Ageing Flashcards
1
Q
What can live more than 5000 years?
A
Pinus longaeva (Bristlecone tree)
2
Q
What is the molecular basis of longevity?
A
Somatic maintenance
3
Q
What is regenerative medicine?
A
Uses stem cells to replace ageing tissues and organs
4
Q
What can ageing refer to?
A
Progressive deterioration of cells, tissues etc, associated with increased age, but also maturational changes, which are positive, such as getting wiser, evolution of lifestyle etc.
5
Q
What is Michael Rose’s definition of senescence?
A
“The decline of fitness components of an individual with increasing age, owing to internal deterioration”
6
Q
What is the difference between ageing and senescence?
A
Senescence only refers to the progressive deterioration- ageing may also refer to the positive aspects.
7
Q
What is gerontology?
A
The scientific study of the biological, psychological and sociological phenomena associated with old age and ageing.
8
Q
What is geriatrics?
A
The branch of medicine that deals with the diagnosis and treatment of diseases and problems specific to the aged.
9
Q
What is biogerontology?
A
The study of the biology of ageing and longevity
10
Q
What does demography refer to?
A
The study of the characteristics of human populations, such as size, growth, density and distribution of vital statistics.
11
Q
Give one way to express the pattern of death or mortality in a population?
A
Survival curves.
12
Q
How can lifespan be expressed?
A
As life expectancy from birth or from a later age
13
Q
What is the difference between changes in life expectancy from 65 and that from birth?
A
LE has changed hugely from birth over time (due to reduction in infant mortality) but from 65 it has changed little.
14
Q
What is median lifespan?
A
The age at which 50% of he population have died.
15
Q
What is maximum lifespan?
A
The age at death of the last surviving individual in a population cohort.
16
Q
How have improvements in health and sanitation affected the different ways to express lifespan?
A
They’ve increased the mean and median lifespan but have changed the maximum lifespan little.
17
Q
Who was the longest-lived human verifiable?
A
Jeanne Calment- lived to 122
18
Q
What is a current estimate of maximum lifespan in english women?
A
That 1.6% will live to reach 100.
19
Q
What is the gender gap?
A
5-7 years in LE from birth
20
Q
What is thought to be the reason for the gender gap?
A
Due to endocrine differences, effects of testosterone on male behaviour and physiology.
21
Q
What is mortality rate?
A
The probability that an individual who is alive at a particular age will die during the following age interval- typically a year in humans.
22
Q
What is the Gompertz law?
A
Mortality rate increases exponentially with increasing age. Acceleration in mortality rate as you get older- demographic senescence.
23
Q
Describe a lot plot of mortality and age.
A
Mortality increases as a linear function of age, except for the “hump” around 20 years- reckless and dangerous decisions.
24
Q
What is the Gompertz parameter?
A
The slope of the log of mortality against age.
25
How can demographic ageing be expressed?
As the rate of increase in mortality rate in the form of mortality rate doubling time (MRDT).
26
What is MRDT?
Mortality rate doubling time: The time required for the mortality rate to double (to be twice as likely to die)
27
What is the MRDT in humans?
8 years
28
What are the three major aspects of biogerontology?
Evolutionary biology of ageing, traditional gerontology (biological mechanism) and model organism lifespan genetics.
29
What was first thought to be the reason for ageing evolving?
To be for the good of the species, to remove worn out individuals and reduce the competition for limited resources.
30
Who had the first insight into evolution of ageing, and what were they studying?
J.B.S. Haldane. Studying Huntington's.
31
What is Huntington's?
A genetic, neurodegenerative disease caused by a highly penetrant dominant mutation.
32
How did Haldane reach his conclusions? (ageing)
Av. age of Huntington's onset= 35.5 years- natural selection hasn't removed it because for most of evolutionary history people didn't live that long, so selection pressure to remove the mutation is weak, as it's after children have been born.
33
What was Haldane's conceptual leap?
The later the timing of onset of a deleterious effect, the weaker the force of natural selection acting against it, predicting an accumulation in the population of late acting deleterious mutations.
34
Who developed the mutation accumulation theory?
Peter Medawar
35
What is the mutation accumulation theory?
Even in a population free of ageing, death will occur, from extrinsic hazards such as disease, predators and accidents. Recurrent, deleterious germ line mutations occur, and fewer bearers survive to express later- acting mutations. The force of natural selection against them declines with age, and these mutations can therefore reach a higher frequency under mutation- selection balance. There's a strong force of natural selection on early acting mutations but not late acting mutations, as fewer bearers are still alive.
36
Who came up the the pleiotrophy theory of evolution of ageing?
George Williams
37
What are other names for the Pleiotrophy theory?
Trade-off, antagonistic pleiotrophy
38
What is the pleiotrophy theory of the evolution of ageing?
