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Human Life Cycle 8 - Ageing and Diseases
Anil Chopra
Endocrinology of Puberty
6 8 10 12 14 16 18
6 8 10 12 14 16 18
Puberty is defined as the point in life where reproductive capability is achieved. It
begins with the increased night-time pulsatile release of LH (and FSH) from
adenohypophysis resulting in increased gonadal steroid production.
• in girls, clear indication is occurrence of first menstruation (menarche)
• In boys, first erection/ejaculation probably occurs at night
Adolescence: the period of development that occurs between the ages of 12-18 years.
Adrenarche: this is the increase in activity of the adrenal glands which produces
androgens and predates the increase in gonadal steroid production. The reason for this
increase is unclear other than to promote the growth of pubic and axillary hair.
Growth: the adolescent “growth spurt” is due to the increase in production of gonadal
steroids which increase the production of growth hormone (adenohypophysis).
Evidence that environmental factors may influence the maturation of the CNS –
secular trend towards earlier puberty:
 Improved health care
 Improved socio-economic factors
 Nutrition (this has changed dramatically over the years)
Evidence that age of menarche has decreased over the last 150 years. Over the last 3-4
decades it seems to have levelled off. However, population studies suggest that body
weight at menarche has remained relatively constant at ~47kg.
Puberty occurs due to:
- maturation of the CNS resulting in increase production of gonadotrophin
releasing hormone (increased pulstatile release)
- change is set point to gonadal steroid negative feedback
Puberty is also thought to be initiated by the
KiSS gene in the hypothalamus. This gene is
expressed at a particular time in a person’s life which
results in the production of the hormone kisspeptin,
which itself causes the production of metastin. Metastin
acts on GnRH receptors in the hypothalamus an causes a
pulsatile secretion of GnRH. The KiSS gene is:
• Also found on pituitary gonadotrophes
• Co-localised in same LHbimmunoreactive cells
• Oestradiol increases pituitary KiSS-1 expression
• Pituitary GPR-54 upregulated by GnRH
Ageing and Longevity
The prevalence of age-related frailty, disability and disease is rapidly increasing and
will continue to increase. It is the single largest risk factor for a very wide range of
diseases of current public health importance.
The ageing in society is caused by the increase in life expectancy and the falling birth
and fertility rates. It presents a problem to the healthcare system, the government and
the economic infrastructure.
 We live, on average, about twice as long as we did 200 years ago.
 Life expectancy has increased by about 10 years in the last 50 years.
 85 per cent of children born today can expect to reach their 65th birthday
There are number of other social changes that also affect the shift in population:
• Shift from rural to urban populations
• Change in education levels and income
• More elderly women then men
• Living arrangements
– Elderly women twice as likely to be living alone
– Institutional rates are highest in those aged 80+
This all results in an increased demand for health care, fewer workers that generate
taxes and increase in the number of pensions.
Ageing is associated with an increase in age-specific mortality. There are a number of
theories that have been put forward for its causes:
- Simply a process of wear & tear in more complex organisms
- Adaptive evolution – ageing is selectively advantageous (thus under genetic
o Stops old warn out individuals competing for resource
o Prevents overcrowding
- Non-adaptive evolution – ageing is deleterious but is an indirect consequence
of the forces shaping life history
o Force for natural selection declines with age thus loose genetic control
over the late portions of the lifespan
o By product of selection for other beneficial traits
o Disposable soma theory – the ‘germ line’ benefits to the detriments of
other organs (soma) – all energy into reproduction (organisms must
allocate resources among competing metabolic priorities: growth,
reproduction, maintenance and repair, storage. Under pressure of
natural selection, organisms can only afford limited investment in
somatic maintenance and repair  ageing results from the
accumulation of unrepaired cellular and molecular damage)
Mechanisms of Ageing:
• Oxidative damage
• By product of the flux of reducing sugars
• Decline in genomic stability
• Decline in the rate of protein synthesis and turnover
• Result of neuro-endocrine cascade
• Decline in proliferative homoeostasis
• Autoimmunity
• Mechanical stress
The factors affecting these include genes, nutrition, lifestyle, environment and sheer
chance. Changes in these can affect the process of ageing.
