BoA Flashcards

(77 cards)

1
Q

The four primary drivers of ageing (Lopez-Otis at al 2013)

A

Genetic instability
Telomere shortening
reduced DNA damage repair
Loss of proteostasis

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2
Q

What is one of the responses to the four primary driver of ageing?

A

Cellular senescence

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3
Q

Define cellular senescence

A

Triggered by DNA damage response pathways such as telomere shortening, oncogene activation and other stressors such as ROS and misfolded proteins

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4
Q

Antagonistic pleiotropy theory is proposed by whom and what is this. Give an example

A

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.

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5
Q

The role of microvesicles in atherosclerosis

A

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

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6
Q

Lee et al, 2018 injected old mice with exosomes derived from young mice, what happened?

A

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)

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7
Q

What miRNA are associated with human ageing

A

miR34a

Let-7

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8
Q

Which miRNA is associated with atherosclerotic progression and increased perivascular fat found in senescent cells microvesicles or atherosclerotic plaque derived vesicles

A

MiR-19b

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9
Q

Criteria for identifying the hallmark of ageing

A

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

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10
Q

Proof that genome instability is one of the causes of ageing

A

Accumulation of genome damage throughout life

Progeriod syndromes such as Werner and Bloom syndrome are consequence of increased DNA damage

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11
Q

Genetic cause of ageing account for ( )% and whats studies proves this

A

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

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12
Q

What is the Gompertz law? (1825)

A

Predict that mortality increases exponentially with increasing age

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13
Q
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

A

Endocrine - brown-séquard
Rate of living - Loeb and Northrop
Oxidative damage + rate of living - Denham Harman
Mitochondira… ?
Cellular theories - Hayflick and Moorhead

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14
Q

How is AGE (advance glycation endproduct) cleared ?

A

Determined by genetics

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15
Q

What are the AGE products that actually matters? (Terman 2001)

A

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

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16
Q

Cellular pathology of AMD (age-related macular degeneration)

A

Accumulation of druses (cell debris) and lipofuscin below the RPE (retinal pigment epithelium) layer. This causes RPE atrophy and neovascularisarion in the choroid.

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17
Q

Treatment for AMD

A

Avastin - anti-VEGF

Lucentis (dame as avastin)

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18
Q

How are AGE products generated

A

Non-enzymatic condensation of the amino acid side chain (Lys/Arg)

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19
Q

How does AGE contribute to ageing

A

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

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20
Q

Age limit currently is ? And what is the max age limit we are hitting, and at what rate?

A

Age limit ~85 for female and 79 for male. Max age currently predicted to be 115, increasing by 2years/decade.

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21
Q

By 2034, what is the proportion of people age over 65 and what’s the proportion age over 85?

A

> 65 = 23%
5%

  • currently around 16% of >65 in NHS but use over 40% of NHS budget
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22
Q

Ageing is independent of evolution?

