2.5 Pathology Lecture.pptx

The Pathology of Ageing SCI1018-N PATHOLOGY Dr. Ahmad Khundakar Learning outcomes • At the end of the lecture you should be able to: • Discuss the theories of ageing • Analyse the impact of cellular senescence on the ageing process • Understand the roles of the ageing process in the changes to con...

The Pathology of Ageing SCI1018-N PATHOLOGY Dr. Ahmad Khundakar Learning outcomes • At the end of the lecture you should be able to: • Discuss the theories of ageing • Analyse the impact of cellular senescence on the ageing process • Understand the roles of the ageing process in the changes to connective, muscle, epithelial and neuronal/neural tissue • Discuss age-associated conditions, such as agerelated macular degeneration, hearing loss and GI tract disorders Ageing: Key Terminology • Ageing (aging U.S.): • • Senescence: • • ‘The scientific study of the biological, psychological, and sociological phenomena associated with old age and ageing’ Geriatrics: • • ‘The decline of fitness components of an individual with increasing age, owing to internal deterioration’ Gerontology: • • ‘The process of becoming older’, particularly applies to humans but can also apply to other animals' ‘The branch of medicine that deals with the diagnosis and treatment of diseases and problems specific to the aged’ Biogerontology: • ‘The study of the biology of ageing and longevity’ Theories of Ageing - History • Ancient Greece (~5th Century BC) • Old age consequence of gradual consumption of ‘innate heat and inevitable loss of body moisture’, according to Hippocrates’ system of four‐humours • Galen (129–199 AD) • • Ageing was due to changes in body humours that began in early life These changes caused a slow increase in dryness and coldness of the body • Roger Bacon (c. 1220–1292) • • • One of the first to suggest a “wear and tear” theory Ageing is the result of abuses and insults to the body system Good hygiene might slow the ageing process • Charles Darwin (1809–1892) • Attributed ageing to the loss of irritability in the nervous and muscular tissue Theories of Ageing • Programmed theories • Ageing has a biological timetable or internal biological clock • Error (or ‘random/stochastic’) theories • Ageing is a result of internal or external assaults that damage cells or organs so they can no longer function properly Error theories Programmed theories • • • • Evolutionary Programmed Senescence Endocrine Immunology Unified theories • • • • • • Wear and Tear Rate-of-Living Free Radical Cross-linking Error Catastrophe Somatic Mutation Theory The Ageing Cell López-Otín, 2013 Cellular Senescence • Phenomenon characterised by cessation of cell division • “Hayflick’s Limit” (reproductive senescence) • Fibroblasts removed from umbilical cord & cultured • Fibroblasts divide and repeated until ~ 50 divisions • Will not divide past this point • Can be initiated by wide variety of stress inducing factors • Include both environmental and internal damaging events, abnormal cellular growth, oxidative stress, autophagy factors • Thought to involve telomere shortening Telomeres • Repetitive DNA sequences at the ends of all human chromosomes containing thousands of repeats of the sixnucleotide sequence, TTAGGG • Humans have 46 chromosomes, thus 92 telomeres (one at each end) • Protect and separate chromosomes from others in DNA sequence • Act like a ‘cap’ to prevent unravelling Cellular Senescence – Telomeres • When human cell divides, DNA splits into two strands – one with a gap at the end • End gets shorter with each division • Cell can no longer divide • Could explain Hayflick’s limit! Programmed Senescence – Telomerase • When human cell divides, DNA splits into two strands – one with a gap at the end • • • End gets shorter with each division Cell can no longer divide Could explain Hayflick’s limit! • Telomerase fills the gap by attaching bases to the end of the chromosomes • While cells have enough telomerase, telomeres kept long enough to prevent information from being lost through each replication • However, telomerase levels decrease over time • With decreasing telomerase levels, the telomeres become shorter Programmed Senescence – Telomerase • Telomerase changes found in patients with: • • • • • Heart disease Atherosclerosis Hepatitis Cirrhosis Cancer • Thus, a target for treatments! Programmed Senescence – Telomerase Question: You are a researcher who has discovered a treatment that enhances telomerase levels in cells. Why would this be viewed as a positive statement in particular diseases (e.g. Parkinson’s disease) but not in cancer? Telomeres and Cancer • 90% of cancer cells have been found to possess