Pathology Revision 2024 PDF

**Pathology Revision** Malignant Disease ================= What is cancer? --------------- Cancer is a problem of multicellular organisms - It is a cellular phenomenon that occurs because cells acquire certain abnormal properties - Is a collection of different diseases - Displays unc...

**Pathology Revision** Malignant Disease ================= What is cancer? --------------- Cancer is a problem of multicellular organisms - It is a cellular phenomenon that occurs because cells acquire certain abnormal properties - Is a collection of different diseases - Displays uncontrolled growth (core features) Terms ----- **Neoplasia:** formation of an abnormal mass of proliferating ------------------------------------------------------------- cells, possessing a significant degree of autonomy. **Anaplasia:** lack of differentiation in neoplastic cells; seen as a mass of pleomorphic primitive cells. **Hyperplasia**: cell response to a specific stimulus, the proliferation of cells within an organ or tissue beyond normal; may result in the gross enlargement of an organ, the formation of a benign tumour. **Metaplasia**: One differentiated cell type changes into another mature differentiated cell type. **Dysplasia**: abnormality of development, alteration in size shape and organization of adult cells. Dysplastic nevus(DN) -------------------- - Are atypical moles that are larger than ordinary moles - Have irregular shape and tend to have uneven colour; usually begin as flat, but parts may rise above the skin surface. - show rete ridge bridging: epidermal thickenings that extend downward between dermal papillae - show moderate nuclear atypia - People who have DN are at increased risk of developing melanomas Characteristics of malignant cells ---------------------------------- - loss of growth control (growth signal autonomy; insensitivity to inhibitory signals) - resistance to apoptosis - unlimited replicative potential (telomere, telomerase) - sustained angiogenesis - ability to invade the surrounding tissue - ability to colonize and survive in an ectopic environment (metastasis) - exhibit anchorage-independent growth and lose - sensitivity of contact-inhibition Causes of cancer(aetiology of cancer) ------------------------------------- 1. **acquisition of mutations** - inborn zygotic mutations, somatic mutations 2. **environmental factors** - viruses, chemicals and radiation 3. **abnormal tissue microenvironment** - blood and lymphatic vasculature, fibroblasts, immune cells, extracellular matrix and signalling molecules - characterized by hypoxia 4. **others:** age, lifestyle etc. Genetic mutations and increased risk of cancers ----------------------------------------------- Inborn zygotic mutations, somatic mutations - Breast cancer and ovarian cancer: *BRCA1* and *BRCA2* - Li-Fraumeni syndrome (LFS): *p53*, *CHK2* - Childhood cancers: Wilm's tumour (del 11p13) - Chronic myelogenous leukaemia \[CML, t(9,22), - Philadelphia chromosome\] - Retinoblastoma: *RB* - Colorectal cancer: *APC* (adenomatous polyposis coli gene) Oncogenic Viruses ----------------- During the viral replication process, certain virus's DNA or RNA affects the host cell's genes in a way to be become cancerous. Retrovirus uses RNA for its genetic code. During the replication process, the virus uses reverse transcriptase, which allows the virus to change its RNA genes into DNA. - HPV (human papilloma virus): cervical cancer - Epstein-Barr virus: Burkitts lymphoma - Hepatitis B and C viruses: liver cancer Xeroderma pigmentosum(XP) ------------------------- - an autosomal recessive genetic disorder of DNA repair (NER) - mutated XPA-XPG - sensitive to UV-light and have a 1000-fold increased risk of developing skin cancer - involves both sexes and all races, with an incidence of 1:250,000 symptoms include: - irregular dark spots on the skin - development of many freckles at an early age - severe sunburn when exposed to only small amounts of sunlight - eyes that are painfully sensitive to the sun - Spidery blood vessels Classification of Tumours ------------------------- Behavioural classification: benign or malignant - Histogenetic classification: cell of origin - Precise classification of individual tumours is important for planning effective treatment o TNM classification o Staging o