A

True

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23
Q

Explain the mutation accumulation theory proposed by Peter Medawar

A

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

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24
Q

Example of mutation accumulation theory

A

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
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25
Examples of antagonistic pleiotropy
Fat deposition Testosterone p53 Inflammageing
26
Explain Disposable soma (Kirkwood)
In evolutionally terms, a trade off between fecundity and survival exist - investment in repro when lifespan is short
27
Def for CR
A method to extend longevity by reducing intake of dietary constituents without inducing malnutrition (I.e. supplement with vitamins and minerals)
28
How does CR improve ageing(mechanisms)
- increase SIRT1 activity - by promoting AMPK pathway to increase autophagy to rid dysfunctional mitochondria - reduce IIS signalling pathway (reduces IGF1/insulin) - increase insulin sensitivity - promote repair mechanisms But will decrease fertility (trade off, disposable soma by kirkwood) — although possible to try preserve fecundity on future
29
Mimetics for CR
Metformin | Rapamyvin
30
SIRT1 (human homolog of sir2 in yeast) is a NAD dependent deacetylase that has shown to regulate longevity. What can activate SIRT1?
Aerobic exercise - improve muscle quality Lactate Reservertrol Amino acids
31
What factors can regulate PGC1a, a master regulator of metabolic genes such as PPARg, NRF1/2 (promote mitochondria autophagy, biogenesis)
SIRT1 - activate | SRC3 and GCN5 (increase due to high fat diet) - inhibits
32
How does SIRT1 contribute to longevity?
Regulate circadian rhythm Promote activation of PGC1a - mitophagy, biosynthesis (better mitochondria efficiency) Banks et al 2008 found that overexpression of SIRT1 amilorated glucose tolerance when diabetes was induced, indicating that PGC1a and SIRT1 can also regulate glucose metabolism
33
How does melatonin regulate cortisol secretion and what effect does it have in elderly
Melatonin signals decreases with age due to dysregulated clock genes expression Melatonin alters cortisol and ACTH and shows a nocturnal increase in elderly subjects The pineal gland, where melatonin is secreted, seemed to play an inhibitory role on the HPA axis by modulating adrenal sensitivity to corticotroph stimulation and even by limiting the corticotropin response to stressful conditions
34
GH release pattern
Pusatile | Diurnal - highest at midnight with somatostatin nadir
35
Factors that regulate GH secretion
GHRH ( hypothalamus) Ghrelin (promote secretion, act on GHS on ant pit. Somatostatin (act on somatostatin receptor on ant. Pit which inhibits release IGF1 - negative feedback
36
What is Ghrelin
Secretedby stomach (mainly), hypothalamus which positively Act on ant pit to promote secretion
37
What factors increases GH release and decreaSe GH release
Increase - fasting, exercise, Sleep, oestrogen Decrease - ageing, drugs, glucocorticoids
38
GH release falls by X% per decade
14%
39
S/S of GH deficiency in adults
Increase fat mass (adiposity) DecreaSe quality of life DecreaSe BMD Glucose intolerance
40
Change in GH w age
Decrease in secretory burst frequency, half life and daily secretory rate No change in duration of secretion, amplitude or mass
41
Sleep definition and stages
A naturally occurring, reversible, periodical and recurring state in which consciousness and muscular activity is temporarily diminished and responsiveness to external stimuli is reduced NREM and REM
42
SCN structure and signalling
Superchiasmic nucleus is the ant part of the hypothalamus which receives signal from the eyes and subsequently determine melatonin secretion. It is an area that consist of 20000 neurones and each cell has a set of clock genes to regulate rhythmic expression
43
Geroconversion is what phenomenon and what inhibits this (Blagklonny, 2014)
Conversion of reversible cell cycle arrest to permanent cell cycle arrest which promote SASP development Occurs when p21/p16 induced cell cycle arrest with active mTOR pathway drives increased cyclin D production which increase pro-senescent development Rapamycin inhibits this
44
What can delay geroconversion
Anything that inhibits or deactivates mTOR Rapamycin CR Hypoxia
45
Age related changes in the CVS in heart and in vessels
Heart - myocyte hypertrophy - LV hypertrophy - asymmetric increase in the interseptum tissue - decreaSe SNS and paraSNS response (blockade using beta-2 antagonist and atropine resulted in decreased paraSNS variability and lesser increase in SNS mediated increase in HR) Vessels - increase collagen to elastin ratio - increase vessel size in each layer, particularly the intima - increase tortuosity - hardening/stiffening of vessel - imbalanced protease:synthesis activity
46
EA ratio in elderly and in normal young adults
Less than one in elderly due to distension difficulty (stiffening of heart reduces the amount of blood that enters into the chambers following dialatation) Normal ~1.5
47
