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Flashcards in lecture 34 Deck (25):
1

Objectives?

- understand the relationship between cell health and ageing and the factors and mechanisms which impact upon cells
- be able to relate the role of the IGF-1 pathway and autophagy in cellular senescence

2

What is ageing/senescence?

senescence: deterioration that is associated with ageing

maximum life span: the maximum number of years that a member of a species has been known to survive

drosophila: 3 months
mouse = 3 years
humans = 120 years
some turtles and lake trout = 150 years
some trees = >1000 yeras
dahlia anemone - non ageing

3

What is stem cells and tissue homeostasis?

- balance between stem cells self renewing and replenishing baseline cell population
- differentiation.
- proliferation
- apoptosis

4

What are principle structural targets for cell damage?

- cell membranes
→ plasma and organelle membranes
- DNA
- proteins
→ structural
→ enzymes
- mitochondria
→ oxidative phosphorylation

5

What is the general pathogenesis of cell injury?

- reduced ATP synthesis/mitochondrial damage
- loss of calcium homeostasis
- disrupted membrane permeability
- free radicals (as cell gets older gets less able to deal with free radicals)

6

What are general protective mechanisms?

heat shock response genes
- comprise a large group of genes
- expression is up-regulated in the face of cell stressors
- serve to protect proteins from stress-related damage
- "clean up" damaged proteins from the cell

many tissues and organs can survive significant injury if they are "pre-stressed" = adapt
- ways to exploit this phenomenon to improve organ transplantation and tissue repairs are being tested in clinical trials

7

What is the key factor that determines reversible and irreversible injury?

time
duration of injury → age

8

What are differences between reversible and irreversible injury?

reversible
- loss of ATP
→ failure of Na/K pump
- anaerobic metabolism
→ increased lactic acid and phosphate
- reduced protein synthesis

irreversible
- massive intracytoplasmic calcium accumulation
- enzyme activation

irreversible arrest of cell proliferation (senescence)/tumour suppressor mechanism initiated by:
- DNA damage
- chromatin instability
- short/dysfunctional telomeres (replicative senescence)
- stress signals (oxidative damage, culture shock)
- oncogenes (oncogene-induced senescence)

9

What is autophagy?

- process in which a cell eats in own contents
- it is a survival mechanism in times of nutrient deprivation, which the starved cell lives by cannivalising itself and recycling the digested contents
- autophagy is important in maintaining cell health as it clears cellular 'rubbish'
- when autophagy is inefficient, cellular rubbish accumulates and cells senesce faster
- important in ageing → becomes less efficient over time

10

What are factors that contribute to cellular ageing?

- telomere shortening
- environmental insults
- DNA repair defects
- calorie restriction
- abnormal growth factor signalling (e.g. insulin/IGF)

- genetic factors and environmental insults combine to produce the cellular abnormalities characterstic of ageing

11

What is the evolution of ageing?

- Huntington's chorea: a genetic, neurodegenerative disease caused by a highly penetrant dominant mutation
- 1941 Haldane: why has natural selection not acted to remove the Huntington's mutation from populations
- average age of onset of Huntington's 35.5 years
- for much of the evolutionary history of mankind, most people did not live to be that old
→ the selective pressure to remove the Huntington's mutation is therefore weak
- therefore is ageing the result of late-acting (in oder people) deleterious mutations?

12

What is the mutation accumulation theory in ageing?

- even in a population free of ageing, death will none the less occur, from extrinsic hazards such as disease, predators and accidents
- mutation accumulation theory predicts that genetic diseases should increase in frequency with age and that there could be large heterogeneity in deleterious genes between different individuals throughout the entire genome – this is by and large accurate

13

What are causes of cell injury?

- hypoxia
- chemical
- physical
- infection
- immune
- nutritional deficiency or excess

14

How does protection from ROS change?

- superoxide dismutases, catalases, peroxidases, down regulate as time goes on

15

What is a feature of telomeres?

- cells with long replicative capacity have very long telomeres

16

What is Werner's syndrome?

