Ageing Flashcards
Define ageing.
A time dependent functional decline. Degenerative processes overtake growth to cause senescence. Ageing causes multi-dimensional physical, psychological and cultural changes.
What parts of the body does ageing effect?
Brain, skin, bones, hearing/vision, heart, cellular changes, respiratory system, reproduction.
Factors that effect ageing.
UV
Smoking, drinking
Environmental factors - heat, light, toxins
Diet, exercise, sleep, stress
What is Pleiotropy?
The trade off theory
Ageing evolves as a side effect of natural selection in favour of mutations that cause a benefit during youth. Old age is often accompanied by chronic disease.
Name the 9 hallmarks of ageing
- Telomere attrition
- Epigenetic alterations
- Loss of proteostasis
- Deregulated nutrient sensing
- Mitochondrial dysfunction (oxidative damage)
- Cellular senescence
- Stem cell exhaustion
- Altered intracellular communication
- Genomic instability
Telomere Attrition
- Telomere = cap of repeated DNA (TTAGGG)
- Telomerase = enzyme that adds telomeres
- Loss of telomeres causes shortening of chromosomes, which causes loss of genes, increases ageing.
- Cancer cells have increased telomerase activity, immortal
- Telomerase deficiency is a cause is pulmonary fibrosis
- Every DNA replication cycle loses some of the repeats and the cell will enter crisis if the telomere becomes too small.
Epigenetic alterations
Cyt in CpG islands can be methylated, causing more tightly packed DNA around histones, stopping transcription of genes.
Global hypomethylation - loss of Cyt Me from entire genome, increased expression of ageing genes.
Local hypermethylation - loss of compartmentalisation of methylation, silencing of promoters and associated genes.
DNA acetylation - HATs and HDACs add/remove acetyl groups to enable/repress transcription.
Loss of proteostasis (dysfunctional proteins)
DNA damage from mutations produce faulty protein transcripts.
- Autophagy: Autophagosome degrades faulty proteins, increases lifespan.
- Proteasome: degrades ubiquitinated proteins, could be used in therapy to target faulty proteins for degradation.
- Heat shock proteins: chaperones that stop degradation. HSP70 = stress inducible HSP, over expressed in malignant melanomas. Inhibits apoptosis.
Chaperone decline affects longevity, accumulation of misfolded proteins, age related conditions (alzheimer’s)
Deregulated nutrient sensing
The IIS pathway - production of insulin, gives the ability to inform cells of glucose presence.
SENSORS - mTOR (AA increase), AMPK (AMP increase), Sirtuins (NAD+ increase)
Sirtuins - Affect ageing, transcription, apoptosis and inflammation. SIRT6 over expression = 15% lifespan increase in mice.
Resveratrol = mimics dietary restrictions, activating Sir2, AMPK and down regulates mTOR, slows ageing.
Mitochondrial dysfunction (oxidative damage)
Free radicals cause oxidative damage, produced by the ETC.
Causes cell ageing.
Cellular Senescence
Prevents propagation of damaged cells, by removing them from the cell cycle through the immune system, prevents ageing.
Accumulation of senescent cells = ageing
p53 expressed more with age, under tissue regeneration exhaustion, causes ageing –> cardiovascular disease and diabetes.
Stem cell exhaustion
As age increases, the stem cells have begun to proliferate too much and become exhausted, reducing the amount of all cells available to be produced.
Adaptive immune cells (immunosenescence) = increased anaemia and myeloid malignancies.
Rapamycin inhibits mTOR, increases stem cell function.
Altered intracellular communication
Proinflammatory tissue damage and insufficient pathogen clearage.
Senescence causes NFkB release, increases ageing.
Bystander effects - senescent cells promote in neighbouring cells.
Anti-inflammatories may reduce ageing.
Genomic Instability
2 types of damage:
- spontaneous = replication errors and chemical changes
- external = radiation (UV), environment chemicals
DNA repair mechanisms
Genes can influence the varying susceptibility to diseases of the old.
Name the longevity genes that have been found in animal models.
- Clock class mutations (Clk1) = decrease metabolic rate, increase lifespan
- IIS pathway mutations = resistant to oxidative stress, increase lifespan
- Klotho = involved in suppression of several ageing phenotypes, defects resemble human ageing.