EF of the heart in normal and the aged
Normal 65% | Lower but above 55%
48
Factors that contribute to vessel calcification
``` Increase Ca2 deposit Cross linking of elastin to Ca2 or crosslink adductor such as AGE miR19b Annexin V CD9 ```
49
How does VO2 decline with age? Peak aerobic fitness improvement after exercise (8 week) in the elderly and after 30 years of follow up for 6 month exercise
3%/year after 40s | Increase by 18% and 14%
50
Age related change in vascular angiogenesis (decreaSe vessel density and ability to produce collateral vessel) can be due to
1) decreaSe angiogenic factor production, sensitivity, down reg of receptor, downstream signalling problems 2) change in BM 3) SC production decrease and enter senescence due to increase fat accumulation in BM + epigenetic alterations 4) change in coagulation profile
51
What happens in the obese OA joint (berry et al 2011; de Boer et al 2012)
Increase inflammation in the OA joint compared to the normal OA (increase inflammatory cytokines level in synovial fluid) Increase proliferation capacity of the fibroblast ex vivo Increase bone remodelling
52
Properties of adiponectin and leptin
Adiponectin - considered as anti inflammatory, anti atherosclerotic and increase insulin sensitivity Leptin - considered as inflammatory, increases with BMI and central adiposity and reduce insulin sensitivity
53
How does Fat inhibit IIS singalling and increase insulin insensitivity
Intramuscular fat can be metabolismed and produce ceramide and DAG which inhibits IRS thereby preventing GLUT4 translocation even after insulin binds to the receptor (increase insensitivity) GLUT4 receptor decreases with age part. In old obese people (intrinsic) Obese myotubes are resistant to insulin
54
Rate of thymic regression with age
Slowly after birth but 3%/year after 20 - increase fat infiltration and reduce thymic cellularity
55
Mitochondria changes with age.
Biogenesis/mitophagy/fusion and fission ability decrease Changes in MFN1 (mitofusin) Decrease efficiency mitophagy Decrease energy production (8%/decade) complementary increase in ROS production
56
Describe mitochondria flexibility/plasticity
The ability of mitochondria to switch between fusion and fission state
57
Describe fusion and fission of mitochondria
Fusion - fusing of the mitochondria into reticular networks to protect from damage and increase density of MT/area therefore increasing MT mass and increase capacity to generate O2 (mediated by MFN1) Fission - separation of dysfunctional MT into small puncate structure
58
What does ROS do to the mitochondria
Induce DNA damage which accumulated over time - MR doesn’t have good DNA repair and thus can contribute to genome instability and result in dysfunction Induce mutations Protein misfolding Damage cell membrane and interfere with phospholipid peroxidation
59
Role of immune system
Remove senescent cells (Sagiv et al 2012) Kill pathogens Respond better upon secondary exposure Not to damage self
60
Cause of inflammageing
Asymptomatic infections (low level of infection that is doesn’t show up on routine assays) Increase production of cytokines in MPs at basal but not when stimulated Increased adiposity (GH decreaSe/sarcopenia) SASP Reduced sex hormone (most sex hormones are anti inflammatory) Sleep - disrupted circadian rhythms
61
statins MoA as an anti ageing drug (Wang et al2007; Sapey et al 2014)
HMG co A reductase which inhibits cholesterol synthesis in the hepatocyte - increase LDLR which help takes up LDL in the blood, reducing hyperlipidaemia. Inhibit endothelin-1 (vasoconstrictor) Act to promote eNOS activity by increasing eNOS mRNA half-life. Decrease caveolin which binds to eNOS which prevents eNOS production. Activate Pi3K pathway** The effect of statins on fixing wonky NPs is inconclusive although pneumonia patients on statins showed better survival (Douglas et al 2011) and that administration of simvastatin improved NP chemotaxis to IL8 in vitro. Nonetheless, due to the wide ranging effect, it is likely that a combination of these factors contributed to better NP function. Dampen expression of IL1b and TNFa in MPs (Pahan et al 1997).
62
Evidence of GH declining in rats suggest
GH content does not change with age in the ant pit of the rats Suggest that the change in GH secretion with age may me due to altered regulation such as - decreaSe sensitivity of somatotroph to GHRH - increase somatostatin release and sensitivity with age (more likely) - likely to involve a number of factors such as hormones, gender, nutritional status, activity levels and sleeping pattern
63
Age associated changes in the adaptive immune system
Thymic atrophy 3%/ year after 20 Decrease thymic cytokine influencing the microenvironment Decrease naïve T cell exiting the thymus - reduce T cell diversity in the pool Shortened T cell telomeres compared to young and comparable to X linked lymphoproloferative disease Senescence of T cells Reduced proliferation capacity Increase CMV specific T cells up to 15% - affect diversity. These T cells are also present with shortened telomeres, reduced proliferative capacity and highly differentiated Increase Treg no. But decrease suppressive functions. Bregs were decreaSe in no and in function
