Genetics and Ageing Flashcards
What is a chromosome and how does it differ from chromatin
Chromatin is compacted into chromosomes during mitosis and meiosis forming 22 pairs of autosomes and 1 pair of allosomes. Chromatin is made up of compacted DNA wrapped around histone proteins.
Classify the four nucleobases and define how this nucleobases are paired in DNA
Pyrimidines (CuT Pie or ‘py’)
Cytosine
Thymine
Purines (Pure gold - ‘Ag’ periodic table)
Adenine
Guanine
Pairing
AT
CG
Define DNA
Deoxyribonucleic acid or DNA is a polymer of 4 nucleotides in sequence bound to a complementary DNA strand and folded into a double helix. The strands run antiparallel 5’ to 3’.
Simplify the structure of DNA and differentiate nucleotide from nucleoside from nucleobase
Posphate - Pentose Sugar - Nucleobase - hydrogen bond - Nucleobase (complementary) - Pentose sugar - Phosphate.
Sugar phosphate backbone attached to nucleobases.
Nucleobase = CTAG Nucleoside = nucleobase + Pentose sugar Nucleotide = nucleobase + Pentose sugar + PO4
Which pathway forms the sugars found in DNA
The pentose phosphate pathway
What is RNA
The amino acid sequence of protein is encoded by the DNA sequence in the cell nucleus. When the cell needs to synthesize protein, the code is anchored in the cell nucleus, and protein manufacturing apparatus (ER/Golgi) is located within the cytoplasm. RNA is produced as a copy of DNA genetic code in the nucleus and exported to the cytoplasm, where it is used to synthesize protein.
List the differences between RNA and DNA
RNA - extra hydroxyl group on sugars (hence ‘deoxy’)
RNA - has Uracil instead of thymine
RNA - single strand - no antiparallel strand to form double helix
What are the 3 types of RNA and what is their function?
messenger - mRNA - produced by transcription in nucleus and then transferred to ER for use in protein synthesis
transfer tRNA - 20 types gather 20 aa’s in cytoplasm and transfer to ribosome for protein synthesis
ribosomal rRNA - Aligns tRNA units in their correct positions along the mRNA sequence
The amino acids are joined together and a complete protein released.
Define a codon
Triplet of nucleosides that encodes for an individual amino acid - e.g. GCA represents aa alanine
mRNA - codons
tRNA - anticodons
Jigsaw match
Give three examples of errors may occur during DNA replication/repair. Which of these has to most significant effect on changing protein synthesis and why?
- Point mutation
- Deletion
- Insertions
Deletions and insertions are the worst because “frame shift’ can occur with the ensuing DNA encoding a significantly different protein
Describe the gene mutation in sickle cell disease and how this mutation leads to the the ‘sickling’ of red blood cells
Chromosome 11
Point mutation in the DNA code for the beta chain of Hb
GAG (Glutamic acid) is changed to GTG (Valine)
Glutamic acid - polar
Valine - non-polar
This causes aggregation of Hb and thus shape change of the erythrocyte under conditions of low O2 tension.
Describe the genetic defect in cystic fibrosis and how this manifests clinically
Chromosome 7
> 1000 point mutations described of Cystic Fibrosis Transmembrane conductance Regulator (CFTR) gene –> encodes a transmembrane Cl- channel
Most common is delta F508 mutation
–> deletion of 3 nucleotides (an entire codon which codes for phenylalanine, F) at the 508th position.
Thickened secretions that prevent clearance by ciliated epithelium resulting in blockages of:
- Small airways (pneumonia)
- Pancreatic ducts (malnutrition)
- Vas deferens (incomplete development and infertility)
Describe the genetic defects in Huntingdon’s disease
Chromosome 4
Insertion of repeated segments of DNA
Codon for glutamine (CAG) is repeated multiple times within the Huntingdon gene on chromosome 4 = trinucleoside repeat disorder
What is haploid and diploid
haploid - cell containing 23 chromosomes (gametes)
diploid - cell containing 46 chromosomes (human cells)
What is an allele
A gene that codes for a specific trait e.g.blue alleles and brown eye alleles. (Mendelian).