Grading Benign and Malignant tumour --------------------------- Benign Malignant -------------------------------- ------------------------ Generally Encapsulated Non-encapsulated Non-invasive Invasive Highly Differentiated Poorly differentiated Few Mitotic Figures Mitotic Figures Common Slow Growth or No Net Growth Can have rapid growth Little Anaplasia Relatively Anaplastic Non-Metastatic (by definition) Metastatic Histogenetic Classification (Classification by Cell/Tissue Type of Origin) -------------------------------------------------------------------------- **Epithelial Tissue** Carcinoma ------------------------------------------ ------------------------------ **Connective Tissue** Sarcoma **Hematopoietic Tissue** Leukemia & Lymphoma myeloma **Nervous tissue** Neuroectodermal malignancies **Germinal Tissue & Mixed Tissue Types** Teratoma The clinical effects of tumours ------------------------------- - General effects - Local effects - Endocrine effects - Paraneoplastic syndromes General effects of tumours -------------------------- - Nausea/vomiting - Poor appetite - Fever - Pain - Fatigue - Weight loss - (cachexia) Cancer cachexia --------------- Cachexia, a multifactorial syndrome associated with numerous diseases, such as tuberculosis, AIDS, congestive heart failure and cancer. - Cancer cachexia is characterised by a progressive loss of skeletal muscle mass (sarcopenia), along with adipose tissue wasting, systemic inflammation and other metabolic abnormalities leading to functional impairment. - the presence of cancer cachexia does not depend on the tumour size. - cancer cachexia varies with the tumour type: in gastric or pancreatic cancer patients, the incidence is over 80%. - Within a given type of cancer, the degree and extension of cachexia depends on tumour stage. - chemotherapy and radiotherapy may exacerbate cachexia. The clinical effects of tumours ------------------------------- Local effects: - compression - obstruction - ulceration - haemorrhage - rupture - perforation - infarction Paraneoplastic syndromes ------------------------ This refers to symptoms in cancer patients not readily explained by local or metastatic disease. - hypercalcaemia - endocrine effects - Cushing's syndrome - clubbing of the fingers - skin rashes - hypertrophic osteoarthropathy - peripheral neuropathy - cerebellar degeneration Endocrine effects ----------------- Insulinoma: a tumour of the pancreas that produces excessive amounts of insulin. Cancer Diagnosis ---------------- **Typical Clinical signs** - a lump in the breast or testicles, unusual bleeding, changes in a mole\... **Screening** - Pap smear test **Routine investigations** - X-rays, blood tests **Imaging methods** - computed tomography (CT) or conventional pluridirectional tomography; MRI (magnetic resonance imaging); PET (positron emission tomography); ultrasound **Fibre Optic Scope (endoscopy)** **Special Investigations** (tumour markers: eg. Catecholamine serum levels in neuroblastoma) **Surgical biopsy** (Histopathology of tissue-appearance; immunohistochemistry; histochemistry; electron microscopy) **Genetic testing** Malignant tumour histology -------------------------- - Loss of differentiation - Loss of cellular cohesion - Nuclear enlargement - Increased mitotic activity Tumor Markers ------------- - A substance found in blood, urine or tissue which is associated with the presence of malignancy. Possible uses: - Screening at-risk populations - Diagnosis of a particular type of malignancy - Staging extent of tumour spread - Monitoring therapy and recurrence - Determining the most advantageous treatment - Target of tumour scanning or therapy - \"Ideal\" tumour marker test: Sensitive, specific, easily detected, marker levels correlate with the extent of the disease **PSA** (prostate-specific antigen) ----------------------------------- - PSA is a protein produced by the cells of the prostate gland - Clinical levels correlating with stage - Signals cancer recurrence after prostatectomy - Benign prostatic hyperplasia - 50-80% elevated - \< 4.0ng/ml is considered as normal Management of cancers --------------------- Common Side Effects of Chemotherapy ----------------------------------- - Frequent infections - Diarrhoea - Nausea and loss of appetite - Hair loss - Anaemia Targeted cancer therapy ----------------------- Targeted cancer therapies are drugs or other substances that block the growth and spread of cancer by interfering with specific molecules involved in tumour growth and progression. - Also called "molecularly targeted drugs" ,"molecularly targeted therapies". - Targeted cancer therapies that have been approved for use in specific cancers include drugs that interfere with cell growth signalling or tumour blood vessel development, promote the specific death of cancer cells etc. - Treatments based on the unique set of molecular targets produced by the patient's tumour. Proton therapy -------------- Proton therapy (proton beam therapy), is a type of radiation treatment that uses protons rather than x-rays to treat cancer. A proton is a positively charged particle. Doctors may use proton therapy alone, or they may combine it with standard radiation therapy, surgery, chemotherapy, and/or immunotherapy. Infectious Disease ================== Pathology and infectious diseases. ---------------------------------- Infectious disease can be detected when causing pathological effects to tissues and cells. To determine the cause of the pathology to be infective has implications for 1. Diagnosis 2. Treatment 3. Prognosis 4. Prevention (control of disease) Pathological effects of infectious diseases ------------------------------------------- An infectious disease can be passed easily from one person to another, especially through air or water. (Oxford Dictionary) An infectious disease has a causative agent. (aetiological agent) This causative agent typically is microscopic, termed a microorganism or microbes. Etiological agent, substances that contain infectious microorganisms. An infection is when there is damage to tissues or cells leading to symptomatic disease Causes of infectious disease ---------------------------- Includes: - Bacteria (Prokaryotes) - Viruses (Non-cellular) - Fungi (Eukaryotes) - Protozoa (Eukaryotes) - Prions (Proteins, non-cellular) - Helminths (non-microbial, Eukaryotes) - Arthopods (non-microbial, Eukaryotes) \*Archaea, have no infectious agent identified to date however possible role in periodontal disease \* Recap: what causes infectious diseases -------------------------------------- Routes of transmission ---------------------- - Aerosol: by inhalation of air droplets containing microorganisms - Oral: by ingestion of contaminated food or water - Direct contact: contact with infected individual tissues or bodily fluids, via entry sites, - e.g. eyes/mouth/nose or wound (e.g. bite/scratch) - Fomite transmission: contaminated surfaces of inanimate objects e.g cages/door - handles/medical equipment - Vector-borne: (by other living organisms e.g. mosquitoes, ticks) - Zoonotic: (originating from other animal species through routes above) Transmission of disease-causing agents -------------------------------------- Infectious agents must be transmitted between hosts Transmission of infectious agents in multiple different routes; Routes are related to the specific type of microorganism and the type of tissue or cell it can infect. CASE STUDY :Bacillus anthracis ------------------------------ - Gram-negative positive bacilli. - Present in the environment, in soil and water and contaminated animal products (wool, hides or hair) Depending on the transmission route, it may cause; - Cutaneous anthrax - Gastrointestinal anthrax - Inhalation anthrax - Injection anthrax(needle) - Welder anthrax Routes of transmission: RTI agents ---------------------------------- Diversity of microorganisms via inhalation of air droplets containing microorganism. How can ID be characterised? ---------------------------- Infectious diseases are defined by their; **Signs** (objective, can be detected/measured) e.g. fever, coughing, vomiting **Symptoms** (subjective, can be described) e.g. pain, nausea  Case study: Influenza Syndrome ------------------------------ Causative agent - Influenza virus Segmented --ve sense ssRNA genome Pleomorphic nucleocapsid Signs and symptoms - Fever - Cough - Sore throat - Congestion - Muscle/body aches - Fatigue - Vomiting and diarrhoea Characteristics of infectious diseases -------------------------------------- - Phases of an infectious disease - Duration of infectious disease - Location of infectious disease - Timing of infectious