Biology of ageing Flashcards
(41 cards)
1
Q
What is the theory of ‘programmed’ ageing?
A
- Genes to turn on ageing (similar to development)
- Activated at a certain stage of life
- Self destruct mechanisms
- A deterministic theory
2
Q
List examples of evidence for programmed ageing
A
- Species-specific lifespan
- Hayflick limit
- Progeria
- Gerontogenes
3
Q
What is the hayflick limit ?
A
- Limited cell division
- Cellular clock
- Cells in culture can divide only a set number of times
- Cell senescence
4
Q
Why are senescent cells a problem?
A
- Morphological changes: reduced strength
- Secrete pro-oncotic factors (increased cancer risk)
- Secrete MMPs (matrix metallo proteases) degrade tissues
- Lack of cell division=reduced tissue/wound repair
5
Q
What are telomeres?
A
- End regions of chromosomes
- Lost with each cell division
6
Q
What is the function of telomeres?
A
- They cap chromosomes: protect DNA ends from degradation and faulty repair(end joining)
- Act as a ‘buffer’ for loss of DNA during DNA replication
7
Q
Why are telomeres lost every time a cell divides?
A
- The ‘end replication problem’
- During cell division, DNA polymerase can’t make new DNA to the very end of chromosomes
- So the telomeric DNA gets shorter
- Ageing of these cells (they can’t divide anymore) is caused by imperfect copying of DNA because they don’t have the gene for telomerase
8
Q
What is Werner’s syndrome?
A
- Fast ageing syndrome
- Aka Progeria
- Premature white hair
- Reduced skin suppleness
- Cataracts
- Diabetes
- Osteoporosis
- Vascular disease
- Cancer
- Reduced number of cell divisions
9
Q
Why may the WRN gene be a candidate gene in Werner’s syndrome?
A
- WRN gene mutation chromosome 8 (recessive) codes for protein helicase
- Helicase helps DNA ‘unzip’. allows in enzymes for:
- DNA synthesis; proteinsynthesis;DNA repair
- mutated WRN gene produces disfunctional helicase: causes DNA synthesis to stop & cells reach senescence early
10
Q
What is the end replication paradox?
A
-During cell division, DNA polymerase can’t make new DNA to the very end of chromosomes
11
Q
What is cell senescence
A
-Cell division stops
12
Q
Why isn’t Werner’s syndrome (WS) a model for programmed ageing?
A
Fast ageing of cells is due to very poor:
- Copying of DNA
- Repair of DNA
- Production of new proteins
i. e poor cell ‘maintenance activity’ because they don’t have functioning helicase
13
Q
What are gerontogenes?
A
- Genes which have an effect on lifespan, when mutated or their expression is changed ( usually increased)
- All gerantogenes increase resistance to physical stressors: free radicals, UV light etc
14
Q
There is currently no evidence for programmed ageing, but why are genes important regardless?
A
-Build up of damage is counteracted by genetically-regulated mechanisms
The genes responsible are all involved in cell maintenance and repair e.g
- Hayflick limit: telomere loss can be prevented by re-expression of telomerase gene
- Progeria: DNA maintenance, protein synthesis requires expression of helicase gene
- Gerontogenes: additional genes are protective against ‘stress’ damage
15
Q
State the possible random, stochastic damage that can occur during ageing
A
Damage caused by the ‘stuff of life’
- ) OXYGEN: Oxygen free radicals
- ) GLUCOSE: protein damage by reducing sugars (glycosylation)
16
Q
Outline the role of oxygen in cellular damage
A
- oxidative stress theory
- cell damage caused by reactive oxygen species (ROS)
- ROS include free radicals- molecules with an ‘unpaired electron’
- Free radicals are unstable
- To stabiltise, they take electrons from nearby molecules and disrupt their structure= oxidation
- eg hydroxyl (molecule) or superoxide(ion) radicals
17
Q
What are sources of ROS?
A
- The cell metabolism (mitochondrion)
- Infection
- Environment
- Lifestyle
- Pollution
- Lipid (fat)
18
Q
How can the mitochondrion act as a source of ROS?
A
- Electron transport chain:
- -.5-2% of electrons are leaked
- About 1% of oxygen is converted to superoxide free radical
- In 70 year life-span, we generate 17 tons of free radicals
- Mitochondria produce ROS & are damaged by them
- Over time: more ROS= less ATP production
19
Q
Outline lipid oxidation
A
-Lipofuscin accumulation: yellow-brown pigment granules composed of lipid-containing residues of lysosomal digestion
20
Q
Outline protein oxidation
A
-formation of protein carbonyls
21
Q
Outline DNA oxidation
A
- Altered bases or broken strands
- Nuclear bases~ 10000 hits per day
- Mitochondrial DNA~40000 hits per day
22
Q
What are the consequences of DNA oxidation?
A
Broken strands—> cell senescence(stop dividing)
Altered bases—> mutation
23
Q
What is the relationship between oxidative damage & ageing
A
Oxidative damage increases with ageing
24
Q
What is the Maillard reaction?
A
- Spontaneous chemical reaction between sugars and protein, increased by ROS
- Forms advanced glycosylation end products (AGE)
25
What are the consequences of AGE?