Give 3 examples of autosomal dominant diseases
- Hypertrophic cardiomyopathy
- Polycystic kidney disease
- Myotonic dystrophy
- Malignant hyperthermia
Give 3 examples of autosomal recessive diseases
- Sickle cell disease
- Wilson’s disease
- Cystic fibrosis
Give 3 examples of X-linked recessive diseases
- Haemophilia A
- Duchenne muscular dystrophy
- Red-green colour blindness
Define functional reserve
The difference between maximum and basal levels of function - safety margin for trauma/disease/surgery/healing
What are the hypothesized mechanisms of aging
- Stochastic -> dependent on time and probability - due to random errors in protein synthesis
- Non - stochastic -> “biological clock for each species dependent on neuroendocrine or immune mechanisms
Progressive imbalance between oxidative stress and metabolic protection of oxidative stress –> increased ROS –> damaged membranes/proteins/DNA –> decreased antioxidant scavenging capacity –> progressive cycle –> decreased bioenergetic capacity –> loss of functional reserve –> susceptibility to disease and infection –>Increased probability of death
What happens to the heart with age
- Decreased myocytes
- Decreased conduction fibre density
- Decreased sinus node number
- LV wall thickening
- Interstitial fibrosis
Systolic dysfunction (reduced contractility) Diastolic dysfunction (reduced compliance)
Why is sinus rhythm vital in aged patients
Reduced LV compliance –> decreased earl diastolic filling with compensatory increase in late diastolic filling of LV to maintain EDV and SV –> therefore strong reliance on LA filling of LV in the aged.
How does cardiac output change with age
An 80 year old has 50% CO at aged 80 (vs CO at 30 yrs)
How is the vasculature affected by age
Arteriosclerosis –> AAA/Carotid artery stenosis etc.
How is the autonomic nervous system affected by age?
SNS - beta receptors less sensitive –> 2% loss of HR response during dynamic exercise.
PSNS - Reduced vagal tone –> therefore can’t reduce vagal tone below an already reduced baseline.
What happens to elastic recoil of the lungs and chest wall compliance with age –> how does this affect the pressure volume curve
Elastic recoil decreases –> increased static compliance
Chest wall compliance decreases
Pressure-volume curve shifts to the left. Lest change in pressure required for same volume change.
What happens to static lung compliance with age?
Increases
What happens to dynamic lung compliance with age?
Becomes more frequency dependent
How does residual volume change with age
Increases by 10% per decade after 50
How is vital capacity changed by increasing age?
Decreases
How does closing volume change with age
Increases
How does FEV1 change with age and why
Chest will stiffens with age - calcification of costo-chondral cartilage/costo-vertebral joints and progressive weakening of the auxiliary musculature of ventilation —> decreased FEV 1 and increased WOB
Describe the changes to the pulmonary vasculature that occur with aging
Decreased cross-sectional area of pulmonary capillary bed –> increased PVR –> higher pulmonary artery pressure.
Hypoxic pulmonary vasoconstriction is blunted in the elderly which may cause difficulty with one lung ventilation.
What happens to mean PaO2 with age and why?
PaO2 = 102 - (0.498 x Age)
- CC encroaches FRC
- Closing volume is more –> V/Q mismatch
- Deteriorating parenchymal integrity –> decrease surface area –> increased (A - a)dO2.
- Decreased sensitivity of respiratory centres to hypoxia and hypercapnoea –> diminshed or delayed response to injury
How is Nervous system effected by aging
Reduced functional reserve
Nerves - high O2 utilization –. altered mitochondiral bioenergetics with age compromise reserve –> alters the response to anaesthetic agents and perioperative stress.
Brain weight at 20 yrs = 1400 g
Brain weight at 80 yrs = 1200 g
How are the kidneys affected by age
Progressive reduction in renal mass
- Glomerulosclerosis
- Thickening of vascular intima
- Fibrosis of stoma
- Chronic infiltration by inflammatory cells
RPF decreases more than GFR
FF increases to a state of hyperfiltration (adapatation for loss of functioning glomeruli)
Reduced ability to concentrate urine
Reduced ability to excrete acid load
Sodium loss in the face of adequate sodium intake
How is liver function affected by age
- Decreased hepatic blood flow –> but large reserves
- Reduced hepatic drug clearance
- Reduced hepatic synthesis of plasma cholinesterase
How does body composition change with age
Increased abdominal fat mass
Increased obesity
Decreased resting BMR
Decreased energy expenditure (1% per year after 20yrs)
How is glucose metabolism affected by age
Plasma glucose higher due to glucose intolerance
How is the locomotive system affected by age
Reduction in height (atrophy of spinal muscles etc. - spinal anaesthesia more difficult)
Osteoporosis –> positioning patient in theatre.
Which plasma protein binds acidic drugs and how is it affected by age. Which plasma protein binds basic drugs and how is it affected by age?
