lecture 34

Question 1

Objectives?

Answer 1

• 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

Question 2

What is ageing/senescence?

Answer 2

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

Question 3

What is stem cells and tissue homeostasis?

Answer 3

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

Question 4

What are principle structural targets for cell damage?

Answer 4

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

Question 5

What is the general pathogenesis of cell injury?

Answer 5

• 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)

Question 6

What are general protective mechanisms?

Answer 6

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

Question 7

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

Answer 7

time

duration of injury → age

Question 8

What are differences between reversible and irreversible injury?

Answer 8

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)

Question 9

What is autophagy?

Answer 9

• 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

Question 10

What are factors that contribute to cellular ageing?

Answer 10

• 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

Question 11

What is the evolution of ageing?

Answer 11

• 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?

Question 12

What is the mutation accumulation theory in ageing?

Answer 12

• 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

Question 13

What are causes of cell injury?

Answer 13

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

Question 14

How does protection from ROS change?

Answer 14

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

Question 15

What is a feature of telomeres?

Answer 15

• cells with long replicative capacity have very long telomeres

Question 16

What is Werner’s syndrome?

Answer 16

• 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

Question 17

What is progeria?

Answer 17

• 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

Question 18

What is the role of macrophages in ageing?

Answer 18

• 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’

Question 19

What is the role of caloric restriction?

Answer 19

• 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?

Question 20

What is insulin/IGF-1 signalling pathway?

Answer 20

• 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)

Question 21

What is polypathology?

Answer 21

• 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

Question 22

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

Answer 22

• 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

Question 23

What is inflammageing?

Answer 23

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

Question 24

What are contributing factors to inflammageing?

Answer 24

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

Question 25

What does inflammageing cause?

Answer 25

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