Biology of ageing
Loss of reserve - homeostenosis
- Ageing = progressive loss of physiological reserve across all organ systems, so that resting function is preserved but the response to stress is not
- *Homeostenosis* - the gap between baseline function and the threshold for failure narrows with age
- This, not any single disease, is why a UTI causes delirium and a fall causes irreversible decline
- Distinguish normal ageing from disease - a raised creatinine is disease; a lower GFR at 85 is ageing; dementia is disease, mild slowing of processing speed is ageing
Body composition changes - drive drug handling
- inc total body fat (and redistribution to visceral/central)
- dec lean body mass and muscle (sarcopenia)
- dec total body water (~10-15%)
- dec albumin (mildly), inc alpha-1 acid glycoprotein
Demography and frailty
- Australians over 65: ~17% of the population, projected >20% by 2040; the over-85 group is the fastest growing
- Life expectancy is rising faster than healthy life expectancy - more years lived with disability
- ~50% of people over 85 are frail; frailty, not age, predicts outcome
Hallmarks of ageing - no single unifying mechanism
- Genomic instability - accumulated DNA damage
- Telomere attrition -> replicative senescence
- Epigenetic alteration - methylation drift ("epigenetic clock")
- Loss of proteostasis - misfolded protein accumulation (the link to amyloid and synuclein diseases)
- Mitochondrial dysfunction - dec oxidative phosphorylation, inc ROS
- Cellular senescence - non-dividing cells persisting with a senescence-associated secretory phenotype (SASP) -> chronic low-grade inflammation
- Stem cell exhaustion, altered intercellular communication, deregulated nutrient sensing (insulin/IGF-1, mTOR)
- "Inflammageing" - chronic sterile low-grade inflammation; inc IL-6 and CRP
- Immunosenescence - thymic involution, dec naive T cells, dec vaccine response, inc autoantibodies and reactivation of latent infection (zoster, TB)
System-by-system physiological change
| System | Change | Clinical consequence |
|---|---|---|
| Cardiovascular | inc arterial stiffness, LV hypertrophy, dec beta-receptor responsiveness, dec maximal HR (~220-age) | Isolated systolic hypertension, wide pulse pressure, diastolic dysfunction, blunted tachycardic response to shock |
| Renal | dec GFR ~0.75-1 mL/min/yr after 40, dec concentrating and diluting ability, dec renin/aldosterone | Drug accumulation, hypo- and hypernatraemia, dehydration |
| Respiratory | dec elastic recoil, dec chest wall compliance, dec PaO2, dec cough and mucociliary clearance | dec reserve, inc aspiration and pneumonia |
| Neurological | dec brain volume, dec neurotransmitters (esp. cholinergic and dopaminergic), slowed processing | inc delirium susceptibility, inc drug sensitivity |
| Musculoskeletal | Sarcopenia (~1%/yr after 50), dec bone density, dec cartilage | Falls, fracture, frailty |
| Endocrine | dec glucose tolerance, dec vitamin D activation, dec testosterone/oestrogen, dec thirst | Diabetes, osteoporosis, dehydration |
| GI | dec gastric acid, slowed transit, dec hepatic mass and blood flow | Constipation, dec first-pass metabolism |
| Sensory | Presbycusis, presbyopia, dec smell and taste | Isolation, delirium risk, malnutrition |
| Thermoregulation | dec shivering, dec sweating, dec vasomotor response | Hypo- and hyperthermia |
Why disease presents atypically in the old
- Blunted or absent classical signs - afebrile sepsis, painless MI, apyrexial peritonitis
- Presentation via the weakest organ system, not the diseased one - "geriatric giants"
- Delirium, falls, incontinence, immobility, functional decline are the presenting complaints for almost any acute illness
- Multiple simultaneous problems, each contributing a little - the single-diagnosis model fails
Comprehensive geriatric assessment
Assessing what is actually happening - comprehensive geriatric assessment
- Medical - problem list, medications, nutrition, continence, senses
- Functional - ADLs and IADLs, gait and balance, falls
- Cognitive and psychological - cognition, mood, capacity
- Social and environmental - supports, housing, carer, finances, advance care plan