Acidic drugs –> Albumin –> decreases with age –> Increase free fraction
Basic drugs –> alpha 1 - acid glycoprotein –> increases with age –> decrease free fraction
How does body composition change with age and how does this affect
Decreased lean body mass
Increase body fat
Decrease in total body water
EFFECT
- Smaller central compartment with increased serum concentrations after bolus administration
- Increased Vd –> prolonged effect
Do elderly patients need more or less volatile and why
MAC falls by 6% per decade 1. Decreased cell density 2. Lower Cerebral O2 consumption 3. Lower CBF Alterations in ion channels/synaptic activity or receptor sensitivity
Does age directly affect the duration of neuraxial anaesthesia
No
Define elderly
> 65 years
By how much does perioperative mortality increase per decade after 65 years of age
35% per decade
What are the two theories of aging
Extrinsic (Stochastic = random)
- cellular damage / ROS / Radiation / Errors protein synthesis
Intrinsic
- Pre-programmed genetically determined process
Whatever the underlying cause, the process occurs at very different rates between individuals and between organ systems within an individual
What is the ultimate effect of aging
Reduced functional reserve of organ systems with a threat to homeostasis in the face of stress.
Summarise the change in body composition in the elderly
Decreased % lean body mass from
- Cell loss in solid organs
- Decrease body water
- Loss of muscle mass
- loss of bone mass
- Loss of skin an SC tissue
Body fate % increases, with a shift in distribution from peripheral to visceral sites
Why do the elderly develop isolated systolic hypertension and what haemodynamic effects result from this
After 40 years:
- Collagen accumulates whilst elastin production falls
- Collagen also accumulates damage over time with stiff, non-enzymatic cross-linking between fibers.
- Connective tissue thus stiffens in the arteries, veins and the myocardium
Haemoodynamic effects
- Isolated systolic hypertension
- Widened pulse pressure (reduced diastolic pressure too)
- Increased afterload (Aorta cannot accommodate SV)
- LVH (increased afterload)
- Reduced LV compliance with diastolic dysfunction
- Increased dependence on atrial contraction due to diastolic dysfunction
- Reduced DBP –> compromise coronary perfusion
How do SV, HR and LVEF vary in the elderly vs younger individuals at rest
Actually unchanged
However, there is reduced beta-adrenergic sensitivity and reduced cell numbers in the SA node
Reduced maximum heart rate (SA cells down) Reduced contractility (myocyte numbers down) ---> Result in reduction in maximum CO in response to exercise or stress
Describe the pattern of decline of maximum cardiac output in the elderly
Maximum cardiac output declines by 1% per year after 50.
So by 80 years –> Max CO is 30% less than at 50 years.
How is the conducting system of the heart affected by age
Fibrosis in the conducting system may cause conduction abnormalities
Summarise the changes in the blood vessels in the elderly
- Reduced elastin and increased damaged + stiff collagen (stiffer arterial walls even in the absence of atherosclerosis)
- Intimal thickening
- Media calcification
- Endothelial dysfunction (less NO)
Venous stiffening –> impairs venous capacitance and ability to maintain stable preload
Summarise the changes to autonomic tone in the elderly
Increased SNS tone
Reduced PSNS tone
Diminished baroreceptor responses
Summarise the changes to respiratory mechanics in the elderly
- Reduced chest wall compliance
- Calcification costal cartilage
- Arthritis costovertebral joints
- Stiffness intercostal muscles
- Reduction height thoracic spine (osteoporosis) - Reduced respiratory muscle mass
- Intercostals and diaphragm weaker
Overall –> Increased WORK of breathing
- Breathing rapid and shallow
- Lung parenchyma
- Loss elastic tissue –> dilatation/enlargement airways + increased alveolar size + fusion adjacent alveoli –>reduction in alveolar surface area and a decrease in surface tension inward recoil
How do the physiological changes associated with aging affect lung function tests?
- RV - increase 5% - 10% per decade
- FRC - increase 1 - 3 % per decade
- Closing capacity increase –> airway closure –> V:Q mismatch during tidal ventilation
- TLC - unchanged
- VC - Reduced as RV increased
- FEV1 - falls by 25 ml/year after age 20
- FVC - falls by 20 ml/year after 20
- FEV1 : FVC ratio therefore falls
- Diffusing capacity - decreased due to thickened alv-capillary barrier
Why does arterial oxygenation decrease with age
- Decrease diffusing capacity (thickened alv-cap barrier)
- Reduced alveolar surface area –> V:Q mismatch
- Small airways close prematurely (Increased closing capacity)
- Increased shunting of blood due to alveolar destruction
Give one formula to predict PaO2 in the elderly
Predicted PaO2 = 13.3 - (Age/30) kPa
How does age affect the respiratory response to hypercapnoea and hypoxia
There is a 50% decrease in the response to hypercapnoea and hypoxia
What are the airway considerations in the elderly
- No teeth
- Collapsed cheeks - difficult BVM
- Cervical spondylosis - reduced ROM
- Pharyngeal muscle weakness (POPC + OSA + aspiration risk)
Why is the risk of post-operative pulmonary complications increased in the elderly
The physiological changes with ageing result in a significant increase in the required work of breathing
Summarise the anatomical changes in the kidneys that occur with age
Kidneys enlarge until 50 years
25% of their mass then lost over 30 years
- Cortical tissue lost –> glomerulosclerosis
- Acellular obliteration of glomeruli with vascular shunts forming around the lost units
How does renal blood flow change with age?
