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ATU 3 > Aging > Flashcards

Aging Flashcards

1
Q

Define ageing?

A

A process of general, irreversible, and progressive physical deterioration that occurs over time.

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2
Q

Define senescence?

A

The decline of fitness components of an individual with increasing age or owing to internal deterioration.

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3
Q

Define gerontology?

A

The scientific study of the biological, physiological and sociologocial phenomena associated with old age and ageing.

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4
Q

Define geriatrics?

A

The branch of medicine that deals with the diagnoss and treatement of diseases and problems specific to age.

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5
Q

How is life expectancy different to ageing?

A

Life expectancy has increased in the past 100 years, due to increased public health and medicine, but the rate of ageing hasn’t changed.

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6
Q

Give a list of organisms that don’t age?

A

Bacteria don’t age.
Hydra don’t appear to age.
Some rockfish live 200+ years; it’s not clear if they age.
Red sea urchin is still fertile at 200+ years.
Tortoises, amphibians, American lobster
Trees: giant Sequoia 2,000+ yrs, bristlecone pine 4,000+ yrs.

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7
Q

What is the current life expectancy in the UK?

A

81.5 years

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8
Q

What are supercentennaerians?

A

People who have lived past 120 years of age.

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9
Q

What was the earliest ageing theory?

A

Programmed Death Theory:
August Weismann 1889

First to formalise the mechanisms of Darwinian evolution. ‘Ageing is part of lifes program because the old need to remove themselves from the theatre to make room for the next generation’

Ageing of cells is genetically programmed, supported by the idea that within species, life span is fairly constant and dependent on the number of somatic regenerations.

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10
Q

What did the easiest theory of ageing explain?

A

Purpose for ageing is identified, but not a mechanism by which purpose can be achieved.
How individuals would acquire genes that make them get old and die or why ageing genes would make individuals more successful than others lacking those genes.

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11
Q

What are the three evolutionary theories of ageing?

A

Mutation accumulation, antagonistic pleiotropy and the disposable soma theory.

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12
Q

What are the three mechanistic theories of ageing?

A

The rate-of-living, Hayflick’s limit: molecular clock and the free radical theory.

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13
Q

Which theory was thought of by Medawar? Explain.

A

Mutation accumulation, 1952.

Even a population free of ageing, death will nonetheless occur, from extrinsic hazard such as disease, predators and accidents’.
Random mutation accuulte later in life so that they cannot be selected against, as offspring have already been born. Increase later life mortality, increased late onset disease (eg. Huntington’s disease).

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14
Q

When and by who was the antagonistic pleiotropy theory proposed? Explain.

A

George Williams, 1957

Refers to genes that offer benefits early in life but at the cost of a higher rate of ageing later on. More individuals will survive to express the early benefit, than will survive to suffer from the higher rate of ageing.

Early fertility would be selected, even if that come at the cost of decline and deaths. Suggest that if the benefits outweigh the negatives, the gene will be selected for (eg. Testosterone).

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15
Q

Which theory did Kirkwood propose? Explain.

A

The disposable Soma Theory, 1977

Comes from the analogy of disposable products. Organisms only have a limited amount of energy that has to be divided between reproductive activities an the maintenance of the non-reproductive aspects of the organisms (soma)
Genes survive, our bodies (soma) do not, they degrade once past peak of reproductive age.

Ageing is the result of natural degrading process that result in accumulation of damage. Damage can only be repaired by the organism at the expense of reproductive effort.

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16
Q

Which theory from 1928 did Pearl propose?

A

The rate-of-living theory- the duration of life of an organism is dependent upon exhaustion f a fixed quantify of vital substance at a rate proportional to the metabolic rate.

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17
Q

Describe Hayflick’s limit theory?

A

1961, Molecular clock.
Celsl can multiply a limited number of times.
Average cells divides 50-70 times before death.
As the cell divides, telomeres on the end of chromosome get smaller. Due to telomeres shortening through each division telomeres will no longer be present = senescence.