disease - Stages in infection Phases of infectious disease ---------------------------- **Incubation period** time between infection and the appearance of sings and symptoms **Prodromal phase** mild, non-specific symptoms that signal onset of some diseases **Clinical phase** a person experiences typical signs and symptoms of disease **Decline phase** subsidence of symptoms **Recovery phase** symptoms have disappeared, tissues heal, and the body regains strength. Characteristics of infectious diseases -------------------------------------- ### By duration: ### By location: Local -- confined to a specific area of the body Systemic -- infects across multiple body sites and across tissues ### By timing **Primary** -- initial infection in a previously healthy person **Secondary** --infection that occurs in a person weakened by a primary infection Pathogenesis of infectious diseases ----------------------------------- How infectious agents cause disease Mechanisms of pathogenicity depend on infecting pathogen For example: - Production of poisons such as toxins and enzymes that destroy cells and tissues (e.g. often produced by bacteria) - Direct invasion and destruction of host cells (e.g. viruses, some bacteria). - Triggering responses from the host's immune system leading to disease signs and symptoms (e.g. fever/sneezing/vomiting triggered by the immune system to rid the body of the pathogen). Steps in infection ------------------ Pathogenesis of infectious diseases ----------------------------------- Some shared pathology by site of infection: - Respiratory infections - Bloodstream infections - Encephalitis (inflammation of the brain) - Meningitis (inflammation of the lining around brain and spinal cord) - Endocarditis (infection of the heart) - Gastrointestinal disease - Skin and soft tissue infections Insight to site specific pathogenesis ------------------------------------- CASE STUDY:  Enteric Fever: S. Typhi ------------------------------------ Gram negative bacteria Host tropism: Vi Capsule -- attachment to human cells -- (antigen) N -acetylneuraminic acid (Neu5Ac) sialoglycans - Primary infection, secondary infection and carrier state - Low initial immunological response -- regulation of Vi Capsule fimbrae - Acute typhoid fever cellular response - Elevated anti-Vi antibody - Decreased zinc concentration - Decreased platelets and lymphocytes (anemia) - Markers of liver damage- α1-antitrypsin Reducing the spread of infectious diseases ------------------------------------------ Diagnosis - Clinical presentation of symptoms - Laboratory detection Treatment - Antimicrobial drugs - Antibiotics- antivirals - antifungals Prevention - Vaccines - Good hygiene and sanitation - Protection against vectors (e.g. mosqmosquitoes/ticks) - Isolation or quarantine of patients Treatment of infectious diseases -------------------------------- Antibiotics - Only work against some bacteria, **and do not work against viruses or other agents** - Target bacteria-specific structures/functions in the prokaryote cell: - Resistance of bacteria increasing globally (AMR); - CDC identified 18 infectious agents that are of concern.- \$4.6 billion annually. Antiviral drugs - Work against some viruses - Block parts of viral replication, e.g. nucleotide incorporation Antifungal drugs - Challenging to develop due eukaryotic nature of cells targeting/parasitic life cycles Prevention of infectious diseases --------------------------------- - Work by stimulating the body's immune system to fight off future infection - Vaccination programmes successfully eradicated smallpox - Global led campaigns to tackle polio Case study: Influenza --------------------- - Acute - Contagious via airborne transmission/indirect contact - Respiratory tract infection, symptoms felt throughout body Epidemiology of infectious diseases ----------------------------------- Is a science that examines patterns, causes and effects of disease (not just infectious disease) on the health of a given population. The focus is to control and reduce the incidence of disease via the identification of factors that : - Cause disease - Transmission of disease - Help prevent/reduce future disease Use of infectious disease epidemiology -------------------------------------- To identify those factors epidemiologists can breakdown into four