RBF decreases 10% per decade
Increased proportion of blood flow to the medulla (GS)
Intrarenal blood vessels show the same changes seen in the blood vessels in the rest of the body with age
Why does GFR decline with age. Why can Creatinine be decreased despite this
- Glomerulosclerosis
- Thickened basement membrane
Reduced creatinine production (loss of muscle mass)
Which formula should be used to calculate GFR
CKD-EPI formula
What is tubular senescence
With age comes reduced tubular length, interstitial fibrosis and basement membrane changes resulting in disruption of tubular function
- -> Impaired ability to reabsorb sodium
- -> Impaired ability to excrete K and H
Reduced ability to regulate electrolytes
How is the renal response to aldosterone and ADH affected by age?
Renin production is reduced –> reduced response to aldosterone
Response to ADH is reduced
Reduced ability to regulate fluid
Why are elderly patients more susceptible to dehydration
Decreased thirst response
How do elderly patients excrete drugs differently from younger patietns
Reduced capacity to clear drugs by the renal route and are more susceptible to injury for nephrotoxic agents
What happens to the volume and weight of the brain after age 40. why does this occur? And where do the losses predominate. Which area of the brain is mostly affected by this
It decreases by 5% per decade after age 40
- cell loss
- decrease dendritic density
Losses more pronounced in white matter vs. grey matter. Not uniformly distributed throughout the brain.
Most affected: prefrontal cortex
What changes occur with regard to neurotransmitters and nerve conduction in the elderly
Reduced
- Dopamine
- Serotonin
- Brain derived neurotrophic factor
Increased
- Monoamine levels –> free radical release
SLOWING of nerve conduction in the PNS and CNS
What happens to the blood brain barrier with age
Permeability increases possibly leading to increased neuroinflammation and inapprpriate modulation of CNS function
Describe the vascular changes in the brain in the elderly
- Same as everywhere else
- Capillary density decreases
- Microvessel deformities increase
- CMRO2 and CBF decrease with age
Discuss the observable neurological deficits often present in the elderly
- Cognitive impairment (memory loss)
- Auditory impairment
- Visual impairment
- Decreased mechanoreceptor and proprioceptor density increases risk of falls
Post operative delirium is common in the elderly
How is autonomic function altered in the elderly
It is decreased.
- Impaired thermoregulation (shivering, VC
- Reduced beat to beat variation in response to postural changes
- Reduced baroreceptor reflex sensitivity
What are the requirements for analgaesics and anaesthetics in the elderly population
The requirements are diminished
Summarise the age related changes in the GIT
Oesophagus
- Decrease contraction amplitude and number. Increased number of disordered contractions
Stomach
- Slowed gastric emptying
- Atrophic gastric mucosa –> decreased acid and IF production
- Reduced gastrin secretion
Pancreas
- Normal exocrine function
Small and large bowel
- minimal (polyps / diverticuli)
How is Hepatic function affected by age
Liver mass and hepatic flow decrease by 20 - 40%.
Decline in phase 1 drug metabolism (loss of endoplasmic reticulum)
How does age affect the sex hormones
Decreased secretion from endocrine glands and diminished tissue responsiveness to hormones.
E.g. Menopause
- bone loss
- Loss of oestrogen cardioprotective effects
E.g. Testosterone levels decline with age (?significance)
How does age effect thyroid
E.g. Thyroid levels decreased (?clinical effects)
How does age effect parathyroid
E.g. Parathyroid levels increased (–> osteoporosis)
How does age effect GH and ILGF-1
E.g. GH and ILGF-1 decreased
- loss of lean body mass and increased % body fat)
How does age effect Insulin
E.g. Insulin
- Decreased and insulin resistance (abdominal fat)
- glucose intolerance
How are circadian rhythms affected in the elderly
Shifted –>Cortisol release earlier in the day
How are secretion and levels of adrenalin and noradrenalin affected in the elderly. why is this important in the perioperative period
Baseline levels are elevated
but secretion in response to stress is diminished
NB as inability to regulate temp/HR/CO/BP in the face of surgical stress
how is immune function affected by age
Immune function declines with age
- Impaired T cell mediated immunity
- Increased susceptibility to infection
- T-cell response to IL-2 diminished
- Blunted increase in NK cells to infection
Markers of SIRS are elevated in the elderly
- IL6 / TNF alpha / CD 11b/ CD 18 expression