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18
Q

How did Hayflick produce this theory?

A

Hayflick and Moorhead mixed equal numbers of normal human male fibroblasts that had divided many times with female fibroblasts that had divided only a few times.

When the male control culture stopped dividing, the mixed culture was examined and only female cells were found. Male cells remembered they were old, even when surrounded by young cells.

Cells had stopped dividing and had become senescent based purely upon how many times the cell had divided.

These results disproved the immortality theory of Carrell, which was the dogma at the time (cells can divide an unlimited number of times).

Hayflick interpreted his findings that the limited replicative capacity of cultured normal cells was a sign oftheir aging and longevity.

He also concluded that immortal cultured cells are mostly cancer cells.

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19
Q

Which theory did Harman propose? Explain.

A

Free radical theory of ageing, 1956.

Cells continuously produce free radicals by normal metabolism and oxidation of organic compounds and these free radicals damage cellular macromolecules (DNA, proteins, lipids). Accumulation of this damge over time causes ageing.

Controversial theory.

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20
Q

What observations did Harman study?

A

He studied two observations:

  1. Lifespan is an inverse function of metabolic rate which in turn is proportional to oxygen consumption
  2. Oxygen toxicity and radiation toxicity could be explained by the same underlying phenomenon: oxygen radicals.
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21
Q

What is the classic genetic approach of studying ageing in model organisms?

A
  1. Isolate mutants which altered rates of ageing
  2. Map, clone and sequence genes concerned
  3. Identify lifespan-determining proteins/biochemistry
  4. Understand ageing…
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22
Q

Give the most commonly used animal models in ageing?

A 
C.elegans (nematoden)
Yeast 
Drosophila
Rats 
Mice
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23
Q

What are beneficial requirements for animal models to study ageing in?

A

Short lifespans, easily maintained, inexpensive, less complex systems, easy to genetically modify.

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24
Q

Who first observed the effect of caloric restriction on ageing? Explain.

A

Clive McKay, 1930
3 groups of rats, 1 group fed normally, another group fed normally until weaning and then on a reduced calorie diet and a final group fed normally until 2-weeks post weaning.

The earliest group that was put on calorie restriction lived longer.

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25
Q

What other animals has caloric restriction been found to increase lifespan?

A

Rats, drosophila, nematodes and monkeys.

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26
Q

Describe c.elegans and their signs of ageing?

A

A microbiverious terrestrial nematode, 1.3 mm long Genome: ~97 000 000 bases, ~19 00 genes. Life span is ~30 days, short life-cycle.

Signs of ageing:
• reduced fertility, feeding movement
• increased cuticular irnkling
• increase protein, carbonyl, mitochodniral DNA deletion and lipofuscin.

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27
Q

Who first screened for c.elegan lifespan mutants?

A

Klass in 1983

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28
Q

Who found the lifespan mutants for c.elegans?

A

Johnson, in 1988. age-1 (hx546) mutation which caused a 65 % increase in mean lifespan and a 110 % increase in maximum lifespan.

Daf-2 mutants double lifespan due to decreased signalling in insulin signalling pathway. This has also been shown in mice and dogs.

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29
Q

What did Harman do to his theory in 1972?

A

Modified his theory:

Mitochondrial energy metabolism is important part source of ROS in the majority eukaryotic cell types.

95 % energy of cell is produced in Mitochondria and 97% - 99% of Oxygen is used in energy formation. 1-3% of Oxygen is utilized in Reactive Oxygen Species (ROS) formation.

ROS are produced in Mitochondria during the ETC cycle and cause damage to proteins, lipids and DNA which leads to ageing.

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30
Q

What observation led to the MFRTA?

A

There is a strong correlation between age and the level of ROS generation and of oxidative damage.
Mitochondrial function is gradually lost during ageing.
Inhibition of mitochondrial function enhance ROS production.
Several age-dependent diseases are associatied with severe increases in oxidative stress. Mitochondrial DNA does not have any repair mechanism.

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31
Q

What are free radicals and when are they formed?