branches - Disease aetiology (causing agent) - Outbreak investigation - Disease screening and surveillance - Comparisons of treatment or effects (-- clinical trials) Reducing the spread of infectious diseases ------------------------------------------ - Good personal hygiene and sanitation - Basic measures for frequent and thorough handwashing to limit the spread of disease - E.g. mosquitoes against Malaria and West Nile virus - E.g. ticks to prevent Lyme disease Quarantine (physical separation to prevent transmission) - COVID-19 and Ebola as recent examples to physically stop transmission occurring Diagnosis of infectious diseases -------------------------------- - Molecular pathology - assess the tissue reaction induced by an infectious organism and lesion characteristics - associate morphologically recognized lesions with the presence of an infectious agent Diagnosis using Microscopy -------------------------- Diagnosis of infectious diseases -------------------------------- Diagnostic histopathology laboratory involvement - Uses in emerging infectious diseases such as Zika, initial investigation of HIV and AIDS - Observations of associated pathologies contribute to understanding in pathogenic effects/mechanisms of disease by aetiological agents - Limitations are availability of specific antibodies, possibility to be replaced by genomics In Summary ---------- - Infectious diseases can result in pathological disease - Varied and diverse causes of infectious diseases Determining the causative agent permits treatment and helps aid prevention - Considerations around detection and causation of infection versus asymptomatic carriage - Also insights from microbiota studies examining health and disease states - Diagnosis may need combination of signs, symptoms, clinical diagnosis (detection of microorganism/toxin/antibody), and epidemiological insight - Infectious disease management Cardiovascular Disease ====================== - Coronary heart disease( including angina and myocardial infarction ) - Stroke - Transient ischemic attack (TIA) - Peripheral arterial disease Risk factor ----------- 1. **Non modifiable risk factors** Age -- CVD is strongly age-dependent, primarily affecting people aged over 50, the older the person, the higher the risk of developing CVD Gender -- at all ages, men have a higher risk of CVD than a women, and on average develop CVD about 10 years earlier. Family history of CVD -- genetic factors, shared environment Ethnic background -- South Asian or Saharan African origin have an increased of CVD 2. **Modifiable risk factors include :** - Smoking - Low blood level of high-density lipoprotein(HDL) cholesterol - High blood level of non- HDL cholesterol - Sedentary lifestyle/lack of physical activity - Unhealthy diet - Alcohol intake above recommended levels - Overweight and obesity A screenshot of a medical information Description automatically generated  Aortic Vale Stenosis -------------------- - Progressive narrowing, stiffening and thickening of the aortic valve - Normal value area is 3.5- 4cm - Once symptoms develop, poor life expectancy (2 to 5 years if untreated) - Symptoms : chest pain( angina pectoris), fatigue , syncope and congestive ### Risk factors - Old age - Congestial heart disease - Infection of the heart - Degenerative ( calcification) - CKD - CVD risk factors (diabetes, high cholesterol, high blood pressure obesity)  Treatment --------- ### Complications - Heart failure - Arrhythmias - Blood clots - Bleedings - Endocarditis - Stroke - Death Cardiomyopathies ---------------- A disease of the heart muscle Heritable disease -- runs in families Three main types: 1. Hypertrophic cardiomyopathy (HCM) 2. Dilated cardiomyopathy (DCM) 3. Arrhythmogenic right ventricular cardiomyopathy (ARCV) Hypertrophic cardiomyopathy --------------------------- An inherited disease(autosomal dominant) of the heart muscle - caused by a change or mutation in one more genes, - components of the sarcomere Diagnosis often via Echocardiography ### Treatments: - Pharmacotherapy - Cardiac Resynchronisation Therapy(for arrhythmias) - Septal ablation - Surgical myectomy Dilated cardiomyopathy ---------------------- Dialted cardiomyopathy (DCM) is disease of your heart muscle where it becomes stretched , thin and floppy. Genetic \$ acquired Diagnosis often via patient