Ageing: Theories and Disease PDF

AGEING : Theories and Disease Friday, 1 November 2024 18:02 The definition of ageing is a decreasing ability to survive. Importance of ageing - Reduced ability to do work - Increased susceptibility to major diseases - Large health care commitment Ageing terminology Life expectancy is th...

AGEING : Theories and Disease Friday, 1 November 2024 18:02 The definition of ageing is a decreasing ability to survive. Importance of ageing - Reduced ability to do work - Increased susceptibility to major diseases - Large health care commitment Ageing terminology Life expectancy is the mean age of individuals at time of death. Lifespan is the maximum age that can be attained by a species. Features of Ageing - Senescence - Age-related disease Senescence changes may be cause age-related disease and may increase susceptibility to disease Theories of ageing Wear and tear theory - Free radicals - Glycation - Waste products - Error-catastrophe Free radical are atoms or molecules which contains one or more unpaired electrons. Their nature is high reactivity, short half-life and propagate chain reactions. They types of free radicals are hydroxyl radical (OH), superoxide radical (O2) and nitric oxide (NO). The sources of free radicals are phagocytic cells, ionising radiation, smoking, oxidation-reduction reactions and hyperglycaemia. And they damage DNA/RNA, proteins, enzymes, membrane lipids and cells. Antioxidant is a substance that will delay or inhibit the oxidation of an oxidisable substrate. There are 2 types of antioxidants, extracellular such as vitamin E and intracellular such as superoxide dismutase and catalase. Superoxide dismutase (SOD) is an important enzyme in the body that helps protect cells from damage caused by free radicals, specifically a harmful molecule called superoxide. Free radicals in ageing Increased free radical damage with age. Decreased antioxidant defences with age. Protein glycation Elderly susceptible because decreased glucose tolerance and increased incidence of diabetes Effects of glycation on proteins are: - Increased cross-linking - Increased fluorescence - Altered activity of enzymes - Altered immunogenicity - Altered half-life - Altered recognition by receptors Accumulation of waste products Lipofuscin is a waste material that accumulates in cells as we age. It is a lipid rich pigment which means it contains a lot of fats and gives cells a brownish yellow colour. They cant be easily broke down or removed they tend to build up in some cells especially long-living cells like those in the heart, brain and muscles They are produced by membranes and organelles through free radical peroxidation (a process that damages lipids in cell membrane which leads to production of by-products that contribute to formation of lipofuscin). The effects of lipofuscin are unknown. Error-Catastrophe Theory This is the abnormal proteins made by random errors of transcription and translation. The accumulation of abnormal proteins impairs cellular function. genome-based: - programmed ageing - mutations Programmed ageing - Number of cell division if fixed, a concept known as Hayflick limit - Limit of cell division is not affected by external environment - Cells can memorise of how many times they have divided - Telomeres shorten and limit cell division - Telomerase (enzyme that can rebuild telomeres) can extend cellular division. Gene mutations - Errors in replication of DNA which are not repaired will affect viability of cells cause mutations. - Repair systems of DNA decrease with age. 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 in ageing - Decrease in antibody production - Decline in T cell function - Atrophy of thymus - Increase in autoimmune reactions Skin in ageing - Increased wrinkling - Skin pigmentation - Greying of hair - Los of hair - Delayed wound healing Lungs in ageing - Decrease in lung size - Decrease in lung elasticity - Reduced gaseous exchange - Reduces capacity for strenuous work Cardiovascular system in ageing - 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 in ageing - Decrease in kidney weight/volume - Loss and replacement of nephrons with scar tissue - Reduced renal filtration rate - Reduced elimination of waste Liver in ageing - Reduction in liver size and hepatocytes - Decline in some liver functions e.g. Drug detoxification. Muscle in ageing - Muscles undergo atrophy - Decreased capacity for work endocrine system in ageing - Decline in hormone production - Decline in hormone receptors Brain in ageing - Loss in weight - Loss of nerve cell - Increase in amyloid deposition - Accumulation of lipofuscin Eye in ageing - Decreased ability of lens to change shape - Increased cross-linking and browning of lens proteins Body composition - Decrease in muscle mass - Increase in total body fat Progeria (Hutchinson-Gilford syndrome) This is a disorder characterised by accelerated ageing. It affects children age approximately 10 times faster than normal. It is a rare disease 1:10 million. There are only 30 cases worldwide and 100 cases in history. Aetiology of progeria are: - Sporadic dominant mutation - Reduced life-span of cells - Reduced repair of damaged DNA Clinical presentations of progeria are: - 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 Outlook of progeria Average lifespan is 13 years Deaths of patients with progeria are caused by coronary heart disease and stroke. Diagnosis of progeria - Clinical is difficult due to rarity - History insidious onset - Laboratory, raised urinary hyaluronic acid Management of progeria - No cure for progeria - Education and psychological support is provided - Drugs to relieve symptoms Calorie restriction is the only known method of slowing ageing in mammals. Reduced calorie intake: - Extends lifespan - Delays age-related disease Extends lifespan in numerous species such as: - Protozoa - Spiders - Water fleas - Chickens - Rhesus monkeys Effect of calorie restriction: - Reduces age-associated mutations - Reduces free radical damage - Reduces advanced glycation end products Anti-Ageing Therapy We don’t want to make ourselves older longer, we want to make ourselves younger longer. Companies researching and developing anti-ageing therapy are: - Centagenetix - Elixir - Eukarion - Alteon - Geron Corporation Centagenetix - Seeking genes responsible for longevity - Collecting DNA from people with long lifespan (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 can't make superoxide dismutase - Such mice die withing 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.