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ATU3 > Ageing Pathways In Health And Disease > Flashcards

Ageing Pathways In Health And Disease Flashcards

1
Q

What is gerontology?

A

The scientific study of the biological, physiological and sociological phenome associated with old age and aging

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2
Q

What is geriatrics

A

The branch of medicine that deals with the diagnosis and treatment of diseases and problems specific to the aged

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3
Q

What organisms do not age?

A

Bacteria
Hyphae
Some rockfish live 200+ years
Red Sea urchin is still fertile at 200 years plus

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4
Q

What is the current lifespan in the uk?

A

81.5 years

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5
Q

How long have supercentenarians lived for?

A

120 years

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6
Q

What are the two biological theories of aging?

A

The programmed theory of aging - August Weismann 1889

The damage theory of aging

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7
Q

Describe programmed theory of aging

A

Programmed longevity
Endocrine theory
Immunological theory

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8
Q

Describe the damage theory of aging

A

Wear and tear
Rate of living (metabolism)
Oxidative damage theory
Somatic DNA damage theory

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9
Q

What is darwins contribution to aging?

A

Too many offspring are produced for the limited resources and competition:
- better adapted individuals survive

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10
Q

What did August Weismann do?

A

First to formalise the mechanisms of darwins theory - aging is part of life’s programme because the old need to remove themselves from the theatre to make room for the next generation
Supported by the idea within a species - constant lifespan

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11
Q

What are the three mechanistic theories?

A

Mutation accumulation theory - Sir Peter Medawar (1952)
Antagonistic pleiotropy - George Williams 1957
The disposable soma theory - Tom kirkwood 1997

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12
Q

Describe the mutation accumulation theory

A

Random mutations accumulate later in life past the reproductive period hence not passed on
Late acting mutations - only a few bearers with still be alive so weak natural selection
Early acting mutations - most bearers still alive so a strong force of natural selection
Diseases with late onset are more common than early onset I.e. Huntingtons disease

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13
Q

Describe antagonistic pleiotropy

A

George Williams 1957
Genes that offer benefits early on in life with increased rate of ageing later on
Most individuals survive to express the early benefit
Benefits out weigh the negatives
Testosterone - sperm fertility but prostrate issues when older

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14
Q

Describe the disposable soma theory

A

Tom kirkwood 1997
Genes survive (germline) our bodies don’t (soma)
Bodies degrade once past peak of reproductive age
Aging is the result of a naturally degrading process that result in accumulation of damage

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15
Q

What are the three mechanistic theories of aging?

A

Rate of living theory - 1928
Hayflicks limit - molecular clock (Leonard hayflick 1961)
Free radical theory of aging (Denham Harman 1956)

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16
Q

Describe the rate of living theory

A

Degradation of live organisms is dependent on the exhaustion of a fixed quantity of a vital substance
Drosophila flies
15 degrees - 120 days
30 degrees - only lived for 21 days

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17
Q

Describe hayflicks limit - molecular clock

A

A cell can multiply a limited number of times
Placed male fibroblasts (divided many times) in with female (few times) - male remembered they had divided many times
Disproved the immortality theory of carreli - dogma at the time
Average cells divides 50 to 70 times
Also concluded most immortal cells are cancerous

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18
Q

Define life expectancy

A

Lifespan, the period of time in which the life events of a species typically occurs

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19
Q

Describe the free radical theory of aging

A

Denham Harman 1956
Lifespan is an inverse function of metabolic rate which in turn is proportional to oxygen consumption
Reactive oxygen species are produced in the mitochondria

This theory is not true

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20
Q

Describe the classical genetic approach to understanding aging

A

Isolate mutants with altered rates of ageing
Map, clone and sequence genes concerned
Identify lifespan determining proteins, biochemistry
Understand ageing?

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21
Q

What animals are used for models of ageing?

A

Nematodes, rabbits, drosophila
Ideally want animals that are short lived to collect the results quickly and over many generations
Humans are too complex

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22
Q

Who came up with the theory of dietary or calorific restriction?

A

Clive McKay 1930

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23
Q

What was the hypothesis of Clive McKay?

A

The lifespan of rats can be extended with a diet that is low in calories but adequate in nutrients

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24
Q

What were the three groups of rat Clive used?

A

Group 1: the rats were fed normally
Group 2: rats fed normally until weaning then on a calorie restricted diet
Group 3: fed normally until two weeks after weaning, then put on a calorie restricted diet

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25
Q

Out of the three groups Clive used which lived longer?

A

The calorie restricted group and had a higher median lifespan
Do not know the exact mechanism

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26
Q

What is c.elegans?

A

Microbiverious terrestrial nematode around 1.2mm long
Genome: around 97000000 bases
Around 19000 genes

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27
Q

What is c.elegans signs of ageing?

A

Reduced fertility, feeding, movement
Increased cuticular wrinkling (collagen cross linking)
Increased protein carbonyl, mitochondria DNA deletions, lipofusions

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28
Q

What is the average lifespan of c.elegans?

