L5, Mitochondria and Telomeres in aging Flashcards
1
Q
Mitochondrial dysfunction with age:
Enzyme example in mice
A
- Rate of mtDNA mutation is 100-1000x higher than nucleus
- Mitochondrial function declines with age
- Lots of conflict opinions about mitochondrial involvement and FRT in field
- Lon protease declines with age in sedentary mice
- Lon protease = mt matrix protein which degrades misshapen proteins
- However, there is not a vicious cycle in place (mutation cycle)
2
Q
Mice engineered with proof-reading deficient PolgA:
A
- 2007 study in mice
- PolgA= catalytic subunit of mtDNA polymerase
- Expecting more mtDNA mutations to arise -> increased rate of aging
- Results showed increased pathologies, increased aging side effects (greying, hearing loss, cardiomyopathy etc)
- Shorter lifespan
- Effect was prevented by endurance exercise -> known to stimulate mitochondrial biogenesis
- Further study: mitochondrial point mutations found not to limit natural lifespan of mice, but deletions do
3
Q
Quality control of mitochondrial proteostasis (3 levels):
Grouped by severity of damage
A
- Minor damage: Managed at molecular level by chaperones and proteases -> protein folding and turnover, e.g. reduced Lon protease
- IM damage I (Organellar QC): mitochondrial fusion causes content mixing, SIMH (e.g. stress-induced mt hyperfusion)
- IM damage II (Organellar QC): Mitochondrial fission -> segregation and mitophagy (cf. Lysosomes, lipofuscin)
- Major damage: Managed on cellular level -> Apoptosis (MOMP, cytochrome c release, cellular turnover)
4
Q
Hormesis:
A
- Dose-response phenomenon
- Low dose: stimulation, high dose: inhibition (or vice versa)
- First observed in tracheal cilia under different doses of strong oxidants
5
Q
Mitochondrial hormesis under mild stress:
A
- Mild mitochondrial stress promoting cellular health
- Stress signalling (retrograde response / ETC disruption, exercise or DR induced metabolic stress) -> upregulation of stress coping mechanisms in nucleus -> promotes gene stability, energy mobilisation, autophagy and mitophagy upregulation, TOR inhibition
- Process appears to be inhibited by antioxidants
6
Q
Signalling in rapidly growing cells (AP in mitochondria):
(In mitochondria)
A
- Rapidly growing cells limited by ATP production -> actively inhibiting mitophagy to maximise mitochondrial ATP production
- This process maximises early growth and reproduction, but permits the persistence of damaged mitochondria
- In this case, mitophagy is inhibited via ROS-dependent activation of insulin signalling
7
Q
Role of telomeres in lifespan of a chromosome:
A
- Protect against uneven chromosome segregation and cancer
- Chromosomes lose telomeric DNA with each division -> arrested when sufficiently eroded -> Hayflick limit
- Telomerase activated in many cancers to evade this (85-90% of malignant biopsies are telomerase positive)
8
Q
Stem cell depletion argument:
A
- Debunked
- Idea that telomere erosion causes stem cells to senesce -> no rejuvenation
9
Q
Evidence against stem cell depletion argument:
A
- Mice have constitutively active telomerase (and thus long telomeres)
- Humans have repressed telomerase
- Mice don’t get stem cell depletion yet they have hugely shorter lifespans
- -> telomere shortening and replicative senescence unlikely cause of aging
10
Q
Purported role of replicative senescence in cancer suppression:
Links to evolutionary theories
A
- Theory that the evolution of homeotherms with increased metabolic rate and thus DNA damage/telomere erosion due to ROS production -> cancer
- Selective pressure to upregulate replicative senescence to root out more frequent damaged cells
11
Q
Mammalian ancestors vs aquatic poikilotherms and telomeres:
A
- Mammalian ancestors had human type with short telomeres and repressed telomerase
- Aquatic poikilotherms had short telomeres but expressed telomerase
- -> telomerase repression likely evolved to protect against tumours
12
Q
Telomeres in humans:
A
- Short telomeres associated with CVD (not causative)
- Short telomeres generally speaking, with repressed telomerase
- No correlation/causative link found between telomere length and frailty or CVD (West of Scotland Coronary Prevention Study)
13
Q
Telomerase gene therapy in mice:
A
- 2021 paper investigating intranasal and injectable gene therapy route
- Used cytomegalovirus virus to transfect mice with TERT
- Lifespan extended considerably (max lifespan 29 mths vs 40)
14
Q
Cell senescence: How is it induced, hallmarks?
A
- Stress or damage induced
- Irreversible, non-dividing state
- Cell still able to metabolise and express genes
- Larger with increased lysosomal mass
- Express p16INIK4a (cyclin-dependent kinase inhibitor; tumor suppression)
- May be labelled using SA-beta-gal
15
Q
Key initiators of cell senescence:
A
- Telomere erosion
- Oncogene overexpression
- ROS-mediated DNA damage
- Mitochondrial dysfunction
- Inflammation
- -> DDR -> p53 activated -> G1 arrest
