AGEING Basic terms epidemiology theories of ageing and
AGEING Basic terms, epidemiology, theories of ageing and the genetic background of ageing LECTURE FROM PATHOLOGICAL PHYSIOLOGY OLIVER RÁCZ INSTITUTE OF PATHOLOGICAL PHYSIOLOGY MEDICAL SCHOOL, ŠAFÁRIK UNIVERSITY, KOŠICE 12. 11. 2007 agee. ppt 1
WHAT IS AGEING ? • • 1973 – my first assay on ageing 1987 – you can’t study aging, it just happens Tear and wear or a programme ? 1999, TIME - can I live to be 125 ? (or 300) Don’t do it! (quality of life) New problem – did not exist until XIXth century (? ) Death in nature mostly is not (or very distinctly) associated with ageing 12. 11. 2007 agee. ppt 2
WHAT IS AGEING ? New (medical) problem – did not exist until XIXth century Death in nature mostly is not (or very distinctly) associated with ageing A very old problem Tithonus, a lover of Goddes Eos, after a quarrel of Eos with Zeus acquired immortality but not eternal youthfulness !!! (see also Swift’s Gulliver and a lot of other literature, alchemy, etc. ) Or Henrietta Lacks, 33 y old mother of 5 children in 1951 ? ? ? 12. 11. 2007 agee. ppt 3
WHAT IS AGEING ? • GERONTOLOGY (SCIENCE) & GERIATRICS (PRACTICAL MEDICINE) • WHO: – Middle age 45 - 59 y. – Presenium 60 - 74 y. – Senium – old age 75 - 90 y. – Very old age > 90 y. • PRACTICE – Old age > 65 y. 12. 11. 2007 agee. ppt 4
THE FEATURES OF AGEING _ Irreversible changes of biological macromolecules _ Gene dysregulation _ Decreased metabolic capacity _ Decrease of physiological functions _ Decreased adaptability in stress situations and pathological conditions _ Higher occurrence of diseases, multimorbidity _ Decreased quality of life _ Increased mortality 12. 11. 2007 agee. ppt 5
THE MATHEMATICS OF AGEING • MORTALITY (“J”) • LIFE EXPECTANCY (AVERAGE OR MEDIAN LIFE SPAN, Gompertz) • AGE PYRAMID • MAXIMAL LIFE SPAN (MLSP) 12. 11. 2007 agee. ppt 6
AVERAGE LIFE SPAN LIFE EXPECTANCY AT BIRTH v For a cohort of people at birth (1000): ØPoint of time (years) when 50 % already passed, 50 % yet lives v For an individual: Ø 50 % probability to live so long v Variable – short time changes are possible, too v Does not depend on old generation !!! v Continuous rise in the past – luring menace of decrease (AIDS, obesity) 12. 11. 2007 agee. ppt 7
GOMPERTZ CURVE 12. 11. 2007 agee. ppt 8
LIFE EXPECTANCY AT BIRTH, XXth CENTURY - USA 2000 75 YEARS 1900 50 YEARS 12. 11. 2007 agee. ppt 9
AVERAGE LIFE SPAN, EXPLANATION • 100 HEALTHY PEOPLE V 75 – 95 y. • 10 more Vin age 25 y. • 10 more. Vin age 70 y. (average = 85 y) (average = 79 y) (average = 84 y) IN PAST – PERINATAL AND INFANT MORTALITY, PANDEMIES (PEST XVI-XVII cent. , FLU 1918), WARS TODAY: CHD, OBESITY, MALIGNANCIES, ACCIDENTS, AIDS 12. 11. 2007 agee. ppt 10
LIFE EXPECTANCY • AT BIRTH (75) BUT ALSO LATER – At 50, 75, 90… – Women > men (also in nature, XX > X) – Social status – Smokers < nonsmokers, obese < lean, etc. 12. 11. 2007 agee. ppt 11
AGE PYRAMID 12. 11. 2007 agee. ppt 12
MAXIMUM LIFE SPAN Biological constant but species specific 12. 11. 2007 agee. ppt 13
