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Ageing block > Biology of ageing > Flashcards

Biology of ageing Flashcards

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
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2
Q

List examples of evidence for programmed ageing

A
  • Species-specific lifespan
  • Hayflick limit
  • Progeria
  • Gerontogenes
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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
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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
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5
Q

What are telomeres?

A
  • End regions of chromosomes

- Lost with each cell division

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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
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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
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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
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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
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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

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11
Q

What is cell senescence

A

-Cell division stops

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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
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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
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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
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15
Q

State the possible random, stochastic damage that can occur during ageing

A

Damage caused by the ‘stuff of life’

  1. ) OXYGEN: Oxygen free radicals
  2. ) GLUCOSE: protein damage by reducing sugars (glycosylation)
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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
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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
Q

What are the consequences of AGE?

A

-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
Q

What pathologies/ problems do AGEs contribute to

A
  • Alzheimer’s disease
  • Atherosclerosis
  • Arteriosclerosis
  • Bone fragility
  • Skin wrinkling
  • Renal failure
27
Q

What happens to AGEs during ageing?

A

-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
Q

What is the role of receptors for AGEs in increasing their effects

A
  • Overexpression of AGERs enhance AGE binding & degradation
  • Inflammatory response
29
Q

Outline what occurs with receptors for AGE in ageing

A
  • ‘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
Q

What can help to protect against ROS?

A

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
Q

What are the characteristics of antioxidant enzymes

A
  • 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
Q

What are the characteristics of non-enzyme antioxidants

A

-Not as effective as enzyme antioxidants
-Neutralise one ROS, then must be replaced or repaired
egs:
-glutathione
-uric acid
-bilirubin
-ubiquinol

33
Q

Give examples of nutrient antioxidants in the diet

A
  • alpha-tocopherol–>vit E (fat soluble)
  • Ascorbate—>Vit C (water soluble)
  • Beta-carotene
34
Q

What is necessary to see an effect with non-enzymatic antioxidants

A

-We need combinations for an effect to be present

eg Vit E+ Vit C + glutathione

35
Q

What is oxidative stress an imbalance of?

A

-Oxidative stress is an imbalance between ROS and antioxidants

(some ROS escape neutralisation= oxidative stress )

36
Q

Why might high dose increase antioxidants be harmful?

A
  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
Q

What is the only intervention that has been seen to increase life expectancy?

A

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
Q

Explain the effect of ageing with an excess of calories or a sedentary lifestyle on the ETC

A

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
Q

Explain why calorie restriction works to increase life expectancy

A
  • 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
Q

What other effects may calorie restriction (CR) have on ageing

A

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
Q

What can exercise help to reduce the risk of

A
  • Diabetes
  • Obesity
  • CHD
  • Heart attack
  • Hypertension

Ageing block (16 decks)

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