A

30 days

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29
Q

A mutation in which gene doubled the worms lifespan?

A

Daf-2

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30
Q

What does daf-2 encode?

A

Hormone receptor that is on the outside of cells and responds to a certain ligand (insulin like ligand)

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31
Q

What happens when decreased signalling through the insulin pathway occurs?

A

Increased lifespan/longevity
Also found in mice and dogs
Caloric restriction reduces insulin and IGF-1 (increases mammal longevity)

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32
Q

Who invented the free radical theory?

A

Denham Harman 1956

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33
Q

What was the underlying principle to the free radical theory?

A

Lifespan is an inverse function of metabolic rate which in turn is proportional to oxygen consumption

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34
Q

What percentage of cell energy does the mitochondria generate?

A

95%

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35
Q

What percentage of oxygen is used in energy formation?

A

97%-99%

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36
Q

What percentage of oxygen is utilised in ROS formation?

A

1-3%

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37
Q

Where are ROS a produced?

A

The mitochondria - electron transport chain

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38
Q

What were the observations that led to the mitochondria free radical theory of ageing?

A
  • strong correlation between age and the level of reactive oxygen species generation and oxidative damage
  • mitochondrial function is gradually lost during ageing
  • inhibition of mitochondrial function can enhance ROS production
  • several age dependent diseases are associated with severe increases in oxidative stress
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39
Q

What are the two ways in which radicals can be formed?

A

The loss of a single electron from a non-radical or by gain of a single electron by a non-radical
The breakage of covalent bonds

40
Q

What defines ROS?

A

Any free radical involving oxygen

Not all ROS are radicals e.g hydrogen peroxide is a non-radical

41
Q

How are superoxide anions formed?

A

When oxygen acquires an additional electron leaving the molecule with only one unpaired election

42
Q

What are the most damaging radicals within the body?

A

Hydroxyl - short lived

43
Q

Interaction with what element causes formation of a hydroxyl radical from hydrogen peroxide?

A

Copper or iron

44
Q

What are the sources of oxygen radicals?

A

Enzyme reactions
Cellular sources
Environmental factors

45
Q

What enzyme reactions produce oxygen radicals?

A

Xanthine oxidase

NADH oxidase

46
Q

What cellular sources produce oxygen radicals?

A

Leukocytes and macrophages

Mitochondrial electron transport

47
Q

What environmental factors produce oxygen radicals?

A

UV light
X-Ray’s
Toxic chemicals

48
Q

What two components supply high energy electrons from metabolic substrates?

A

NADH and FADH2

49
Q

What is complex I called?

A

NADH dehydrogenase

50
Q

What is complex II called?

A

Succinate dehydrogenase

51
Q

What is complex iii called?

A

Cytochrome c oxidoreductase

52
Q

What is complex IV called?

A

Cytochrome c oxidase

53
Q

What does complex v use to generate ATP?

A

The proton gradient

54
Q

What are ROS a byproduct of?

A

The ETC

55
Q

when NADH binds to complex I what becomes reduced?

A

Coenzyme Q

56
Q

How are electrons transferred in complex I?

A

Flavin mono nucleotides and series of Fe-S clusters

57
Q

How many protons are pumped across the inner mitochondrial membrane in complex I?

A

4

From the matrix into the inter membrane space

58
Q

What does the leakage of free electrons do?

A

Reduces oxygen to form a superoxide anion

59
Q

What is oxidised and what is reduced in complex III?

A

Oxidation of ubiquinol and reduction of two molecules of cytochrome c through electron transport

60
Q

How many hydrogens are pumped across in complex III?

A

4

Again leakage of electrons allows the formation of a superoxide anion

61
Q

What are the three components of the cell that can be affected through ROS?

A

Membrane
DNA
Proteins
All of which lead to oxidative stress, disease and aging

62
Q

Why are biomembranes particularly susceptible to attack?

A

Presence of polyunsaturated fatty acids in their membrane

63
Q

What effect does the proxy-radical have on membranes?

A

Another hydrogen radical from a different fatty acid can cause auto-catalytic chain elongation leading to peroxidation of many lipid molecules in the cell - damage to the membrane

64
Q

What is one of the major products of DNA oxidation?

A

8-oxo-2’-deoxyguaosine

Concentrations of this within a cell are measurements of oxidative stress

65
Q

What effect can oxidative damage have on DNA?

A

Oxidative DNA lesion by direct or indirect activation of endonuclease enzymes
Oxidative modification of bases - mutation
Oxidative modification of sugar moieties - DNA strand break

66
Q

What are the most susceptible amino acids to protein oxidation?

A

Tyrosine, Histidine, Cysteine and Methionine

67
Q

What proteins are targeted by oxidative damage?

A

Receptors, transport proteins, enzymes

68
Q

What effect can ROS have on cysteine?

A

Lead to cross-linking - disulfide bridge

69
Q

Define antioxidants

A

Any synthetic or natural substance that delays or inhibits oxidative damage to a target molecule and is capable to neutralise radicals by donating electrons or hydrogen molecule - acts as scavengers and prevent cell damage

70
Q

Give two examples of antioxidants

A

Superoxide dismutase (SOD) and catalase (CAT)

71
Q

What reaction does SOD catalyse?