Diseases and Ageing
The diseases caused by ageing are a huge burden on the NHS and on society as a
whole. It uses 40% of the NHS budget and 65% of NHS beds. Falls and fractures
alone account for over 600 000 A&E visits.
There are a number of different features by ageing:
• Cough, sputum, pleuritic chest pain
• Frequency, dysuria, urgency
• Severe chest pain, sweating and dyspnoea
• Failure to thrive
• Falls
• Mental deterioration
• Rheumatism
• Immobility
• Incontinence
Often patients have more than one condition, and multi-system symptoms such as
osteoarthritis, diabetes mellitus, vascular disease and dementia.
The causes of ageing are numerous:
• Impaired immune response
• Altered thresholds and reduced reserves
• Functional effects
• Multiple pathology
• Age related changes
• Chronic disease changes
Disease in old age is common – multiple pathology:
o Age related increases in incidence of common disorders (hypertension,
osteoarthritis, diabetes mellitus, vascular diseases, dementia)
o Accumulation of diseases in survivors
o Gradual development of vascular diseases with acute episodes superimposed
(heart disease and cerebrovascular disease)
o Secondary effects - (eg Immobility secondary to neurological or musculoskeletal
disorders leads to increased risk of complications: falls, urinary incontinence,
infections, pressure ulcers, deep vein thrombosis and pulmonary embolism)
o Increased likelihood of systems failures (eg chest infection leading to atrial
fibrillation and heart failure)
Presentation of disease in old age can be different:
o Non-specific presentation
o Atypical or uncommon presentation
o Multiple pathologies or diagnoses
o Erroneous attribution of symptoms to old age
o Single pathology/illness can lead to catastrophic consequences.
Non specific presentation:
The ‘geriatric giants’
o Intellectual failure – confusion, dementia
o Incontinence
o Immobility
o Instability – falls
o Iatrogenesis – drug induced effects
Underlying mechanisms:
o Reduced reserves
o Age related changes
o Acute disease changes
o Chronic disease changes
Polypharmacy is common:
o 5-17% hospital admissions due to adverse drug reactions
o 6-17% older in patients experience adverse drug reactions
o Many drugs are overprescribed in older people
o Paradoxically, many don’t receive drugs that would be beneficial
Common problems – falls and fractures:
o Sedative drugs,
o Blood pressure lowering drugs
o Alcohol
Assessment is often complicated not always readily available. Tests include cognitive
function, mobility, ability of self care, falls, continence and mood.
Taking a history:
o Too ill to give history
o Confused
o Deaf or other communication problems
o Memory problems
o Complex history with many items
Examination and investigations:
o Normal ageing vs. disease
o Don’t always show common signs/abnormalities
Drug history is important: patients may be taking a number of different drugs.
It is important to consider the balance of the risk that may be caused by a treatment.
E.g. warfarin for atrial fibrillation. It is important that the underlying condition is
treated not the presenting complaint, and remember the risk of drug interactions. Take
into account home situation, carers and don’t forget to treat chronic conditions.
Goals of Treatment
• Basic function Being able to walk
• Basic activity Being able to wash and dress
• Social activity Being able to go to the pub
• Affected by personal factors - sociability, drive
• Affected by environment - access to flat, carers
The international classification function is used in the assessment of treatment of agerelated disease.
The Ageing Brain
Research in the brain function is only very recent. Imaging techniques are very
modern and increasing nutrition means that the brain has changed in weight over the
last 100 years. It is very difficult do judge what a normal brain is supposed to be like
– these can all be affected by
– Diet, good, poor, higher levels of cholesterol, obesity
– Exercise levels
– Genes & gene expression throughout ageing
– Educational level
Consequences can include:
– Slower reaction times
– Lower attentional levels
– Slower processing speeds
– Detriments in sensory functions
– Detriments in perceptual functions
– Less ability to use strategies
– Difficulty in completely separating out aspects of neuropsychological functioning
(e.g. different type of memory)
– Difficulties mapping structure to function & age related change
There are various types of macroscopic and microscopic changes that occur in the
 The brain changes in weight by a decrease of 1% every decade.