telomerase • • Telomerase prevents the telomere from shortening Allows the cancer cells to reproduce, resulting in tumour growth • Possible interventions in cancer • • • Measuring telomerase in the detection of cancer Stopping telomerase may fight cancer by causing death of cancer cells Telomerase in wound healing or immune response Ageing and Disease • Physical changes related to ‘normal’ ageing are NOT disease-related • We all experience ‘natural’ physical changes in old age • Changes have a deleterious effect on the individual • However, age is the main risk factor for many diseases! Physiological changes with Age • 75 vs. 30 years • • • • 92% of brain weight 84% of basal metabolism 70% kidney filtration rate 43% of maximal breathing capacity (Evans et al, 2001) • However, interventions can improve function • Active lifestyle results in less muscle mass loss and greater flexibility with age • Steps taken to prevent illness and injury can maximise independence Ageing and Homeostasis • Homeostatic response altered and maintained at a level of decreased function in ageing Ageing and Homeostasis • Homeostatic response altered and maintained at a level of decreased function in ageing • Ageing of tissue in homeostatic control centres (e.g. hypothalamuspituitary complex) • Also in target glands and organs Menopause • Natural biological process marking end of menstrual cycle in females (last egg produced) • Can happen in 40s (or earlier) but average age 51 • Perimenopause (period leading up to menopause) - ovaries gradually produce less oestrogen (and progesterone) until insufficient to ovulate • Symptoms – hot flushes (sweating, feeling of warmth), changes in membrane lining the vagina, emotional changes (mood, anxiety) Menopause – treatment • Hormone therapy (HRT) – most widely used and effective treatment • HRT a combination of oestrogen and progestin (synthetic progesterone), or oestrogen alone (after hysterectomy) Santen et al, 2010 Question: study the graph, which is taken from a meta-analysis of data on the efficacy and side effects of hormone replacement therapy (HRT). Using the graph, determine the main benefits and risks of different the combinations of HRT. Santen et al, 2010 Levels of Cellular Organisation Levels of Cellular Organisation AGEING AND DISEASE PROCES Types of Tissue • Four main types of tissue • • • • Connective tissue Epithelial tissue Neural/neuronal tissue Muscle tissue • All undergo changes in ageing process Types of Tissue • Four main types of tissue • • • • Connective tissue Epithelial tissue Neural/neuronal tissue Muscle tissue • All undergo changes in ageing process Connective Tissue • Tissue that connects, supports, binds, or separates other tissues or organ • Characteristics of connective tissues (CT): • Fibres – vary in tissue type (not present in blood or adipose tissue • Ground substance – clear, colourless, viscous fluid containing glycosaminoglycans and proteoglycans • Ground substance and fibres create the CT matrix • Cells – usually infrequently spread through matrix Connective Tissue Changes in Ageing • Fibres • Collagen – decreased solubility, reducible cross linkages stabilise, increased rigidity • Elastin – decreased production, increased fragmentation, rupture, loss of ‘rebound’ Connective Tissue Changes in Ageing • In ageing – non-oxidative reactions between glucose and collagen • lead to the formation of so-called advanced glycation end-products (AGEs) • Leads to Schiff base ‘cross link’ formation between a carbohydrate and a protein amino group • AGEs most abundant in collagen tissues • Causes ‘stiffening’ of tissue Types of Tissue • Four main types of tissue • • • • Connective tissue Epithelial tissue Muscle tissue Neural/neuronal tissue • All undergo changes in ageing process Epithelial Tissue • Plays fundamental role in establishing tissue barriers • Separates internal from external environment • Maintains nutrient, fluid, electrolyte and metabolic waste balance in multiple organs Epithelial Tissue • Epithelial cells tightly held together by junctions, adhering junctions and desmosomes • Epithelium attached to basal lamina comprised of mixture of glycoproteins and collagen • Reticular lamina attached to basal lamina, underlying connective tissue forms basement membrane Epithelial Tissue Changes in Ageing • Cell adhesion complexes critical regulators of permeability • Cells lose adhesion in ageing or disease conditions • Impacts on organ function • Skin - more susceptible to maceration, which may lead to development of lesions Epithelial Tissue Changes in Ageing • Cell adhesion complexes critical regulators of permeability • Cells lose adhesion in