symptoms and Echocardiography ### Treatment - Pharmacotherapy - Cardiac Resynchronisation - Therapy ( for arrhythmias) - Ablation Arrhythmogenic right ventricular cardiomyopathy (ARCV) ------------------------------------------------------ - Primarily autosomal dominant (genetic); some heart proteins don't develop properly and can't keep the muscle cells together - Desmosomes keep the myocytes together , providing strength - Myocytes detach fatty deposits build up to repair damage, muscle becomes progressively thin and stretched. - Some acquired cases (viral myocarditis) - Normally affects the RV but can also affect LV leading to bi-ventricular HF ### Diagnosis Often via ECG , Echocardiography, CMRI and myocardial biopsy ### Treatments - Pharmacotherapy (symptoms) - Cardiac Resynchronisation - Therapy(for arrhythmias) - Heart Transplant Heart failure ------------- Diagnosis often via signs and symptoms, ECG, echocardiography and CMRI Causes: - Obesity - CKD - Sleep apnoea - Long tern hypertension - Ischemia associated with coronary artery disease - Myocardial infarction valvular heart disease - Myocarditis - Congenital malformations - Familial cardiomyopathies A black and white text on a white background Description automatically generated  A white figure with a black background Description automatically generated with medium confidence Vascular Disease Endothelium ---------------------------- Endothelium cells form the inner most lining (single cell layer thick) of the blood vessels) - Mechanosensitive ( responsive to the direction of blood flow and the pressure on them - Actively help regulate vascular tone (vasodilate and vasoconstrict) - Key regulator of vascular homeostasis - Responsive to physical and chemical signals produce wide range of factors that help regulate the processes shown here  Pulse wave velocity ------------------- - Arterial stiffness(ultrasound) - Measurements of the speed of arterial pressure waves travelling along the aorta and large arteries. - Calculated by dividing distance with pressure wave transit time at the two points of recording arteries. Vascular Disease Atherosclerosis -------------------------------- Lipoprotein -- a driven disease that leads to plaque formation at the specific sites of the arterial tree through endothelial (initial) activation, inflammation, necrosis, fibrosis and calcification. Leads to the narrowing of the blood vessels, more susceptible to formation of thrombi and plaque rupture. Obstruction of blood flow to peripheral organs , including the heart , brain and or lower extremities Endothelial response to shear stress ------------------------------------ A diagram of a disease Description automatically generated Vascular disease, Vascular calcification ----------------------------------------  Consequences of Atherosclerosis -------------------------------  ---------------------- ### Acute myocardial infarction - Occurs when one of the coronary arteries becomes occluded by an embolus, leading to heart muscle ischaemia - Severity depends on the size and location of the blocked coronary artery - Clinical presentation of chest pain , shortness of breath , weakness and anxiety - Serum troponin is also elevated (indicated cardiac muscle death) ### Consequences of atherosclerosis IN-STENT RESTENOSIS - Neointimal hyperplasia - VSMC proliferation - Caused by vessel injury - Drug-eluting stents have been developed - Inhibition of proliferation - But means that re-endothelialisation takes months Treatments of coronary artery disease: Bypass --------------------------------------------- A diagram of a heart Description automatically generated ### Ischaemic stroke - Ischaemic stroke occurs when the blood supply to a part of the brain is compromised - This can occur due to the thrombus that has developed locally in the brain , or from a plaque rupture elsewhere, commonly the internal carotid artery - Symptoms depend on the area of the brain affected - Acute treatment with tissue plasminogen activator(IPA) a thrombolytic agent , can reduce the adverse effects of the stroke - Ongoing treatment with anticoagulants and carotid endarterectomy may be indicated ### Identifying vulnerable carotid plaques - Patients were referred after displaying symptoms including dizziness, visual disturbances memory loss etc. - Duplex