 Prefrontal cortex* most affected
 Also hippocampus, striatum, temporal lobe & cerebellum
 Prefrontal white matter also affected
 Occipital cortex least affected
 Most studies support this pattern although some put the hippocampus as most
 White matter loss:
o Myelin sheath deteriorates after the age 40
o Late myelinating region
o Leukariosis/white matter lesions
 Grey matter loss:
o Loss of functionality (particularly in hippocampus and prefrontal cortex)
o Reduction in number of dendritic spines and synapses
o Reduction in the ability to use established networks (brain activation more
symmetrical in the elderly)
o Increased dendritic branching
 Enlarged ventricles/sulci
 Regional change
o Decrease in volume not uniform
o Prefrontal cortex most affected
o Also hippocampus, striatum, temporal lobe & cerebellum
o Prefrontal white matter also affected
o Occipital cortex least affected
o Most studies support this pattern although some put the hippocampus as
most affected.
This all results in a decreased ability to learn new information, to adapt to new things
and deal with changing environments. Examples of this include:
- A reduction in the ability to form long term increases in post-synaptic
potentials (Long term potentiation) – learning.
- Impaired acquisition of conditioning (eg eyeblink)
- Changes in task related regional brain activation:
o Older brains – more symmetrical activation
o In elderly, increased activation in hemisphere less activated in young
o Reduced activation of areas activated in young adults
o Shown for memory and visual perception
There are 4 main types of memory:
Episodic memory – ‘a form of memory in which information is stored with
‘mental tags’, about where when and how the information was picked up’.
This declines from middle age onward
Semantic memory – ‘memory for meanings’. This increases from middle age
to young elderly but decreases in the very elderly.
Procedural memory – eg how to ride a bike: least likely to be affected by
aging/dementia not discussed further.
Working memory – ‘short term holding memory’
Their function in humans is initiation, planning, hypothesis generation, cognitive
flexibility, decision making, regulation, judgement, feed-back utilization and self
perception. They all decline with ageing.
o Mechanisms of change – all these increase with age and have been related to
memory loss:
o Neurofibrilliary tangles
o Amyloid plaques
o Lewy bodies
o Hirano bodies
o Lipofuscin
Mechanisms of Brain Ageing
Oxidative damage: production of free radicals from mitochondria can damage cells.
The antioxidants that normally mop up the free radicals are less produced as we
continue through ageing. They can damage mitochondria themselves and DNA in
Gene expression: the expression of certain genes reduces with ageing and results in
deficits in synaptic function & plasticity, mitochondrial function, calcium
homeostasis. The most common gene associated with ageing is the apolioprotien 3
gene of which there are 3 important alleles:
– E2 least common, protective against cardiovascular disease and Alzheimer’s
disease, over represented in centenarians
– E3 most common
– E4 increased risk Alzheimer’s disease (late onset)
Calcium disruption: can increase susceptibility to hypoxia, reduce learning ability
and increase risk of Alzheimer’s disease
Neurotransmitters: Dopamine levels fall 10% per decade from early adulthood.
Hormones: Oestrogen as a protective factor for Alzheimer’s – more women suffer
even when greater survival taken into account. Recent HRT trials suggest
supplementation not a good idea
Reduced input of glucose or oxygen:
Impaired glucose metabolism
Cerebrovascular efficiency falls
White matter lesions possibly stemming from subclinical ischaemia
Hypertension and Stroke: the risk of stroke increased with increasing age (thought
to double every decade after 35 years). Blood pressure also rises with increasing age
and high blood pressure in midlife is a risk factor for te development of dementia in
later life.
Alcohol: red wine is said to reduce the risk of stroke by development of the hippocampus.
Neurotransmitters and Related Substances: dopamine levels fall by 10% per
decade from early adulthood.
Exercise: increases frontal activity and neurone connections, vascularity, cell
proliferation and nerve growth factor.
