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 agedent. 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 agedent. ppt 2

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 agedent. ppt 33 24 16 08 14 23 3

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 ? ? ? agedent. ppt 4

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. agedent. ppt 5

THE FEATURES OF AGEING 1. 2. 3. 4. 5. Irreversible changes of biological macromolecules Gene dysregulation Decreased metabolic capacity Decrease of physiological functions Decreased adaptability in stress situations and pathological conditions 6. Higher occurrence of diseases, multimorbidity 7. Decreased quality of life 8. Increased mortality agedent. ppt 6

THE MATHEMATICS OF AGEING • MORTALITY (“J”) • LIFE EXPECTANCY (AVERAGE OR MEDIAN LIFE SPAN, Gompertz) • AGE PYRAMID • MAXIMAL LIFE SPAN (MLSP) agedent. ppt 7

AVERAGE LIFE SPAN LIFE EXPECTANCY AT BIRTH 1. For a cohort of people at birth (1000): 1. Point of time (years) when 50 % already passed, 50 % yet lives 2. For an individual: 1. 50 % probability to live so long 3. Variable – short time changes are possible, too 4. Does not depend on old generation !!! 5. Continuous rise in the past – luring menace of decrease (AIDS, obesity) agedent. ppt 8

GOMPERTZ CURVE agedent. ppt 9

LIFE EXPECTANCY AT BIRTH, XXth CENTURY - USA 2000 75 YEARS 1900 50 YEARS agedent. ppt 10

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 agedent. ppt 11

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. agedent. ppt 12

AGE PYRAMID agedent. ppt 13

MAXIMUM LIFE SPAN Biological constant but species specific agedent. ppt 14

THE NUMBER OF CENTENARIANS IN GERMANY • 1938 – 37/37 • 1975 – 15/9, 7 • 1990 – 5/1, 65 • 1995 – 7/1, 66 • 2002 4 146 1416 2333 3883 agedent. ppt 15

VARIATION IN MAXIMUM LIFE SPAN ACROSS SPECIES • MAYFLY • C. ELEGANS • DROSOPHILA • ZEBRAFISH, MOUSE • DOG, CAT • MAN, GIANT TORTOISE RANGE • < 1 DAY • WEEK – MONTH • MONTH – YEAR • YEAR – DECADE • DECADE • CENTURY agedent. ppt 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 ? agedent. ppt 17

TEAR AND WEAR OR PROGRAMME ? AGING IS NOT LIKELY TO BE REGULATED IN THE SAME PROGRAMMED WAY AS DEVELOPMENT Kirkwood, 1982, 1996 agedent. 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 agedent. 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 agedent. 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 agedent. 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) agedent. ppt 22

REPLICATIVE AGEING agedent. ppt 23

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) agedent. ppt 24

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% agedent. ppt 25

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 agedent. ppt 26

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 agedent. ppt 27

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 ? agedent. ppt 28

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) agedent. ppt 29

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 agedent. ppt 30