ageing or disease conditions • Impacts on organ function • Lung (alveoli) - single cell structure is highly susceptible to damage Epithelial Tissue Changes in Ageing • Cell adhesion complexes critical regulators of permeability • Cells lose adhesion in ageing or disease conditions • Impacts on organ function • Gastrointestinal - decreased intestinal barrier function associated with systemic inflammation, absorption of certain nutrients (e.g. lipids) affected Types of Tissue • Four main types of tissue • • • • Connective tissue Epithelial tissue Neural/neuronal tissue Muscle tissue • All undergo changes in ageing process The Brain • Made up of three parts: • Forebrain • Cerebrum, thalamus, and hypothalamus • Midbrain • Midbrain structures (e.g. substantia nigra, superior colliculus) • Hindbrain • • Cerebellum Brain stem structures (e.g. medulla oblongata, neurotransmitter nuclei) Cerebrum (cerebral cortex) • The largest part of the human brain is the cerebral cortex (bark in Latin) • • • • All information processing on six surface layers of cortex The cortex sheet folded into fissures inside the (sulci) and ridges (gyri) The brain is split into the left and right hemispheres by the corpus callosum White matter underneath the cortex contains axons connecting brain areas Cerebrum (cerebral cortex) • The largest part of the human brain is the cerebral cortex (bark in Latin) • • • • All information processing on six surface layers of cortex The cortex sheet folded into fissures inside the (sulci) and ridges (gyri) The brain is split into the left and right hemispheres by the corpus callosum White matter underneath the cortex contains axons connecting brain areas Cerebral Cortex Lobes • Four lobes • Frontal (inc. motor cortex) • Parietal (inc. primary somatosensory region) • Occipital • Temporal • (+ allocortex) The Neuron(e) Cell body (soma) • Basic signalling unit of the nervous system • Polarised cell • Can receive, process and transmit electrical information through the action potential Axon • Communicate electrochemically • Specialised connections - synapses • Allow chemical communication between neurones Dendrites Synapse Cellular Structure • Neuron(e) basic function unit • Sensory neurones - receptor cells receiving external stimulus (afferent neurones) e.g. light receptors in retina • Motor neurones – effector cells respond to sensory information (efferent neurones) • Glial cells • Astrocytes • Oligodendrocytes • Microglia The Ageing Brain • Ageing affects molecules, cells, vasculature, gross morphology in brain • Changes to vasculature and increases in blood pressure • Raises possibility of stroke and ischaemia • Development of white matter lesions (hyperintensities) Human brain vasculature MRI image of 80 year old patient with minor white matter hyperintensities Debette and Markus (2010) The Ageing Brain • Atrophic changes, particularly in frontal cortex • Volume of the brain declines around 5% per decade after age 40 (Svennerholm et al, 1997) • Increases over 70 years of age • Thought to be a result of cell death • Compensatory changes in dentritic arbour, spines, and synapses • Help re-establish synaptic connections lost from cell death The Ageing Brain – Neurodegenerative Disease • Age-related diseases of the brain (e.g. Alzheimer’s disease, Parkinson’s disease) are NOT a consequence of ageing • Age main risk factor • Ageing process may leave neuronal/tissue liable to disease • Proteins associated with neurodegenerative diseases (e.g. βamyloid) naturally accumulate with ageing • Not to levels sufficient to cause significant pathology effect Types of Tissue • Four main types of tissue • • • • Connective tissue Epithelial tissue Neural/neuronal tissue Muscle tissue • All undergo changes in ageing process Skeletal Muscle • Striated (‘striped’) muscle • Responsible for voluntary movement • 650 muscles in humans • Stretching and contracting in of cells in orderly manner • Adapt to use (or non-use!) • Muscular atrophy in injury and ageing Skeletal Muscle Changes in Ageing • Sarcopoenia - involuntary loss of muscle mass, strength and function • Muscle mass decreases approximately 3– 8% per decade after the age of 30 (Volpi et al, 2004) • Rate of decline higher after the age of 60 • Loss of muscle mass, strength, and function major contributor to disability in older people • Sarcopoenia increases fall risk, vulnerability to injury (Wolfson et al, 1995) • May lead to functional dependence and disability Sarcopoenia – Treatment • Primarily exercise-based • Specifically resistance training or strength training • Drug therapies not preferred option: • Urocortin II stimulates pituitary gland