A

A non-radical loses an electron or gains an electron. Covalent bonds break (homolytici fission).

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32
Q

What is a free radical containing oxygen called?

A

A reactive oxygen species (ROS).

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33
Q

How are ROS generated in the cell?

A

Enzymatic reaction
• NADH oxidase
• Xanthine oxidase

Cellular sources:
• Leukocyte and macrophages
• Mitochondrial electron transfer

Environmental factors:
• UV light
• X-rays
• Toxic chemicals

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34
Q

How do mitochondria mediate ROS generation via the ETC?

A
  1. NADH and FADH2 supply high-energy electrons from metabolic substrates (krebs cycle) to complex 1 (NADH dehydrogenase) and complex 2 (succinate dehydrogenase).
  2. These electrons are transferred to complex 3 (cytochrome c oxidoreductase).
  3. The electrons flow to complex 4 (cytochrome c oxidase) to reduce molecular oxygen to form water.
  4. Complex 5 uses the proton gradient produced throughout and converts ADP to ATP.

ROS are a by-product of the ETC making mitochondria a major source of cellular ROS. Leakage of electrons from ETC occurs at complexes 1 and 3. Leads to partial reduction of oxygen and a superoxide anion is produced.

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35
Q

Describe in detail the generation of ROS in complex 1?

A

Complex 1- NADH coenzyme Q oxidoreductase:

The reduced coenzyme NADH binds to Complex I and accomplishes the reduction of Coenzyme Q10. NADH provided by TCA. Electrons are transferred through Complex I using FMN (flavin mononucleotide) and a series of Fe-S clusters. The process accomplishes the pumping of four protons across the inner mitochondrial membrane to the intermembrane space. Leakage of free electrons reduces O2 => Superoxide Anion.

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36
Q

Describe in detail the generation of ROS in complex 3?

A

Complex 3- Q-cytochrome c oxidoreductase:

This complex accomplishes the oxidation of ubiquinol and the reduction of two molecules of cytochrome-c through electron transport. Four hydrogens are pumped across the membrane to the intermembrane space. Leakage of free electrons reduces O2 => Superoxide Anion.

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37
Q

What effects can ROS have?

A

ROS can have deleterious effects on cellular function, through the modification of DNA, proteins and lipids.

Membrane:
• lipid peroxidation
• damage to membranes and lipoproteins

DNA:
• DNA strand breaks
• Mutations leading to cancer

Proteins:
• Aggregation and fragmentation
• Enzyme inhibition

All lead to oxidative stress, disease and ageing.

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38
Q

Discuss lipid degradation and peroxidation by ROS?

A

Biomembranes and subcellular organelles are particularly sensitive to oxidative attack due to presence of polyunsaturated fatty acids in their membrane.

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39
Q

Discuss oxidative DNA damage by ROS?

A

Oxidative DNA lesion by: direct attack or indirect activation of endonuclease enzymes.
Oxidative modification of bases causes mutation.
Oxidative modification of sugar moieties cuases DNA strand break.

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40
Q

What can be used to measure oxidative stress in cells?

A

Concentration of 8-oxo-2’deoxyguanosine, a major product of DNA oxidation.

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41
Q

What is most susceptible to ROS damage in proteins?

A

Tyrosine, histidine, cytosine and methionine in receptors, transport proteins and enzymes.

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42
Q

What protection is there against ROS?

A

Antioxidants: synthetic or natural substace that delay or inhibit the oxidative damage to a target molecular. Capable of nueutralising radicals by donating an electron or a hydrogen moleculare. Act as scavnegers and prevent cell damage.

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43
Q

What two types of antioxidants are there?

A

Antioxidant enzymes: several enzymes such as superoxide dismutase and catalase will convert the free radicals into less harmful products. Found within the ETC: superoxide dismuatseis found after complex 3.

