L4 11 Mar 2019

Question 1

cellular ageing

Answer 1

• reflects the progressive accumulation of sublethal cellular and molecular damages
• leads to cell death and diminished capacity to respond to injury, which leads to the ageing of the entire organism

Question 2

ageing in cells

Answer 2

• decline in efficiency of cellular functions
• reduced mitochondria function and inability to survive hypoxic event and perform oxidateve phosphorylation
• increase of ROS
• lack of structural, enzyme and protein receptor creation
• affects gene expression; inability to take up nutrients and repair chromosomal damage –> also triggers more change

Question 3

morphology of aged cells

Answer 3

irregular and abnormally shaped organelles, accumulation of waste products

Question 4

ageing in tissues

Answer 4

muscle atrophy due to reduction in muscle group sizes, loss of muscle fibre and loss of function

Question 5

ageing in organs

Answer 5

decrease in size and activity (in several major organs)

Question 6

ageing in kidneys

Answer 6

• weight and volume may decrease between 20-30% with age as nephrons are lost and replaced by scar tissue
• decreased rate of filtration and excretory capacity
• higher risk of developing renal disease

Question 7

mechanisms of cellular ageing

Answer 7

• environmental and metabolic insults (ROS) –> accumulation of DNA mutations –> decreased cell function and cell loss
• telomere shortening –> lower cellular replication –> cell loss
• abnormal protein homeostasis –> fewer/damaged proteins –> decreased cell function

Question 8

senescence

Answer 8

• causes a loss of tissue repair capacity –> cell cycle arrest in progenitor cells
• senescent cells produce proinflammatory and matrix degrading molecules: Senescence-Associated Secretory Phenotype (SASP)

Question 9

telomeres’ function in replicative senescence

Answer 9

due to continued telomere attrition, a severely short telomere forces cells to stop at G1S checkpoint or G2M checkpoint, this trigger s the cell to go into replicative senescence

Question 10

Werner’s syndrome

Answer 10

• premature senescence
• recessive rare inherited disease
• individuals normal in childhood, but stop growing in their teens
• more susceptible to cancer osteoporosis, diabetes and cataracts, usually die in their late 40s
• WRN: point mutation in gene that encodes a helicase (enzyme that unwinds DNA for replication, DNA repair or transcription)

Question 11

possible causes of Werner’s syndrome

Answer 11

• improper DNA repair and rapid accumulation of mutations
• improper transcription of genes

Question 12

progeria

Answer 12

Hutchinson Gilford progeria syndrome, children age rapidly, senscent changes, die as young as 12, extrememly rare: 100 known cases worldwide, dominant mutant gene lamin A –> role in nuclear integrity

Question 13

symptoms in HG progeria

Answer 13

hair loss, thin transparent skin (w/ age spots), osteoporosis, and atherosclerosis (atherosclerosis is the main cause of 90% of the deaths)

Question 14

possible aetiology for non-HG progeria

Answer 14

shorter telomeres? other genes involved in preventing oxidative damage by free radicals may be involved? aetiology is unclear though

Question 15

cytokines in replicative senescence effects of healthy cells

Answer 15

IL-6 and IL-8 alongside SASP is SASP/cytokine-induced bystander senescence –> inhibits cellular proliferation and promotes senescence

Question 16

effects of senescent cell removal

Answer 16

delayed tumourigenesis, reduced age-related deterioration of several organs (incl. kidney and heart)

Question 17

NFKB (NF-kappa-B) pathway

Answer 17

• receptor activation –> phosphorylation that activates NF-κB –> RelA and p50 enters nucleus and can either activate or repress transcription of genes
• genes: inflammatory responses, cell prolif. and entering apoptosis

Question 18

Why does restriction of calories delay senescence

Answer 18

caloric restriction induces levels of some antioxidant enzymes, it reduces signaling of the IGF-1 pro-ageing pathway and increases SIRT1

Question 19

autophagy and ageing

Answer 19

autophagy is survival mechanism in times of nutrient dep. –> starved cell eats itself is IMPORTANT in ageing because it clears cellular waste (more cellular waste, more likelihood to enter senescence)

Question 20

inflammageing

Answer 20

ageing caused by inflammation, e.g. “aged” macrophages –> chronic inflammation

Question 21

What causes ageing?

Answer 21

combo of: DNA damage and mutation, accumulation replicative senescence, defective protein homeostasis, chronic disease