Ageing evolves as a side-effect of natural selection in favour of mutations that cause a benefit during youth.
39
What is the reasoning behind the pleiotrophy theory of the evolution of ageing?
Some mutations may be beneficial in youth but have a higher rate of ageing; more individuals will survive to express the early benefit than survive to suffer higher rate of ageing due to extrinsic factors. Such mutations can be incorporated by natural selection.
40
What is the adaptive value/ purpose of ageing?
There isn't any.
41
What were Loeb and Northrop's findings (ageing)? What coefficient did they find?
That increasing temperature reduces Drosophila lifespan. Coefficient relating lifespan to ambient temperature = 2-3. The biochemical reactions constituting life processes happen faster at higher temperatures.
42
What did Miquel (1976) find about lifetime oxygen consumption vs physiological temperature range?
That it was constant from 18-27 degrees C (physiological temp). Value for 27 degrees c slightly lower- at top end of physiological range for Drosophila - reflects high rate of living and thermal injury.
43
What is the Rate-of Living Theory?
Pearl (1928). Metabolism rate critical in ageing. "The duration of life varies inversely as the rate of energy expenditure... the length of life depends on the rate of living". Life energy potential is constant.
44
What is the free radical theory of ageing?
Harman (1956): Ageing results from damage to macromolecules caused by free radicals.
45
What is a free radical?
Any species capable of independent existence that contains one or more unpaired electrons. They are usually highly reactive
46
Why may free radicals cause damage and thus ageing?
Superoxides can react with DNA, with lipid and with protein.
47
What are some examples of radicals in the body?
Superoxide, hydroxyl, peroxyl, alkoxyl, hydroperoxyl.
48
What are some examples of non-radical superoxides?
hydrogen peroxide, hypochlorous acid, ozone, peroxynitrie.
49
What theory does it make more sense to talk about than the free radical theory of ageing?
The oxidative damage theory of ageing.
50
How could you link the free radical theory of ageing to the rate-of-living theory?
Mitochondrial oxidative phosphorylation generates superoxide. Hence higher metabolic rate results in more free radicals and therefore faster ageing
51
What is the the pre-1961 view of cellular senescence?
"All metazoan cells (replicating somatic cells e.g. fibroblasts) are potentially immortal. Ageing not cell autonomous."
52
What did Hayflick and Moorhead do in 1961?
Isolated cells from human tissue and cultured them- cells divide and form confluent layer on vessel surface. Discarded half of these, allowed remained to grow to confluency (one passage). Continued to passage the cells.
53
What did Hayflick and Moorhead find (1961)?
Passaged normal cultured human cells eventually lose their capacity to replicate, after 50 +/- 10 passages. Reach the HAYFLICK LIMIT and undergo replicative senescence.
54
Why was Hayflick's finding shocking?
It implied that cell biology could explain ageing; organismal ageing was due to morphological change.
55
Give two examples of very closely related species and how they differ in lifespan.
Chimpanzee (59 years) and humans (110). C. elegans (3 weeks) and Loa loa (20 years)
56
What is the classical genetic approach to ageing?
1) isolate mutants with altered rates of ageing2) map, clone and sequence genes concerned3) identify lifespan-determining proteins, biochemistry, etc.4) Understand ageing!
57
What is the advantage of the classical genetic approach to ageing?
It requires no prior hypotheses about the biology of ageing.
58
What are the four model species for lifespan genetics? What do they all have?
Saccharomyces cerevisae, Caenorhabditis elegans, Drosophila melanogaster, Mus musculus.They all have sequenced genomes and extensive classical genetics.
59
Describe the use of S. cerevisae as a model species for lifespan genetics.
Cheap to work with, has the best genetics (haploid). However, it isn't an animal (unicellular fungus)- does it really age like animals do?
60
What is the disadvantage of using C. elegans as a model species for lifespan genetics?
It's not a mammal- what causes worms to die might be very different to what causes humans to die.
61
What are the advantages of using C. elegans as a model species for lifespan genetics?
It is an animal, very cheap to work with, shows real ageing, a 2-3 week lifespan, and no inbreeding effects.
62
What are the advantages of using Drosophila melanogaster as a model species for lifespan genetics?
Animal, very cheap to work with,shows real ageing, 6-8 week lifespan
63
What are the disadvantages of using Drosophila melanogaster as a model species for lifespan genetics?
Shows inbreeding effects, more expensive than C. elegans.
64
What are the advantages of using Mus musculus as a model species for lifespan genetics?
A mammal, with very good genetics. Get many of the same age-related diseases that humans do.
65
What are the disadvantages of Mus musculus as a model species for lifespan genetics?
2-3 year lifespan, shows inbreeding effects, very expensive to do lifespan tests.
66
Describe C. elegans.