Antioxidant vitamins (natural products):
Vitamin E: fat soluble, prevents the oxidation of lipids,
Vitamin C: water soluble, reacts with several radical species and neutralises them producing semidehydroascorbate acid or ascorbic radical,
Vitamin A: works as an antioxidant in form of carotenoids. Mainly beta carotenoids (CAR) react with free radicals and prevent lipid oxidation.

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44
Q

What evidence is their of MFRTA and oxidative damage?

A

Observation that Mitochondria continously produce ROS, observation that oxidative damage increases with age and the discovery of SOD.

eg. Sohal and Sohal 1991

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45
Q

Why has the MFRTA been questioned?

A

ROS can be beneficial, some observations that show ROS may have a function in the cell, not just a damaging by-product.

Lack of correlation between the level of ROS and longevity.

Administration of antioxidants can be deleterious rather than beneficial on lifespan. Inactivation or overexpression of antioxidant activities in GM organism fail to produce the outocmes supported by MFRTA.

Exstance of long-lived mutants and species with high ROS production and high oxidative damage.

46
Q

What is the role of ROS in the cell?

A

They are second messengers controlled at level of synthesis and removal. They have specific targets and signalling effects are reversible. Often involved in signal transduction pathways to maintain cellular homeostasis in classic signalling cascases such as ERK, JNK and MAPK. These signalling cascaes control activites of TF central to homeostant and stress responses, such as Nrf2, FOXO and HIF-1.

47
Q

Who opted for a ‘sober life’?

A

Luigi Cornaro, decided at the age of 30 to live a very reserved and ‘basic’ life with caloric restriction and lived till 102.

48
Q

What metabolic effects does caloric restriction have?

A

Decreases energy intake,

decreased respiratory exchange ratio, similar metabolism, decreased temperature, decreased white adipose tissue.

49
Q

What physiological effects does caloric restriction have?

A

Increased metabolic flexibility, increased stem cell function, increased DNA repair, decrease age-related disease, decreased inflammation.

50
Q

How is food availability and metabolism coupled to lifespan?

A

There are several nutrient sensing signalling pathways which can regulate lifespan extension which are all independent on each other. They are conserved in yeast and in all model organisms used in ageing.

51
Q

Discuss the TOR/AMPK pathway?

A

Target of rapamycin.
Two parts: upstream is regulated by AMPK and then the actual TOR pathway.

mTOR is a serine/threonine kinase which senses cellular nutritional conditions. It has multiple intercations with the ILS network
and controls protein synthesis and growth in reposnse to nutrient intake. mTOR kinase is part of a two multi-protein complexes mTORC1 and 2.

mTORC1: in complex with raptor and regulates gene expression reposnsible for growth, protein synthesis and ribosome biogenesis.

mTORC2 in complex with rictor and controls gene expression for proliferation and survival

They have distinct constituent proteins and regulate different downstream processes.

52
Q

What has reduced signalling through TOR been shown to do?

A

Reduced signalling through TOR through genetic mutants

extends lifespan in a variety of model organisms.

53
Q

What does rampamycin block?

A

Interaction with mTOR and raptor

54
Q

What does mTORC1 do?

A

Regulates protein synthesis through 4E BP1 and S6K and negatively regulates autophagy through ULK1.

55
Q

What does mTORC2 do?

A

Inhibits FOXO3a through S6K1 and AKT which can lead to increased longevity.

56
Q

Who showed what in C.elegans to do with TOR?

A

Deficiency of TOR, using RNAi and mutants, can lead to lifespan extension.
Vellai (2003)

57
Q

Who showed what in mice to do with TOR?

A

Double knock-out of mTOR showed a longer lifespan, no abnormalities in food intake, glucose homoeostasis or metabolic rate.
Wu JJ et al. (2013)

58
Q

What is AMP-K?

A

AMP-Activated protein kinase

Measures the energy status of cells and functions as a nutrient sensing switch. Under low energy conditions AMPK is activated and it inhibits energy consuming processes such as protein sysntehsis through the inhibition of TOR signalling.

AMPK modulates critical metabolic functions in mammals
Acts in the hypothalamus to promtore feeding and regulates glucose homeostasis in the liver..