A

Rapid disputation of superoxide to hydrogen peroxide

72
Q

What reaction does glutathione/glutathione peroxidase catalyse?

A

Catalyses reaction of hydrogen peroxide to water

73
Q

What reaction does catalase catalyse?

A

High affinity for hydrogen peroxide

Prevents lipid per oxidation and protein oxidation

74
Q

What does MnSOD catalyse?

A

Superoxide into hydrogen peroxide

75
Q

What does an antioxidant enzyme do to hydrogen peroxide?

A

Produce water

76
Q

List the antioxidant vitamins

A

Vitamins E, A, C

77
Q

Describe vitamin E

A

Fat soluble, prevent per oxidation of lipid by donating electrons to free radicals

78
Q

Describe vitamin C

A

Water soluble

Reacts with several radical species producing semihydroascorbic acid this can then go back to ascorbate

79
Q

Describe vitamin A

A

Antioxidant in the form of carotenoids - mainly beta carotenoids - reacts with free radicals and prevents lipid oxidation

80
Q

What did researchers find in older drosophila?

A

Rates of hydrogen peroxide generation by mitochondria was higher in older animals
mROS production was lower in long lived flies

81
Q

What happens to the GSSG/GSH ratio as you get older?

A

Ratio increases
Age induced mitochondrial glutathione oxidation and DNA damage in rats - this is protected by supplementation of antioxidants
Measured by levels of 8-deoxyguanosine

82
Q

How is ageing associated with oxidatively damage macromolecules?

A

Ageing is associated with increased damage

Age-related increase in the level of 8-deoxyguanosine in different tissues of ageing rats

83
Q

What did mice lacking SOD1 show?

A

Shortened lifespan and persistent oxidative damage
Transgenic mice - complete knockout of SOD1
lifespan reduced from 35 months to 25 months

84
Q

What happens in mice lacking SOD2?

A

Neonatal lethality and cardiomyopathy - left and right ventricle becomes enlarged
Shows how important antioxidants are

85
Q

What happens in drosophila when genes encoding SOD and catalase is overexpressed?

A

Sufficient for lifespan extension

Control strain lived for 71 days, over expressed mice lived longer

86
Q

What evidence is there that is incompatible with MFRTA and oxidative damage being the cause of ageing?

A
  • Lack of correlation between the level of ROS and longevity
  • Administration of antioxidants can be deleterious rather than beneficial on lifespan
  • Inactivation or over expression of antioxidant activities in genetically modified organisms fails to produce outcomes that supported MFRTA
  • Existence of long lived mutants and species with high ROS production and high oxidative damage
87
Q

What was found in mice when over expression of catalase and SOD?

A

No increased lifespan

88
Q

What happened in KO SOD in C.elegans?

A

Live as long as wild type
Have normal levels oxidative damage despite missing all 5 SOD
Increased superoxide levels - led to a pro-survival signal which increases lifespan
- More stress sensitive and do have some oxidative damage

89
Q

What is fascinating about naked mole rats?

A

They are the longest living rodent (28 years) however they exhibit high levels of lipid peroxidation and protein carbonisation
DNA oxidative damage occurs at a younger age
Young mole rates show less urea-induced protein unfolding and less protein ubiquitination and higher proteasome activity compared to mice

90
Q

What is Mclk1?

A

A mitochondrial hydroxyls - required for biosynthesis of ubiquinone

91
Q

What happens in Mckl1+/- mice?

A

Sustain high mitochondrial oxidative stress but live longer - mitochondria are dysfunctional in young mckkl1+/- mice
Show lower biomarkers for aging - DNA damage reduced in mckl1+/- mice at 23 months of age

92
Q

In C. elegant what do nuo-1 and isp-1 encode?

A

Complex 1 and 3 in the METC

93
Q

What happens when loss of these genes occur?

A

Decreased electron transport and increased longevity - higher levels of superoxide anion (surprise - as you would expect it t be lower)
- Elevated ROS was necessary for longevity as antioxidants abolished the effect

94
Q

What did the loss of genes nuo-1 and isp-1 in c.elegans suggest?

A

Superoxide is a signal that triggers cellular changes to attenuate effects of ageing

95
Q

What is the role of ROS as second messengers?

A

Involved in a pathway to maintain cellular homeostasis
Controlled at levels of synthesis and removal
Regulate signalling cascades such as ERK, JNK and MAPK
Control activités of TF essential to homeostasis and stress responses

96
Q

From the new evidence what can we conclude?

A

ROS do not cause ageing
- Although can contribute to disease states
ROS are signalling molecules that can modulate stress response pathways
Increased levels of ROS can result in positive effects

97
Q

Should we dismiss MFRTA?

A

No- oxidative damage is still a factor that contributes to ageing
Damage caused by ROS is probably a small part of a broader spectrum of ageing-causing molecular damage

ATU3 (2 decks)

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