Microbiverious terrestrial nematode, ~1.2 mm long. Sequenced genome ~97,000,000 bases, ~19,000 genes. Has 2 sexes.
67
What are the signs of ageing in C. elegans?
Reduced fertility, feeding, movement. Increased cuticular wrinkling (collagen cross linking). Increased protein oxidation (protein carbonyl), DNA damage (e.g. mitochondrial DNA deletions), accumulation of lipofuscin
68
Are long-lived or short-lived mutants more informative in the study of ageing mutants?
Long-lived, because short-lived might just be sick.
69
What did Michael Klass do in 1983 (ageing)?
First screen for long-lived mutants
70
What did Tom Johnson identify in 1988?
The age-1(hx546) mutation
71
What does the age-1(hx546) mutation do?
65% increase in mean lifespan, 110% increase in maximum lifespan, remains youthful for longer.
72
What did Cynthia Kenyon identify in 1993?
That mutations in daf-2 greatly increase lifespan- doubled lifespan. Also affect dauer larva formation.
73
What are dauer larvae?
Developmentally- arrested, alternative third stage larva. Stress-resistant, non-feeding, buccal cavity sealed, survive on stored food. Live for up to 70 days.
74
What does is mean that dauer larvae are non-ageing?
Post dauer adults have normal lifespans.
75
What do dauer larvae form in response to?
High population density (dauer pheromone), high temperature and low food.
76
When does exit from the dauer stage occur? What happens?
When food levels increase and population density drops. Animals develop into adults. The length of time spent in the dauer stage has no effect on the life span of the post-dauer adults.
77
How many genes have been found to control dauer larva formation?
Over 30
78
What are daf mutants abnormal in?
Dauer formation
79
What are the Daf-c mutants?
Dauer-constitutive; form dauers in non-dauer inducing conditions
80
What are the Daf-d mutants?
Dauer-defective; cannot form dauers at all.
81
What are some examples of Daf-c genes?
Daf-2 and age-1
82
What does wild-type daf-2 do?
Shortens ageing.
83
What is an example of a Daf-d gene?
daf-16
84
What does wild-type daf-16 promote?
Longevity
85
What do daf-2(-) and age-1(-) switch on?
Dauer longevity programme in the adult, leads to a long-lived mutant.
86
What are most daf-c sensitive to?
temperature
87
What happens to daf-2 mutants at different temperatures?
Daf-c at non-permissive; develop into long-lived adults at permissive (under 20, bypass dauer stage, double lifespan).
88
Describe age-1 mutants.
All age-1 mutants are long-lived, but only severe age-1 alleles are Daf-c
89
What does wild-type daf-16 promote?
Longevity
90
Describe the lifespan of daf-16 mutants.
Not long lived
91
If you take a long-lived daf-2 mutant and knock out daf-16, what will happen?
it will no longer be long-lived
92
What is the longevity of daf-2 and age-1 adults due to?
Dauer-specific longevity assurance processes, not just due to developmental arrest or dormancy
93
What are the two distinct longevity programmes in C. elegans?
For adult and dauer larva.
94
Who discovered the human homologues of the daf genes?
Gary Ruvkun (1987/1988)
95
What is the human homologue of age-1?
The catalytic subunit of phosphatidyl inositol 3-kinase (lipid kinase)
96
What is the human homologue of daf-2?
Insulin or IGF-1 receptor, cell receptor
97
What is the human homologue of daf-16?
FOXO-class forkhead transcription factor
98
Do the daf-2, daf-16 and age-1 homologues overlap?
They act together in mammalian cells
99
Is insulin/IGF-1 signalling a public or private determinant of ageing?
Public
100
What does IIS stand for?
Insulin/IGF-1 signalling
101
What is the effect of reduced IIS in Drosophila (Partridge, Gems, Tatar labs)?
Increases lifespan
102
What is chico (Drosophila) homolgous to?
insulin receptor substrate
103
What is dINR homologous to?
DAF-2 insulin/IGF receptor.
104
Describe the lifespan of chico and dINR mutants
They are long-lived
105
Describe the action of ageing-related gene products in the insulin-like pathway in Drosophila.
Insulin-like peptides bind dINR (daf-2 homolog). Induces chico binding to P3IK (catalytic subunit = homolog to age-1). Phosphorylates PtdIns(4,5)P2 to form PtdIns(3,4,5)P3. Leads to Protein kinase B phosphorylating dFOXO (daf-16 homolog).
106
What do mutations in dINR lead to?
female lifespan being increased up to 85%
107
What do mutations in chico lead to?
Lifespan increase up to 48%
108
What are the implications in the revelation that insulin/IGF-1 signalling modulates ageing in insects as well as nematodes?
That there is wide evolutionary conservation of the role of insulin/IGF-signalling in the modulation of ageing- it is a public mechanism.