59
Q

What happens to the lifespan extension in worms with non-functional AMPK?

A

It is abolished.
Apfeld J et al. (2004)

Over expression increased lifespan.

60
Q

How is the TOR/AMPK and ILS connected?

A

mTORC1 is activated by ILS through AKT. mTOR and ILS also interact through mTORC2, which activates AKT to repress FOXO.

61
Q

What is the insulin like signalling pathway?

A

A nutrient sensing pathway that regulates lifespan.

62
Q

Discuss daf mutations?

A 
They double lifespan.
Abnormal in dauer formation.
Two types: 
Daf-c: constitutive (increased longevity) 
Daf-d: defective
63
Q

What do c.elegans with mutations in Daf show?

A

Dauer larva are very stress resistant and can live in that stage for a very long time (x7).

Non-feeding (buccal cavity sealed, survive on stored food) , altered fat metabolism and remodelled tissues.

64
Q

What are the human homologous to the lifespan genes: age-1, daf-2 and daf-16?

A

age-1: catalytic subunit of PI3K
daf-2: insulin or IGF-1 receptor
daf-16: FOXO-class forkhead transcription factor.

65
Q

What other mutation must dauer have for longevity?

A

Mutation in age-1

66
Q

Discuss the similarities with daf-2 mutations in drosophila?

A

Ageing also modulated by ILS: Mutations in INR (fly daf-2):
mean female lifespan increased by up to 85%. Mutation of chico (insulin receptor substrate), increases lifespan by up to 48%
1 + chico

67
Q

When is extended longevity seen in mice?

A

Ron Kahn (2003): fat-specific insulin receptor knockout (FIRKO) mouse. Protected against age-related obesity, 18% increase in mean lifespan in both sexes.

68
Q

Discuss ‘can ageing me drugged’?

A

Rapamycin increases the life span of mice (it inhibits mTOR bidning to raptor).
Resverator mimics the effects of dietary restriction, mechanism not well understood thought to up regulates AMPK (found in red wine).

69
Q

How where sirtuins discovered?

A

Maintenance of chromatin silencing and genome stability.
In yeast they looked at how genes worked- not to do with ageing. Mating type loci- 3 alpha helices. There is a transposin upstream which can change the mating type by homologous recombination from a to alpha, this is usually silenced by sirtuins.

Klar et al 1979

70
Q

What does Sir2 do?

A

Represses transcription/ histone deacetlyase

Essential for controlling many cellular process: gene expression, promoters, large regions of the genome in a condensed/activated state.
Sir2 maintains the chromatin silence across the heterochromatin like domains.
Sir2 de-acetylates histones, - remove acetyl groups from an ε-N-acetyl lysine amino acid on a histone, through a NADP dependent reaction.

71
Q

What to HDACs which effect the insulin regulation have similar effects to?

A

Dietary restrcition

72
Q

What type of HDACs are sirloins?

A

A family of NAD+ dependent histone deacetylases that play important roles in gene silencing, DNA repair, rDNA recombination, and ageing.

73
Q

How does NAD+ dependent Sir 2 work?

A

Cleavage of a molecule of NAD+ results in nicotinamide (NAM) and O-acteyl-ADP-ribose which is coupled to de-acetylation of a single lycine side chain.

74
Q

How does Sir2 promoting longevity in yeast correlate with silencing in the ribosomal DNA?

A

Products of rDNA recombination:
extrachromosomal rDNA circles (ERCs) replicate and segregate preferentially to mother cell nuclei.
ERCs accumulate in mother cells as they grow older and trigger senescence. Sir2 in yeast stalls appearance of the first rDNA circle in mother cells by creating silenced chromatin structure. ERCs in daughter cells cause premature senescence.

75
Q

How do ERCs effect ageing in yeast?

A

Do not segregate equally during budding so that the old mother cell retains more than the new daughter. They are amplified during each round of cell division becase of the RAS. They accumulate over time. ERC formation has been causatively linked to ageing.

76
Q

How does silencing genes effect ERCs?