utilises ultrasound technology to provide 2D image of the carotid artery and Dopler sonography to measure flow. - More than 70% stenosis will require carotid endarterectomy surgery - Invasive surgical procedure -- carries certain risks. ### Carotid endarterectomy surgery ### Consequences : Peripheral vascular disease - PVD involves the obstruction of large arteries not within the coronary, aortic arch vasculature or brain - Often occurs due to atherosclerotic blockage in the lower extremities and leads to acute and chronic ischaemia - Symptoms include; colour changes in the limb and wounds and ulcers that are slow healing or don't heal at all - In severe cases, PVD can result in the loss of a limb - Mortality rates are increased after ulcer development, with around 50% dying within 5 years of developing a diabetic foot ulcer. ### Consequences : Aortic aneurysms - Pro-atherogenic stimuli induce stiffening of the aorta - This results in weakening and bulging of the aortic wall - In most cases, there are no symptoms other than occasional pulsating in the abdomen - AA rupture is severe and usually fatal - All men over 65 are invited for ultrasound screening in the UK - At-risk patients can undergo grafting to increase the stability of the aorta Ageing : Theories and disease ============================= **Ageing is** a decreasing ability to survive IMPORTANCE OF AGEING -------------------- - reduced ability to do work - increased susceptibility to major diseases - large healthcare commitment AGEING: TERMINOLOGY ------------------- **Life expectancy:** mean age of individuals at the time of death **Lifespan:** maximum age that can be attained by a species FEATURES OF AGEING ------------------ - senescence - age-related disease SENESCENCE CHANGES ------------------ - may cause age-related disease - may increase susceptibility to disease THEORIES OF AGEING ------------------ **wear and tear:** - free radicals - glycation - waste products - error-catastrophe ### FREE RADICAL: DEFINITION *'atom or molecule which contains one or more unpaired electrons'* ### FREE RADICALS: NATURE - high reactivity - short half-life - propagate chain reactions ### TYPE OF FREE RADICALS - **hydroxyl radical (OH )** - **superoxide radical (O~2~ )** - **nitric oxide (NO )** ### SOURCES OF FREE RADICALS - phagocytic cells - ~ ~ionising radiation -  smoking -  oxidation-reduction reactions -  hyperglycaemia FREE RADICALS DAMAGE - **DNA / RNA** - **proteins** - **enzymes** - **membrane lipids** - **cells** ### ANTIOXIDANT: DEFINITION a substance that will delay or inhibit the oxidation of an oxidisable substrate' types of antioxidants: **extracellular:** vitamin E **intracellular:** superoxide dismutase and catalase ### FREE RADICALS IN AGEING - **increased free radical damage with age** - **decreased antioxidant defences with age** ### FREE RADICALS IN AGEING PROTEIN GLYCATION ----------------- elderly susceptible because: - decreased glucose tolerance - increased incidence of diabetes EFFECTS OF GLYCATION ON PROTEINS -------------------------------- - **increased cross-linking** - **increased fluorescence** - **altered activity of enzymes** - **altered immunogenicity** - **altered half-life** - **altered recognition by receptors** ACCUMULATION OF WASTE PRODUCTS ------------------------------ ERROR-CATASTROPHE THEORY ------------------------ - abnormal proteins produced by random errors of transcription and translation - accumulation of abnormal proteins impairs cellular function THEORIES OF AGEING ------------------ genome-based: - programmed ageing mutations genome-based: - programmed ageing - mutations ### PROGRAMMED AGEING - number of cell divisions is fixed (Hayflick limit) - limit not affected by external environment - cells can memorise divisions undertaken - telomeres shorten and limit cell division - telomerase can extend cellular division ### GENE MUTATIONS - errors in the replication of DNA which are not repaired will affect the viability of cells - repair systems for DNA decrease with age MULTIFACTORIAL NATURE OF AGEING -------------------------------  CELLULAR AGEING --------------- - decline in mitochondrial activity - decline in oxidative phosphorylation - decline in DNA/RNA synthesis - decline in nutrient uptake - decline in chromosomal repair - accumulation of waste products - change