adrenocorticotropic hormone (ACTH) release • HRT can increase lean body mass, reduce abdominal fat and prevent bone loss in the short-term • Long term effects – breast cancer? Ageing and Disease in Organ Systems Skin Changes in Ageing Skin Changes in Ageing • Skin generally divided into three main parts: • Epidermis – outer part contains skin cells, pigment, and proteins • Dermis – middle part contains blood vessels, nerves, hair follicles, and oil glands; provides nutrients to the epidermis • Subcutaneous layer – inner layer under the dermis, contains sweat glands, some hair follicles, blood vessels, and fat Skin Changes in Ageing • Wrinkling, as a result of loss of elasticity and decline in cell replacement • Loss of dermal thickness (20%), especially in sun-damaged skin • Chance of skin neoplasms (benign and malignant) increase • Vitamin D production declines • Decline in Meissner’s (touch), Pacinian (pressure), Krause’s (temperature), corpuscles Eye Changes in Ageing Eye Changes in Ageing • Lens grows during life span, increasing in density and weight • Ptosis – wrinkling and loss of orbital fat • Presbyopia (‘long sightedness’) – progressive decrease in lens elasticity • Glaucoma increased intraocular pressure in aqueous humour Eye Changes in Ageing – Age-related macular degeneration • Age-related macular degeneration (AMD) • • Blurred or no vision in the centre of the visual field Characterised by progressive accumulation of characteristic yellow deposits, drusen • • build-up of extracellular proteins and lipids, in the macula (a part of the retina) Reading and recognising faces difficult Ear Changes in Ageing Ear Changes in Ageing • Hearing loss accompanies aging • • • 10% of population (US) has hearing loss 65–75 years – 33% of population have hearing loss >75 – 50% of population have hearing loss • Presbycusis – ageing of middle ear • Ear drum loses elasticity • Decreased 8th (vestibulocochlear) nerve sensitivity due to noise exposure • Decline in hair cells of the cochlea • Joints of the bones of the ear become stiff • Mechanical blockage – earwax, effusion Gastrointestinal (GI) Changes in Ageing • GI symptoms are common in older people • Prevalence, mortality and morbidity of GI diseases increase with advancing age • Ageing affects absorption and metabolism of foods, vitamins and medications Gastro‐Oesophageal Reflux Disease (GORD/GERD) • GORD becomes more prevalent with increasing age (Howard et al, 1992) • Prevalence in primary care may be >20% although many older people do not report heartburn (Mold et al, 1991) • Many do not present to clinicians but self medicate in the community (Corder et al, 1996) • Most effective treatment is currently regarded as proton-pump inhibitor (PPI; NICE) • • • Proton pump terminal stage in gastric acid secretion Responsible for secreting H+ ions into the gastric lumen Thus, target for inhibiting acid secretion Gastro‐Oesophageal Reflux Disease (GORD/GERD) • GORD becomes more prevalent with increasing age (Howard et al, 1992) • Prevalence in primary care may be >20% although many older people do not report heartburn (Mold et al, 1991) • Many do not present to clinicians but self medicate in the community (Corder et al, 1996) • Most effective treatment is currently regarded as proton-pump inhibitor (PPI; NICE) • Proton pump terminal stage in gastric acid secretion • Responsible for secreting H+ ions into the gastric lumen • Thus, target for inhibiting acid secretion Peptic Ulcer Disease (PUD) • Peptic ulcer disease – duodenal or stomach ulceration • Affects 4 million people around the world • 2%-14% of the ulcers will perforate • Major cause of dyspepsia • • Episodic or persistent pain or discomfort localised to the upper abdomen Symptoms including gas, bloating, nausea, vomiting, and early satiety • Age-related, though peak incidence is in the 40s for men and in the 50s/60s for women Peptic Ulcer Disease (PUD) • Peptic ulcer disease – duodenal or stomach ulceration • Initially thought to be caused by stress, spicy foods, and too much acid • Barry Marshall discovered the bacterium Helicobacter pylori (H. pylori) plays a major role in causing many peptic ulcers • Now treated with antibiotics, often in combination with PPIs Learning outcomes • You should now be able to: • Discuss the theories of ageing • Analyse the impact of cellular senescence on the ageing process • Understand the roles of the ageing process in the changes to connective, muscle, epithelial and neuronal/neural tissue • Discuss age-associated conditions, such as agerelated macular degeneration, hearing loss and GI tract disorders Quiz Time! 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