A

Observed to relocate from the telomers to the nucleolous and this is associated with life span.

Sir2 has been shown to supress recombination of rDNA repeats and to supress the formation of ERCS. Deletion of SIR2 shortens life span, and an additional copy of SIR2 increases life span.
(Sinclair and Guarente, 1997).

77
Q

What does one extra copy of Sir2 do?

A

Increases replicative lifespan of yeast.

78
Q

What is required with caloric restriction in yeast to increase lifespan?

A

NAD and Sir2

Achieved by decreased glycoslyis which increases cellular NAD levels which activates SIR2 increasing silencing.

79
Q

What is the human homologue of Sir2?

A

Also an NAD dependent HDAC which de-acetylates p53 and FOXO and is inhibited by nicotinamide.

80
Q

Describe the evolutionary conserved sirtuins?

A

7 members classified into 4 classes with a 275 aa catalytic core domain. All have different subcellular localisation classified

Drosophilia and c.elegans fall into class 1.

81
Q

What suggests that Sir2.1 and dad-2 are in the same pathway?

A

Sir2.1 over expression does not further extend lifespan in daf-2 mutants.
Lifespan extension requires presence of daf-16 when sir-2.1 is over expressed

82
Q

Describe the function of sir2.1?

A

sir-2.1 functions in a stress response pathway parallel to ILS that impinges directly on DAF-16.

Under normal conditions DAF-16 is sequestered in the cytosol by 14-3-3 proteins, heat stress induces translocation of DAF-16- 14-3-3 complex into the nucleus. There interaction with SIR-2.1 is dependent on presence of 14-3-3 to induce longevity. Under low insulin-like signalling conditions
DAF-16 is un-phosphorylated and dissociates from 14-3-3. Transcriptional activation of life span extension is independent of interaction with 14-3-3/SIR-2.1.

83
Q

What are telomeres?

A

Telomeresare repetitive nucleotide sequences (simple tandem repeats- TTAGGG) located at the termini of linear chromosomes of most eukaryotic organisms.

84
Q

What do telomeres do?

A

One function is to prevent the end of the linear chromosomal DNA from being recognised as a broken end, this prevents DNA end joining, DNA recombination, DNA repair that would lead to unstable chromosomes.

85
Q

What is the replication end problem?

A

During each cell division linear duplex DNA is replicated in an inherent asymmetric fashion.
As DNA replication machinery moves along chromosome, only the leading strand is produced continuously. The opposing (lagging) strand is replicated in short discontinuous segments of DNA called Okazaki fragments. These short strands are initiated by a very short stretch of RNA which primes each round of DNA synthesis. At the termini of chromosomes that are replicated by lagging strand synthesis, removal of the terminal RNA primer results in irreparable loss of a very small portion of chromosomal DNA. With multiple rounds of cell division, cumulative loss would be incompatible with long term maintenance of the genome.

86
Q

What provides a solution to end end replication problem?

A

Telomerase: a special reverse transcriptase which maintains the telomere. It carries its own template RNA, which is complementary to the telomeric repeat sequences.

87
Q

How does telomerase?

A

Comprised of both RNA and protein: a ribonucleoprotein.
RNA component: hTERC, contains the complimentary telomeric TTAGGG sequence
Protein component: hTERT, has the reverse transcription activity

88
Q

How do tetrahymena cells respond if telomerase is non-functional?

A

A telomerase RNA mutant is unable to copy the template. The lack of functional telomerase lead to progressive loss of DNA from the chromosome end and eventual death.

89
Q

Describe the result of Est-1 (a component of the yeast telomerase complex) mutants in yeast?

A

Yeast strains lacking est1 were growing normal initially but after prolonged culture stopped growing.
Their telomeres were shorter, a high rate of chromosome loss was coincident with senescence.

90
Q

In multicellular eukaryotes where is telomerase activity?

A

Only in germ cells, stem cells and certain white blood cells.

Keratinocytes have very low telomerase and are in senescence, they undergo progressive telomerase shortening.