64
Baker et al 2012 experimental design of ATTAC mice
Replaced fabp4 promoter with 2617 bp fragment of the p16INK4a gene that is only transcriptionally active in senescent cells so when p16 is transcribed, caspase 3 is also transcribed and activated
65
Dasatinib and qucertin MoA
Dasatinib, second generation of TKI originally used in CML. Quecertin, a flavonoid that interferes with BCL2 pathway thereby promoting apoptosis. D+Q reduced p16 and SA-B-gal expression in senescent cells in adipose tissue of mice leg and have shown effect in IPF patients (Justice et al 2019)
66
What is the bidirectional relationship between SIRT1 and BMAL:CLOCK complex (Ramsey et al 2009)
Clock is a Histone acetylatase that acetylates BMAL at Lys 537 which promotes heterodimer formation. SIRT1 is a NAD dependent deacetylase that counteract the effect of clock. NAMPT, a rate limiting enzyme of the NAD salvage synthesis pathway contains a EBOX sequence to which the BMAL-clock complex can bind, leading to the transcription of NAMPT, and thus, NAD. Together, NAMPT and SIRT1 exhibits circadian rhythm. And there is a decrease in NAD with age which can be due to disrupted sleeping pattern/ circadian clock/loss of PER2 which can influence SIRT1 levels (decrease) with age. Perhaps affecting on longevity
67
How circadian rhythm regulate inflammation
Patel et al 2012/Xu et al, 2012 NRF1/2 exhibits circadian rhythm similar to PEr1/2 and reverb, with peak late in night. NRF1 contains GC rich motif found in most of the clock controlled genes, indicating that genes are under the control of the BMAL:clock complex. Early et al 2018: NRF2 can limit inflammation via ROS suppression and directly repress ILIb/IL6 BMAL controls expression of NRF2 Via direct EBOX binding to its promoter to regulate its activity. Deletion of BMAL led to blunted antioxidant response and increased proinflammatory cytokine production. Age is associated with decrease in PER2 and dysregulated circadian rhythm which reduces the transcription of NRF1/2 that can reduce antioxidant defence.
68
60-70% decreaSe in CR mice showed
25-30% increase in lifespan Postponed age related decline Blood glucose control (no age related insulin insensitivity) Decreased female repro Maintained muscle mass DNA repair / immune responses maintained Slowed age associate glycation, oxidation Delayed onset of autoimmunity cancer and other phenotypes such as diabetes and cataracts
69
Leptin and cartilage homeostasis (pottie et al 2006)
Leptin receptor is present on chondrocytes which normally upregulate in various articular tissues that undergo structural and biochemical changes. Leptin expression correlated to the grade of cartilage destruction Normally leptin promote proteoglycan synthesis to promote carlage maturation but overexpressuon of leptin can lead to decreased ECM synthesis and increased MMP secretion, which results in the degradation of cartilage instead.
70
Kondo T et al 2006
Longitudinal study shows that exercise lower adipokine levels on obese patients (TBFa, leptin, CRp) and increases adiponectin levels
71
Proteins affected by AGE formation
HbA1c (small effect, quick turnover) Collagen Elastin Crystalline
72
% of total protein in body is made of collagen and % of body is made up of ECM
23% of Body is made up of ECM and collagen make up 25-30% of all proteins
73
Consequence of collegen crosslinkjng
Stiffening Cartilage degradation (OA) Decrease cardiomyocytes contractile efficiency (decreaSe filling; stiffening) Gardening of arteries Reduced perfusion if nutrients, waste, immune cell migration, angiogenesis
74
Nutritional status in ageing and young population in hospital. What can cause this
29-61% of elderly patient in hospital 11-44% for younger cohort Low activity low appetite Reduced nutrient absorption Anabolic blunting
75
Describe how cellular stress activate UPR
Cellular stress is induced by external and or internal cues and can activate processes that aim to restore homeostasis or cell death (such as ERAD, autophagy, UPS) Stressors such as misfolded protein perturba ER homeostasis and activate the there sensors on ER membrane subsequently different outcome (depending on IRE1 ATF6 and PERK)
76
Leptin and ghrelin in the effect of CR and satiety regulation
Leptin and ghrelin have opposite effect in regulating satiety and hunger. Leptin is released in response to feeding which signals the brain for satiety whilst ghrelin, mainly secreted from the gut, signals for hunger. The time for leptin to reach the brain roughly takes 20 mins (for it to take effect) and thus this might be way we are always eating more than we actually should. Ghrelin also promote GH secretion - GH levels increase upon fasting - ghrelin hunger - want food - low energy store - high GH - low IGF
77
Age associated changes in hipposcampus
``` Decrease in volume/cell size 5% Decrease synaptic connection Change in glial cell type Increase microglia reactivity Increase astrogliosis Decrease GR ```