53 is a transcription factor that is an important repressor of cell division leading to cellular senescence.
• p53 blocks cell division.
• It is bound with a repressor protein that keeps p53 inactive.
• UV radiation, oxidative stress cause DNA damage
separating p53 from its repressor.
• p53 is beneficial while destroying cancer cells or deleterious while destroying stem cells or neurons.
• p53 is activated by damage to telomerase.
• There is a positive correlation between telomere length
and longevity.
• Telomere appears to shorten with age.
Pathway to increase longevity
in each case, insulin signalling pathway inhibits the synthesis of Foxo transcription factor proteins that would otherwise increase cellular longevity. This is in c.elegans, mouse and drosophila
Induction of aging process
-The p53 induced by telomere dysfunction binds to and represses the expression of PGC-1å and PGC-1ß
•repression of both blocks mito production of reactive oxygen species (ROS)
•leads to functional decline of post-mitotic tissues and stem cells
•therefore aging
Stem cell Contrbution Curve
Hematopoietic, Stem Cells, Intestine:
- High cell turnover
- High regeneration
- High Contribution
Lier, Adrenal Cortex, Skeletal Muscle:
- High cell turnover
- Low regeneration
- Medium Contribution
Brain, Kidney, Heart:
- Low cell turnover
- Low regeneration
- Low Contribution
Muscle repair in young and old individuals
- Young and old had cast on leg for 2 weeks.
- recovery monitored for 4 weeks
- old individuals don’t recover fully but young does
- ability to regenerate depends on age
- this involves stem cells: satellite
- you can grow satellite cells from old and young
Muscle cells
• Myogenic stem cells are called satellite cells.
• These satellite cells play an important role in the repair of injured muscle cells.
• They are localized in between the myofiber cell membrane and basal
lamina.
• Normally quiescent, in response to muscle injury they are activated and induced to proliferate.
Satellite cells: stem cell divide asymmetrical
Stem cell: is a daughter cell keeping Pax 7
Progenitor cell: daughter cell downregulating Pax7 and expressing Myf5
Stem cells and aging
- Decrease in the stem cell number with increase in age.
- Change in the potential contributes to aging.
- Change in the microenvironment contributes to aging.
Notch-Delta Signaling Pathway
Before:
•CSL TF is on the enhancer of Notch regulatory genes and binds the repressors
Activation: Injured muscle fiber
•ligand (ex. delta) binds to extracellular domain of Notch on an adjacent cell
•causes shape change in intracellular domain of notch
•activates protease
•protease cleaves notch
•intracellular region of notch enters nucleus and binds to CSL
•intracellular notch region displaces repressor and binds activators of transcription (ex.p300)
•activates CSL can transcribe target gene
Experiment:
Notch singalling. Treat young and old with notch inhibition and notch activation
- aged lots of scaring
- young and old treated with notch inhibitor and young was also scarred
- therefore notch NB for aging
- add notch: aged muscle regenerates normally
Parabiosis
- cut on side of organism, then suture together
- after 2 weeks the share a circulatory system
- inflict injury on one other them
- if hurt old: muscle cells regenerate back together like it was a young
- young has all the paracrine factors
plasma of old mice into young
-inject blood plasm from old
-in case of nerve cells: b.plasm. young gets b.plasm from old
-double carton decrease, therefore unable to heal
-new neurons not regenerating back
-old determines regeneration of neurons
-New neurons stained for doublecortin
-Young mice given plasma from young mouse: Normal levels of doublecortin in cortex.
-Young mice given old plasma:
Cells containing doublecortin decreased.