91
Q

Discuss the investigation into immortality?

A

Immortalisation is different from oncogenic transformation. Human TERT was transfected into fibroblast and greatly extended lifespan- limitless.
Control cells underwent senescence at the Hayflick’s limit.

92
Q

What stops us from being immortal?

A

Telomerase regulation.

93
Q

What happens to human telomerase expression during embryogenic development?

A

It is reduced in somatic cells.

94
Q

What are regulators of telomerase?

A

Three tumour suppressor pathways negatively regulate telomerase: Mad1, TGFb, and menin (binds directly to hTERT promoter),
DNA binding proteins,
T-loop conformation,
POT1 binding.

95
Q

Discuss DNA binding proteins as as telomerase regulators?

A

Two main protein complexes are bound to telomeres: telomere repeat binding factor 1 and 2 (TRF)
Both are multiportien complexes their binding prevents acces by telomerase. Once telomere shortens, TRF can’t bind and telomerase has access to restore end.

96
Q

Discuss telomerase t-loopo formation as a regulator or telomerase?

A

Long telomeres including human form t-loop structures the G-strand can also fold back ad anneal with double stranded region on the TTAGGG repeats.
Proposed to represent as a mechanism for chromosome end protection and functions to restrict telomerase.

97
Q

How does POT1 binding regulate telomerase?

A

It binds to the 3’ end and repressors telomerase as it cannot bind when it is present.

98
Q

What diseases are caused by shortened telomerase?

A

Cancer, pulmonary fibrosis, CVD, Vascular dementia, Degenerative conditions, Diabetes, General risk factors for chronic disease.

99
Q

What is werner’s syndrome?

A

Aka. adult progeria, an atusomal recessive disease caused by the loss of WRN protein. Only 20 population doublings.

Symptoms include: signs of scleroderma-like skin changes particularly in the extremities, cataracts, subcutaneous calcification, premature atherosclerosis, diabetes mellitus, cancer.

100
Q

Discuss WRN protein?

A

Nucleolar protein which co-purifies with a 17S DNA replication complex and binds proteins involved in DNA and RNA processing (including DNA repair).

101
Q

What does loss of WRN cause?

A

Transcriptional changes
RNA pol II transcription is reduced by 40–60%.
Deletion of telomeres from single sister chromatids.
Effects genomic instability, telomere maintenance, recombination, transcription, apoptosis, replication andDNA repair.

102
Q

What mutations of WRN causes Werner’s syndrome?

A

Loss of proliferation renewing cell populations fail to replenish themselves.

103
Q

How are cancer and telomerase linked?

A

Cancer, in the early stages, have short telomeres to promote misincoporation and mutation. In later stages telomerase is activated to promote survival, proliferation and metastasis.

104
Q

What is the proteostasis network?

A

The protein quality control network maintains proper function of the cellular proteome or Protein Homeostasis

105
Q

Name some examples of loss of function diseases caused by protein misfolding?

A

Cystic Fibrosis, Tay-sachs

106
Q

Name some examples of gain of toxic function diseases caused by protein misfolding?

A

AD, PD, HD, Prion

107
Q

What are the two major degradation pathways?

A

Ubiquitin proteasome system (UPS) and Autphagy

108
Q

What is the link between ageing and proteostasis?

A

Pathways that regulate ageing modulate many aspects or proteostasis.

Daf-16/FOXO
HSF-1
Transcription factors that regulate chaperone expression
Effector molecules- mTOR

109
Q

List the signalling pathways that regulate proteostasis?

A 
FOXO
HSF1
IRE1
ATF6
PERK
NRF2
Ca2+ signalling 
Proteasome
110
Q

What deteriorates with time (age)?

A

The proteostais landscape, proteostasis becomes less efficient.

111
Q

What is the master regulator of the cytosolic heat shock response?

A

HSF-1

112
Q

What does the HSR induce?

A

Molecular chaperones eg. HSP70/90 and small HSPs

ATU 3 (3 decks)

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