-Protein strands randomly cross-linked making them stiff & irregular
eg leading to hip problems (cartilage protein, collagen) and cataract (lens protein,alpha crystallin)
-Wrinkes skin
-Reduces oxygen carriage in RBCs
-Stiffens arteries
-Reduces insulin secretion by pancreatic beta cells
26
What pathologies/ problems do AGEs contribute to
- Alzheimer's disease
- Atherosclerosis
- Arteriosclerosis
- Bone fragility
- Skin wrinkling
- Renal failure
27
What happens to AGEs during ageing?
-AGEs increase with age and mimic uncontrolled diabetes
Diabetic complications resemble premature ageing:
- cataract
- vascular disease
- retinopathy
- neuropathy
- skin changes
- kidney failure
-Increases are earlier in diabetes
28
What is the role of receptors for AGEs in increasing their effects
- Overexpression of AGERs enhance AGE binding & degradation
- Inflammatory response
29
Outline what occurs with receptors for AGE in ageing
- 'inflammageing': many age-related pathologies involve an inflammatory condition which includes ROS generation
- As autophagy decreases with age,cellular ability to degrade protein-AGEs via AGE-R1 becomes compromised
- More protein AGEs interact with AGE receptors leading to inflammation
30
What can help to protect against ROS?
ANTIOXIDANTS:
- 'Any substance that, when present at a low concentrations compared with those of an oxidisable substrate, significantly delays or prevents oxidation of that substrate'
- Antioxidant enzymes
- Non-enzyme antioxidants
- Nutrient antioxidants in diet
31
What are the characteristics of antioxidant enzymes
- Made by the body under gene control
- Can neutralise many 1000s of ROS molecules each second
1. ) superoxide dismutase(SOD):
- Cu/Zn SOD in cytoplasm
- Mn SOD in mitochondria
2. ) catalase (decomposition of hydrogen peroxide)
3. ) Glutathione peroxidase 1 (requires Se)
32
What are the characteristics of non-enzyme antioxidants
-Not as effective as enzyme antioxidants
-Neutralise one ROS, then must be replaced or repaired
egs:
-glutathione
-uric acid
-bilirubin
-ubiquinol
33
Give examples of nutrient antioxidants in the diet
- alpha-tocopherol-->vit E (fat soluble)
- Ascorbate--->Vit C (water soluble)
- Beta-carotene
34
What is necessary to see an effect with non-enzymatic antioxidants
-We need combinations for an effect to be present
| eg Vit E+ Vit C + glutathione
35
What is oxidative stress an imbalance of?
-Oxidative stress is an imbalance between ROS and antioxidants
(some ROS escape neutralisation= oxidative stress )
36
Why might high dose increase antioxidants be harmful?
1. ) Increased vitamin E reduces Beta carotene absorption in the gut and reduces production of vitamin A
2. ) Increased Vitamin E& C act as pro-oxidants(increase ROS) EG IRON + Vit C=hydroxyl radical
3. ) Antioxidants don't just target harmful ROS. Cells NEED some ROS to function. E.g:
- WBCs to fight infection
- Nitric oxide radicals relaxes SMCs and dilates blood vessels
- ROS increase intracellular signalling (eg ROS increase myosin light chain kinase enzyme activity , through controlling phoshorylation of proteins, resulting in muscle contraction)
37
What is the only intervention that has been seen to increase life expectancy?
CALORIE RESTRICTION:
- Dietary restriction of ENERGY intake by 30-40% of normal calories
- BUT with adequate nutrition ( normal levels of vitamins, minerals, Essential amino acids and fats)
38
Explain the effect of ageing with an excess of calories or a sedentary lifestyle on the ETC
Ageing: excess calories or sedentary lifestyle= excess NADH and/ or ATP not used, also damage to protein V involved in ETC of mitochondria leading to that protein not transferring hydrogen ions.
- Build up of hydrogen ions increases the membrane potential
- Hydrogen ions aren't used by complex V to make ATP because ATP is not being used fast enough
- electrons build up and are leaked as ROS
- Hydrogen ions are lost as heat
39
Explain why calorie restriction works to increase life expectancy
- Little NADH. All electrons are used to drive the ETC and make ATP
- Inner membrane becomes more permeable to hydrogen ions
- membrane potential is reduced (depolarised)
- Less heat and ROS produced
40
What other effects may calorie restriction (CR) have on ageing
Mitochondria change gene expression in nucleus during CR:
-increase SIRT1 (silent info regulator): decreases apoptosis, increased mitochondrial activity, increased insulin sensitivity
(mitochondria increase SIRT1 expression due to high NAD+: NADH ratio
- Increase PGC-1alpha (peroxisome proliferator-activated receptor gamma coactivator- 1alpha)---> increases mitochondrial biogenesis (complex activity)
- More mitochondria are good cos this leads to NADH and electrons being spread over a greater number of complexes. Fewer electrons build up in each mitochondria and so there is less electron leak to form ROS
-CR reduces IGF1, increases FOXO3A and inhibits TOR (target of rampamycin kinase)--> increased gene expression for:
increased autophagy and heat shock proteins( protect & repair); decreased apotosis; increased antioxidants, anti-ageing
41
What can exercise help to reduce the risk of
- Diabetes
- Obesity
- CHD
- Heart attack
- Hypertension