THE NUMBER OF CENTENARIANS IN GERMANY • 1938 – 37/37 • 1975 – 15/9, 7 • 1990 – 5/1, 65 • 1995 – 7/1, 66 • 2002 12. 11. 2007 4 146 1416 2333 3883 agee. ppt 14
VARIATION IN MAXIMUM LIFE SPAN ACROSS SPECIES • MAYFLY • C. ELEGANS • DROSOPHILA • ZEBRAFISH, MOUSE • DOG, CAT • MAN, GIANT TORTOISE 12. 11. 2007 RANGE • < 1 DAY • WEEK – MONTH • MONTH – YEAR • YEAR – DECADE • DECADE • CENTURY agee. ppt 15
THE ECONOMICAL DIMENSION OF AGING (% of people > 60 y) • REGION 1990 2030 • • • 19 16 07 05 07 09 OECD POSTSOC COUNTRIES SOUTH AMERICA AFRICA ASIA WITHOUT CHINA 12. 11. 2007 agee. ppt 33 24 16 08 14 23 16
AGEING AND SCIENCE • Tear and wear ? • Programme ? apoptosis, thymus involution differences in MLSP of different species (mouse – man) progeric symdromes are rare hereditary diseases replicative ageing and telomeres mutations (in experiments) connected with prolonged life span „The oldest old“ • NATURE OR NURTURE ? 12. 11. 2007 agee. ppt 17
TEAR AND WEAR OR PROGRAMME ? AGING IS NOT LIKELY TO BE REGULATED IN THE SAME PROGRAMMED WAY AS DEVELOPMENT Kirkwood, 1982, 1996 12. 11. 2007 agee. ppt 18
TEAR AND WEAR OF WHAT AND HOW ? • • • Biochemical changes of proteins (no) Membrane structure and function (no) Somatic mutations (no) Theory of error catastrophe – Orgel, 1963? Deterioration of control and reparation mechanism of replication, transcription and translation • OXPHOS – the weakest part of the whole chain are the MITOCHONDRIA 12. 11. 2007 agee. ppt 19
TEAR AND WEAR, THE CAUSE ? • Rate of living (an explanation of different MLSP despite similar composition of tissues) • Oxygen consumption of mice and men – Man (80 kg) >> mouse (30 g) but – 1 g mouse tissue >> 1 g human tissue • Maximum life span – Man >> mouse 12. 11. 2007 agee. ppt 20
TEAR AND WEAR, THE CAUSE ? J. Verne: Mr. Ox and his servant Ygen • Rate of living (burning the candle) • Oxygen consumption (ml/g/min) is in inverse relationship with life span • Oxygen and its reactive forms (ROS) • The theory is true but only in general terms • The other side of the story: • ANTIOXIDANT SYSTEMS 12. 11. 2007 agee. ppt 21
EVOLUTION OF AGEING UNICELLULAR Sacharomyces cerevisiae (yeast) Replicative ageing regulated through genes Cells of higher animals Fibroblasts and other mitotic cells – correlation with age of the individuum and MLSP (Hayflick, 1961; Dolly 1998) Telomere shortening during division (association with carcinogenesis and telomerase) 12. 11. 2007 agee. ppt 22
REPLICATIVE AGEING 12. 11. 2007 agee. ppt 23
Tissue heterogeneity and stem cell functionality for repair • High cellular turnover, high regenerative potential – Blood cells, gut epithelium, vascular epithelium, epidermis, mammary epithelium • Low cellular turnover, high regenerative potential – Liver, skeletal muscle, pancreas, adrenal cortex • Low cellular turnover, low regenerative potential – Lung parenchyma, brain, kidney, retina, heart, spinal cord 12. 11. 2007 agee. ppt 24
TELOMERES IN AGEING AND CANCER Germ line Cancer Somatic Progeria 12. 11. 2007 agee. ppt 25