in organelle shapes IMMUNE SYSTEM ------------- - decrease in antibody production - decline in T cell function - atrophy of thymus - increase in autoimmune reactions SKIN ---- - increased wrinkling - skin pigmentation - greying of hair - loss of hair - delayed wound healing LUNGS ----- - decrease in lung size - decrease in lung elasticity - reduced gaseous exchange - reduced capacity for strenuous work CARDIOVASCULAR SYSTEM --------------------- - increased rigidity of blood vessels - arterial calcification and hardening - increase in blood pressure - accumulation of fibrous tissue in heart muscle - reduced cardiac output - reduced blood supply to tissues KIDNEYS ------- - decrease in kidney weight/volume - loss and replacement of nephrons with scar tissue - reduced renal filtration rate - reduced elimination of waste LIVER ----- - reduction in liver size and hepatocytes - decline in some liver functions eg drug detoxification MUSCLE ------ - muscles undergo atrophy - decreased capacity for work ENDOCRINE SYSTEM ---------------- - decline in hormone production - decline in hormone receptors BRAIN ----- - loss in weight - loss of nerve cells - increase in amyloid deposition - accumulation of lipofuscin EYE --- - decreased ability of lens to change shape - increased cross-linking and browning of lens protein BODY COMPOSITION ---------------- - decrease in muscle mass - increase in total body fat PROGERIA (HUTCHINSON-GILFORD SYNDROME) -------------------------------------- - **disorder characterised by accelerated ageing** - **affected children age approximately 10 times faster than normal** PROGERIA: INCIDENCE ------------------- - **very rare (1:10 million?)** - **30 cases worldwide** - **100 cases in history** PROGERIA: AETIOLOGY ------------------- - sporadic dominant mutation - reduced life-span of cells - reduced repair of damaged DNA PROGERIA: CLINICAL ------------------ - **thinning / wrinkling of skin** - **alopecia** - **loss of subcutaneous fat** - **prominent scalp veins** - **beak-like nose** - **characteristic squeeky voice** - **short stature** - **arthritis / stiff swollen joints** - **osteoporosis** - **normal / high intelligence** - **delayed development of teeth** - **delayed sexual maturity** PROGERIA: OUTLOOK ----------------- - **lifespan:** average \~ 13 years - **death:** coronary heart disease stroke PROGERIA: DIAGNOSIS ------------------- - **clinical:** difficult due to rarity - **history:** insidious onset - **laboratory:** raised urinary PROGERIA: MANAGEMENT -------------------- - **no cure for progeria** - **education / psychological support** - **drugs to relieve symptoms** CALORIE RESTRICTION ------------------- **"Only known method of slowing ageing in mammals"** reduced calorie intake: - extends lifespan - delays age-related disease ANTI-AGEING THERAPY: COMPANIES ------------------------------ - **Centagenetix** - ** Elixir** - ** Eukarion** - ** Alteon** - ** Geron Corporation** ### CENTAGENETIX - seeking genes responsible for longevity - collecting DNA from people with long lifespans (over 100 years) - gene identified on chromosome 4 helps carriers have long lifespan - pharmacological compound to mimic activity of proteins coded by gene ### ELIXIR - nematode worms with more than one copy of gene SIR2 live 50% longer - during calorie restriction, SIR2 reduces cellular activity promoting lifespan - identify such genes so can develop anti-ageing drugs against them ### EURKARION - produced genetically engineered mice that cant make superoxide dismutase - such mice die within a week due to damage to liver, brain and heart - injection with compounds possessing superoxide dismutase and catalase activity promotes lifespan - antioxidant drugs could promote lifespan ### ALTEON - anti-glycation drugs reduce AGEs - conducted unsuccessful trial with aminoguanidine - developing drugs capable of breaking AGE-crosslinks ### GERON CORPORATION - telomerase protects telomeres at ends of chromosome - drugs that *switch off* telomerase in cancer cells stops them dividing - drugs that *switch on* telomerase could protect telomeres and extend lifespan CONCLUSION ---------- - ageing caused by wear and tear and influenced by genes - ageing causes senescence and increased susceptibility to diseases - future anti-ageing therapy may have beneficial effects