- characterised by premature senescence
- a rare inherited disease that results in premature ageing
- individuals are normal in childgood but stop growing in their teens
- patients are more susceptible to cancer, osteoporosis, diabetes and cataracts
- they usually die in their late 40s
- WRN: the gene responsible for Werner's syndrome encodes a helicase, an enzyme that unwinds DNA for replications, DNA repair or transcription
- both copies of the gene must be mutated or lost
- one pssobile cause of Werner's syndrome is improper DNA repair and rapid accumulation of mutations
- another possibility is improper transcription of genes that are needed to maintain vigor or normal function
- the ability of cells to grow to a confluent monolayer decreases with increasing population-doubling leveles: indicates change in telomerase and senescence

17

What is progeria?

- clues to specific genetic factors in ageing
- hutchinson gilford progeria syndrome: causes children to age rapidly, undergo senescent changes and to die as young as 12 years old
- it is an extremely rare disease, and there are only 100 known cases worldwide
- it appears to be caused by a dominant mutant gene, Lamin A, which appears to be involved in nuclear integrity

symptoms: are similar to ageing in older persons, these include loss of hair, thin transparent skin with age spots, osteoporosis and atherosclerosis
- the aetiology is unclear: infants with progeria have shorter telomeres than normal children, and this might be important in the pathogenesis of this syndrome
- other genes involved in preventing oxidative damage by free radicals may be involved

18

What is the role of macrophages in ageing?

- more men live past 100 on Sardinia, proportionally than anywhere else in the world
- the T and B cell immunity declines in these individuals, as in all older people
- however macrophages in these older men appear 'younger', more active
- however remember that chronic inflammation promotes injury, 'disease'

19

What is the role of caloric restriction?

- one of the most reliable ways to proling life in laboratory animals is simply to restrict hteir calories
- when rats are maintained on a low calore diet throughout life, ther are 15% smaller but live 50% longer than letter mates that ate ad libitum
- if restriction of calories is started later in life, it still works, but lifespan is only extended 20%
- food restricted rats show less evidence of cancer, atherosclerosis and autoimmune disease

- why does caloric restriction delay senescence?
- caloric restriction induces levels of some antioxidant enzymes
- interacttion of metabolic pathways with the insulin and IGF-1 pathways?

20

What is insulin/IGF-1 signalling pathway?

- hypothalamus releases hormones
- pituitary gland is activated through receptor ligand interactions
- release of growth hormone
- liver
- liver releases IGF-1
- binds IGF-1R
- shortens lifespan

- extended longevity in mice lacking the insulin receptor in adipose tissue
- protected against age-related obesity
- 18% increase in mean lifespan in both sexes

mice heterozygous for a deletion of the IGF-1 receptor gene
- resistant to oxidative stress
- increased mean lifespan (33% females, males not long lived)

21

What is polypathology?

- age
- multiple diseases
- treating one disease won't change a patient long term
- treat multiple diseases in a single patient
- stem cell function decreases throughout life

22

What is the nature of tissue-specific stem cells and ageing?

- the effect of age on (A) short-lived (frequently reneqable) and B) long-lived postmitotic cells
- stem cells acquire toxins
- become diluted
- accumulation of mutations
- quickly dividing cells

slowly dividing
- accumulation of toxins
- less mutation because less division

23

What is inflammageing?

antigenic load and environmental free radicals → immune activation and tissue damage → inflammation and repair (+ oxidative metabolism)
→ reactive oxygen species → further release of pro-inflammatory cytokines → immune activation and tissue damage
and
→ remodelling and inflammageing

24

What are contributing factors to inflammageing?

- obesity
- oxidative stress
- years of exposure to inflammatory proteins
- DNA damage
- immunosenescence

25

What does inflammageing cause?

- exacerbation of the ageing process
- age related chronic diseases
→ chronic renal failure
→ osteoarthritis
→ cognitive dysfunction
→ sarcopenia
→ CV disease
→ cancer