Experience and Education: higher education levels seem to contribute to education
Dementia is a disease of ageing which occurs in around 20% of those aged 80 and
40% of those aged 90. It is incredibly distressing, debilitating and burdensome on
o Types of dementa:
o Alzheimer’s disease (AD) – most common
o Vascular dementia (VaD)
o Lewy-body dementia
o Mixed dementia
Diagnosis of dementia:
Screening tests
Diagnostic Statistical Manual IV / Brain scan
Depression/delirium/drug effects
Blood tests
– Red cell folate
– Thyroid function
– Serum B12
Mini-mental state exams – consists of 11 questions which test cognitive
Generally characterised by:
1) memory impairment (impaired ability to learn new information or to recall
previously learned information)
2) one (or more) of the following cognitive disturbances
– a: aphasia (language disturbance)
– b: apraxia (impaired ability to carry out motor activities despite intact motor
– c: agnosia (failure to identify objects despite intact sensory function)
– d: disturbance in executive functioning (ie planning, sequencing
Cardiovascular Disease and Ageing
The ageing of the heart can have a number of effects on the heart musculature and the
coronary artery.
Afterload: resistance to the ejection of blood faced by the contracting heart. It can
decrease with ageing due to:
» Loss of elastic tissue
» Deposition of calcium
» Change in amount of collagen
» Endolethial cells change causes less laminar flow
» Increase in cell wall thickness
» Dilation of arteries
Normal pulse wave
Older  higher pulse wave velocity
Preload: concept that relates amount of ventricular filling to myocardial contractile
» The volume of the ventricles when the heart is at rest changes with age.
» The increase in after load results in heart muscle hypertrophy
» Ventricular filling decreases with age
» The walls of the left ventricle increase in stiffness with age
Contractility: intrinsic ability of the heart to generate a force
» There is not much change in ejection index with age
» Stoke volume does not change with age.
» Prolongation in duration of contraction and relaxation
Neurohmeral Factors
• Catecholamines increase with age
– -adrenergic vasocontriction does not change
– ß-adrenergic vasodilatation declines with age, most important during
• Changes in histamine, renin and angiotensin do not produce consistent agerelated changes in vascular tone
• Serotonin has increased vasoconstricting effects with age (in animals)
• Decrease in NO release, increase in ET-1 (endothelial factor 1)
• Baroreceptor insensitivity increases
Three is also an age-related decrease in response of the heart to exercise. This is
difficult to evaluate due to occult conditions such as coronary artery disease. VO2 max
decreases with age as well as decreased cardiac output (due to decreased heart rate –
stroke volume does not change).
• Inability of the older heart to empty during exercise one of the most prominent
characteristics of the ageing heart
• Leads to reduction in max EF
• ß-adrenergic modulation during exercise enables the heart to beat quicker.
There is deficient ß-adrenergic modulation with ageing
• Healthy older individuals fail to increase heart rate as much as younger
Hypertension measured by blood pressure – pressure variablility is greater in the
elderly so repeat measurements should be done.
• Treatment benefit it SBP >160 or DBP >90
• Benefit at all ages - even beyond 80
• Diuretics first line (in uncomplicated)
– Stroke is most common cause of disability
– There are approximately 250,000 disabled stroke survivors in UK
– CVD is 2nd leading cause of dementia
– Stroke is most common cause of epilepsy in the elderly
– Stroke is a frequent cause of depression
Heart Failure
• CHF probably most significant cardiac problem in the elderly – 8% prevalence
in 80+
• Mortality increased with age – worse prognosis than many cancers
• Most common cause of hospital admission
• Patients often under treated
• In elderly IHD, HTN and valvular disease main causes
• Due to physiological changes when disease is superimposed effects are greater
Ischaemic Heart Disease
• Main cause of death in the elderly
• Atypical presentation
– Classic symptomatic disease is less than 50% of true prevalence on
post-mortem studies
– Significant disease in coronary arteries as high as 60% in men aged
• Often MIs develop from the non-significant plaques.
• Age associated changes mean symptoms of CHF appear more readily as a
result of ischeamia
• Greater prevalence of atrial fibrillation in the elderly
Valvular Heart Disease
With increasing age shift from MS to MR as condition responsible for mitral
valve problems (IHD/ mitral degeneration)
AS not infrequent in older people + often rapidly progressive
Treatment similar to younger individuals
Fatality among over 65s for MVR/ AVR generally low
Prevention by Lifestyle Modification
• Stop Smoking
• Salt restriction
• Weight loss
• Alcohol reduction – if excessive (1-2 units per day seems best)
• Increased exercise