- Frailty measurement: Clinical Frailty Scale (1-9), Fried phenotype (weight loss, exhaustion, weakness, slow gait, low activity), Frailty Index
- *Frailty predicts mortality, delirium, surgical outcome and institutionalisation far better than chronological age*
Prescribing for the aged body - pharmacokinetics
A. Prescribing for the aged body - pharmacokinetics
- Absorption - largely unchanged; but dec first-pass metabolism -> inc bioavailability of drugs with high hepatic extraction (propranolol, morphine, GTN)
- Distribution
- inc fat -> inc volume of distribution and prolonged half-life of LIPOPHILIC drugs (diazepam, amiodarone) -> accumulation
- dec body water -> dec Vd and inc peak concentration of HYDROPHILIC drugs (digoxin, lithium, gentamicin, ethanol) -> reduce loading doses
- dec albumin -> inc free fraction of highly protein-bound drugs (phenytoin, warfarin) - interpret total phenytoin levels with caution
- Metabolism - dec hepatic mass and blood flow -> dec phase I (CYP oxidation); phase II (conjugation) is relatively preserved
- Prefer drugs cleared by conjugation - oxazepam, lorazepam and temazepam over diazepam
- Excretion - dec GFR with a normal creatinine because of low muscle mass
- *Never judge renal function from creatinine alone in the elderly* - use eGFR/Cockcroft-Gault, and dose renally cleared drugs accordingly (DOACs, gentamicin, digoxin, metformin, gabapentin, opioids)
Pharmacodynamics - altered sensitivity
B. Pharmacodynamics - altered sensitivity
- inc sensitivity: benzodiazepines, opioids, anticholinergics, antipsychotics, warfarin, antihypertensives
- dec sensitivity: beta agonists and beta blockers (dec receptor responsiveness), so heart rate is a poor guide to beta blockade
- Impaired baroreflex -> postural hypotension and falls with any vasoactive drug
Deprescribing and rational prescribing
C. Deprescribing and rational prescribing
- "Start low, go slow" - but titrate to an effective dose; under-treatment is as common an error as over-treatment
- Review the whole list at every encounter: indication, benefit, time to benefit vs life expectancy, adverse effects, patient goals
- Screening tools: STOPP/START, Beers criteria, anticholinergic burden score
- Withdraw one drug at a time and monitor; taper where withdrawal syndromes occur (benzodiazepines, beta blockers, PPIs, steroids, SSRIs)
- Time to benefit matters - a statin for primary prevention or intensive glycaemic control has a time-to-benefit of years; do not start it in someone with months
What actually modifies ageing
D. What actually modifies ageing
- Exercise - resistance and aerobic - is the only intervention with consistent benefit on sarcopenia, falls, cognition, mood and mortality
- Nutrition (adequate protein 1.0-1.2 g/kg/day), vitamin D where deficient
- Smoking cessation, alcohol moderation, treatment of hearing and vision loss, social engagement
- Vaccination - influenza, COVID, pneumococcal, herpes zoster (recombinant, non-live), RSV
- Senolytics, metformin and rapamycin remain experimental - do not present them as established
Geriatric syndromes
- Frailty, sarcopenia, falls and fracture
- Polypharmacy and adverse drug events
- Delirium and dementia
- Multimorbidity; atypical disease presentation
- Immunosenescence - poorer vaccine responses, reactivation of latent infection, higher cancer incidence
- Malnutrition, dehydration, pressure injury
- Social isolation, elder abuse, carer strain
Trajectories
- Ageing trajectories diverge with age - an 85-year-old cohort is far more heterogeneous than a 25-year-old one; never treat "age 85" as a description of a patient
- Reserve is lost before function is - the decline is invisible until a stressor exposes it
- Frailty is dynamic and partly reversible - exercise, nutrition and deprescribing move people back along the scale
- Typical end-of-life trajectories: sudden death; cancer (late steep decline); organ failure (sawtooth decline with exacerbations); frailty/dementia (prolonged slow decline)
- Recognising which trajectory a patient is on drives the timing of advance care planning
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