BoA Flashcards
(77 cards)
The four primary drivers of ageing (Lopez-Otis at al 2013)
Genetic instability
Telomere shortening
reduced DNA damage repair
Loss of proteostasis
What is one of the responses to the four primary driver of ageing?
Cellular senescence
Define cellular senescence
Triggered by DNA damage response pathways such as telomere shortening, oncogene activation and other stressors such as ROS and misfolded proteins
Antagonistic pleiotropy theory is proposed by whom and what is this. Give an example
Proposed by George C Williams in 1957 as an evolutionary explanation for senescence.
Pleiotropy theory suggest a gene that has at least one opposite trait that is beneficial and detrimental to the organism.
Example: cellular senescence. Cellular senescence is regard as an anti-cancer mechanism and facilitate wound healing. However, senescent cells display SASP which secretes proinflammatory cytokines which contributes to inflammageing, increasing risk of CVD and such.
The role of microvesicles in atherosclerosis
Microvesicles can be secreted by wide range of tissues. Particularly, those derived from SMCs or ECs can contain pro-calcification factors such as CD9 and annexin V.
Senescent cells also secrete higher amounts of MV as compared to the younger cohort
Lee et al, 2018 injected old mice with exosomes derived from young mice, what happened?
The levels of miR-126b-5p levels were reversed in the lungs and liver in old mice along with increase telomerase gene expression such as men1. Sig down regulation of p16, mTOR and IGF1R (senescence associated pathways)
What miRNA are associated with human ageing
miR34a
Let-7
Which miRNA is associated with atherosclerotic progression and increased perivascular fat found in senescent cells microvesicles or atherosclerotic plaque derived vesicles
MiR-19b
Criteria for identifying the hallmark of ageing
1) should manifest during normal ageing
2) it’s experimental aggravation should accelerate ageing
3) it’s amiloration should retard the normal ageing process and hence increase health span
Proof that genome instability is one of the causes of ageing
Accumulation of genome damage throughout life
Progeriod syndromes such as Werner and Bloom syndrome are consequence of increased DNA damage
Genetic cause of ageing account for ( )% and whats studies proves this
Accounted for <20% (indicating that it is highly malleable)
Twin study by Kalman 1957 showed that long lived parents generally have long lived children
Genetic ageing syndromes such as progeroid syndromes (bloom/Werner) mostly have mutations in the DNA damage repair pathway and die early
What is the Gompertz law? (1825)
Predict that mortality increases exponentially with increasing age
Theories of ageing include Endocrine theory Metabolism (rate of living) Oxidative damage theory Mitochondria free radical theory of ageing Cellular theories (senescence)
Who proposed them
Endocrine - brown-séquard
Rate of living - Loeb and Northrop
Oxidative damage + rate of living - Denham Harman
Mitochondira… ?
Cellular theories - Hayflick and Moorhead
How is AGE (advance glycation endproduct) cleared ?
Determined by genetics
What are the AGE products that actually matters? (Terman 2001)
Periodisation of lipids: Lipofuscin - brown autoflurescent spots on skin - indication of decline in autophagy. Accumulated in post motoring cells, cardiomyocytes, skeletal muscle fibre, retinal pigment epithelial cells. Normally rid by lysosomes. Defective riddance can interfere with cellular process which makes cells more stressed and can induce senescence.
Protein oxidation - carbonyl formation
DNA oxidation to 8-hydroxyguanine which induces senescence and mutation
Cellular pathology of AMD (age-related macular degeneration)
Accumulation of druses (cell debris) and lipofuscin below the RPE (retinal pigment epithelium) layer. This causes RPE atrophy and neovascularisarion in the choroid.
Treatment for AMD
Avastin - anti-VEGF
Lucentis (dame as avastin)
How are AGE products generated
Non-enzymatic condensation of the amino acid side chain (Lys/Arg)
How does AGE contribute to ageing
AGE products accumulating in slow turnover cells such as cardiomyocytes or neurones can result in impaired cellular function and stress as they accumulate in cells
Age limit currently is ? And what is the max age limit we are hitting, and at what rate?
Age limit ~85 for female and 79 for male. Max age currently predicted to be 115, increasing by 2years/decade.
By 2034, what is the proportion of people age over 65 and what’s the proportion age over 85?
> 65 = 23%
5%
- currently around 16% of >65 in NHS but use over 40% of NHS budget
Ageing is independent of evolution?
True
Explain the mutation accumulation theory proposed by Peter Medawar
Early acting mutation are subjected to strong forces of natural selection whilst late acting mutations aren’t
Thus, the force of natural selection declines with age as reproduction goal have been achieved
Medawar suggest that ageing is a side effect of mutation pressure because of the decreasing ability of natural selection to counter its effect at later ages
Example of mutation accumulation theory
ApoE gene
- ApoE2/E3 - common allele but E2 more common in centenarian
- ApoE4 (5% Caucasian) and increases probability of stroke, MI and AD particularly of two allele are acquired