109
How does the IIS system differ in mammals from worm and flies?
worms and flies have one insulin/IGF-1 receptor, whereas mammals have an insulin receptor, an IGF-1 reeptor, an insulin-receptor-like receptor etc.
110
What does mild reduction in the function of the insulin receptor gene lead to, and why is this significant to its impact on ageing?
Type 2 diabetes, which shortens lifespan and therefore it is unlikely that insulin signalling promotes ageing
111
What did Ron Kahn (2003) do?
Studied the fat-specific insulin receptor knockout (FIRKO) mouse, which lacked the insulin receptor in white adipose tissue
112
What does FIRKO stand for?
Fat-specific receptor knockout
113
What was found in FIRKO mice? What may this suggest
They were protected against age-related obesity and showed an 18% increase in mean lifespan. May suggest a role of adipose tissue in regulating ageing.
114
What is the role of IGF-1?
Insulin-like growth factor 1- a cell growth and survival factor. Roles in puberty, gonadal function and reduced adiposity.
115
How is IGF-1 produced?
Production stimulated by growth hormone from the anterior pituitary gland. Circulating IGF-1 in blood mainly produced in the liver
116
What do GH and IGF-1 control?
Body size
117
What is the somatotropic axis?
GH, GH-receptor and IGF-1
118
What is the major role of GH?
To promote IGF-1 production.
119
What does no growth hormone lead to?
Dwarfism
120
What is the Ames dwarf mouse?
A very small mouse with a mutation in the Prop-1 gene
121
What does the Prop-1 gene code for?
A transcription factor required for the development of anterior pituitary gland, hence mutants don't produce GH.
122
What did Bartke (1996) find?
That the mean lifespan of the Ames dwarf mouse was increased by 70-80%.
123
Which hormones does the combined pituitary hormone deficiency seen in the Ames dwarf mouse include?
GH, thyroid stimulating hormone, prolactin.
124
What does combined pituitary hormone deficiency in the Ames dwarf mouse lead to?
Greatly reduced fertility, obesity, low circulating insulin and glucose, dwarfism and undetectable circulating IGF-1 levels.
125
Apart from the Ames dwarf mouse, what other long-lived dwarfs are there?
Snell, Little, Laron
126
What gene is mutated in the Snell mouse?
Pit1- codes for a transcription factor
127
What gene is mutated in the Little mouse? What does this cause?
Ghrhr- codes for GH releasing hormone receptor, so don't produce GH.
128
What gene is mutated in the Laron mouse?
GHR, coding for the GH receptor
129
What appears to be the role of growth hormone with regards to ageing?
It promotes growth and ageing.
130
What did Holzenberger (2002) find?
That mice heterozygous for a deletion of the IGF-1 receptor gene were resistant to oxidative stress and the females showed an increase in their mean lifespan of 33%.
131
What do Holzenberger's (2002) findings show?
Evidence that IGF-1 accelerates ageing.
132
How do GH levels vary with age? What is this referred to as?
They drop with age. Referred to as the Somatopause.
133
What occurs during the Somatopause?
Reduced muscle mass, increased adiposity.
134
What is the 'proportionate dwarf' deficient in?
GH
135
Is there any correlation between body size and longevity?
There's a negative correlation seen in mice, rats and dogs. This is also seen among affluent humans.
136
What do both height and longevity correlate with?
GH and IGF-1 levels.
137
What were the findngs of comparing weights of baseball players and lifespan?
For every kg, they lived on average 0.4 years less.
138
What did Guevara-Aguirre et al find in a recent 2011 study of 99 Ecuadorian GH receptor deficient dwarfs?
Monitored them for 22 years; no dwarves died from cancer whereas ~20% of their relative's from age 30-70 did. No dwarves got diabetes. Suggests that dwarves are possibly resistant to age related diseases but not long lived.
139
How have allele frequency studies been carried out to study age-related genes?
Changes in frequency of polymorphic variants of genes related to GH synthesis, IGF-1 signalling and insulin action with age were studied.
140
What did Bonafe et al. (2003) find in their study of Allele A of IGR-1R?
It was more frequent among long lived people.
141
What is Allele A of IGR-1R associated with?
Low plasma IGF-1
142
What did van Heemst et al. (2005) find in their study of a SNP variant of the GH1 gene?
They found a 0.8- fold reduced mortality.
143
What is the SNP variant of GH1 gene that van Heemst et al. (2005) studied associated with?
Carriers are 2cm shorter.
144
What did Willcox et al. (2008) find in their study of the FoxO3A allele?
It was associated with longevity and there was less cancer and cardiovascular disease.
145
What do the studies by Bonafe et al (2003), van Heemst et al (2005) and Willcox et al (2008) show?
Mounting evidence that the somatotropic axis and FoxO controls human ageing.
