Ageing: Theories and Disease PDF

AGEING: THEORIES AND DISEASE Dr Nessar Ahmed PhD CSci FIBMS FRCPath Reader in Clinical Biochemistry Department of Life Sciences  DEFINITION OF AGEING Ageing: a decreasing ability to survive IMPORTANCE OF AGEING reduced ability to do work...

AGEING: THEORIES AND DISEASE Dr Nessar Ahmed PhD CSci FIBMS FRCPath Reader in Clinical Biochemistry Department of Life Sciences  DEFINITION OF AGEING Ageing: 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: mean age of individuals at time of death Estimates and Projections of the Total Population in the United States and the Percentage of Elderly, 1900—2030 TOTAL OVER 65 YEAR POPULATION NUMBER % 1900 75,600,000 3,100,000 4.1 1940 132,300,000 9,000,000 6.8 1960 181,000,000 16,600,000 9.2 1970 203,100,000 20,300,000 10.0 1980 228,000,000 25,600,000 11.2 1990 250,000,000 31,200,000 12.5 2000a 268,500,000 34,900,000 13.0 2030a 304,700,000 64,600,000 21.2 Projected. a PERCENTAGE OF ELDERLY IN THE U.S. POPULATION BY AGE GROUP  AGEING: TERMINOLOGY 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 (O2 ) 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 catalase SUPEROXIDE DISMUTASE: ACTION superoxide dismutase 2H+ + 2O2 H 2O 2 + O 2 catalase 2H2O2 2H2O + O2 FREE RADICALS IN AGEING increased free radical damage with age decreased antioxidant defences with age FREE RADICALS IN AGEING FREE RADICALS IN AGEING  PROTEIN GLYCATION elderly susceptible because: decreased glucose tolerance increased incidence of diabetes GLYCATION OF A PROTEIN  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 lipofuscin: lipid-rich pigment produced by: membranes / organelles free radical peroxidation effects of lipofuscin: unknown  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  PROGRAMMED AGEING number of cell divisions is fixed (Hayflick limit) limit not affected by external environment cells can memorise divisions undertaken  PROGRAMMED AGEING telomeres shorten and limit cell division telomerase can extend cellular division  GENE MUTATIONS errors in replication of DNA which are not repaired will affect viability of cells repair systems for DNA decrease with age MULTIFACTORIAL NATURE OF AGEING  DECLINES IN VARIOUS HUMAN FUNCTIONAL CAPACITIES WITH AGE CONSIDERING FUNCTION AT AGE 30 TO BE 100% PERCENTAGE OF FUNCTION REMAINING 60 YEARS 80 YEARS Nerve conduction velocity 96 88 Basal metabolic rate 96 84 Standard cell water 94 81 Cardiac index 82 70 Glomerular filtration rate 96 61 Vital capacity 80 58 Renal plasma flow 89 51 Maximal breathing capacity 80 42  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 FEATURES OF PROGERIA AND AGEING Progerla Ageing Alopecia + + Decreased adipose tissue + + Hypermelanosis + + Sclerosis + + Poikiloderma + + Ulcerations + + Nail dystrophy + + Atherosclerosis + + Osteoporosis + + Wrinkling + + Atrophy + + Brain atrophy — + Dementia — + Neoplasms — + Cataracts — + Facial disproportion + —  PROGERIA: OUTLOOK lifespan: average ~ 13 years death: coronary heart disease stroke  PROGERIA: DIAGNOSIS clinical: difficult due to rarity history: insidious onset laboratory: raised urinary hyaluronic acid PROGERIA: MANAGEMENT no cure for progeria education / psychological support drugs to relieve symptoms CALORIE RESTRICTION “Only known method of slowing ageing in mammals”  CALORIE RESTRICTION reduced calorie intake: extends lifespan delays age-related disease  CALORIE RESTRICTION extends lifespan in numerous species: protozoa spiders water fleas chickens rhesus monkeys  CALORIE RESTRICTION effect of calorie restriction: reduces age-associated mutations reduces free radical damage reduces advanced glycation endproducts ANTI-AGEING THERAPY “We don’t want to make ourselves older longer, we want to make ourselves younger longer” Olshansky, 2001 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 ESSENTIAL READING Ahmed et al (2007) Biology of Disease Taylor & Francis Pages 515-530  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 Thank you