TELOMERES IN AGEING AND CANCER Germ line Somatic Acceleration of telomere loss: Stress, smoking, obesity and ? ? ? 12. 11. 2007 agee. ppt 26
PROGERIA AND CANCER – A PARADOX • Werner sy (WRN) • Ataxia teleangiectasia (ATM) • Bloom sy (BLM) • Dyskeratosis congenita (DKC 1) • Aplastic anaemia (TERC) • Fanconi anaemia (Fanc genes) 12. 11. 2007 agee. ppt Progeric syndromes are associated with increased occurence of malignant tumors 27
EVOLUTION OF AGEING Caenorhabditis elegans (simple multicellular) _ age 1 – prolonging of MLSP by 110 % Resistance against oxidants, increased temperature, UV rays Activity of SOD and catalase _ Daf 2, 23, 28 mutations _ Genes of signal transduction ! STRESS RESPONSE GENES _ spe 26 (gamete production), clk 1 (internal rytmus) 12. 11. 2007 agee. ppt 28
EVOLUTION OF AGEING Drosophila melanogaster _Different lines with prolonged life span Resistance against oxidants Resistance against starvation and dehydratation But also flies in small boxes and without wings (? ) _Transgenic drosophila +SOD = 0; +CAT = 0; +(SOD & CAT) = 30% 12. 11. 2007 agee. ppt 29
EVOLUTION OF AGEING Mammals, primates, man _Very important role of neuroendocrine and immune system _Economics (cost/benefit) of complex system ü In very complicated systems the „costs“ of maintenance are inappropriate high („STK“ system of cars) ü Nakano - lipofuscin begins to accumulate after reproductive period 12. 11. 2007 agee. ppt 30
EVOLUTION OF AGEING • • Caloric restriction and longevity Works in rats, mice. . . (different life cycle) Okinawa CALERIE = Comprehensive assesment of Longterm Effects of Reducing Intake of Energy • Slowing down of metabolism (rate of living) or something more complicated? • Sirtuin genes (7, DNA stabilisation, copy fidelity) • Resveratrol from red wine(and other plant molecules) activates them 12. 11. 2007 agee. ppt 31
THE OLDEST OLD SELECTIVE SURVIVAL ? Mortality over 90 – turn on the curve men < women Incidence of Alzheimer disease Short period before death Which genes? APO E ? , ACE ? 12. 11. 2007 agee. ppt 32
THE OLDEST OLD a a a TIZIANO V 1477 - 1576 98 – PIETA VERDI G 1813 - 1902 80 – FALSTAFF PICASSO P 1881 - 1973 86 – LE COUPLE CHURCHILL, CASALS, KŇAZOVICKÝ. . . QUEEN MOTHER, MOJSEJEV (102) a JOHN GLENN, 1922 (1962, 1999 and his 96 years old friend) 12. 11. 2007 agee. ppt 33
PRIMARY AND SECUNDARY AGEING ? Sooner or later something breaks down! • BRAIN – ALZHEIMER (AND OTHER DEGENERATIVE) DISEASES • VESSELS – ATHEROSCLEROSIS, CORONARY DISEASE • REGULATION OF BLOOD PERFUSION – HYPERTENSION • REGULATION OF METABOLISM – DIABETES • BONES AND JOINTS – OSTEOPOROSIS • SENSES – SIGHT AND HEARING ARE DECISIVE IN NATURE 12. 11. 2007 agee. ppt 34
Nature collections - Ageing • Spinney L: Eat your cake and have it N 441, 2006, 807 -809 • Finkel T et al: The common biology of cancer and aging N 448, 2007, 767 -774 • Rando TA Stem cells, ageing and the quest for immortality N 441, 2006, 1080 -1086 12. 11. 2007 agee. ppt 35
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