12.11.2007agee.ppt1 ageing basic terms, epidemiology, theories of ageing and the genetic background...
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12.11.2007 agee.ppt 1
AGEINGBasic 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
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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
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WHAT IS AGEING ?
New (medical) problem – did not exist until XIXth centuryDeath in nature mostly is not (or very distinctly) associated with
ageing
A very old problemTithonus, 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.)
OrHenrietta Lacks, 33 y old mother of 5 children
in 1951 ???
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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.
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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
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THE MATHEMATICS OF AGEING
• MORTALITY (“J”)
• LIFE EXPECTANCY (AVERAGE OR MEDIAN LIFE SPAN, Gompertz)
• AGE PYRAMID
• MAXIMAL LIFE SPAN (MLSP)
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AVERAGE LIFE SPAN LIFE EXPECTANCY AT BIRTH
For a cohort of people at birth (1000):Point of time (years) when 50 % already
passed, 50 % yet livesFor an individual:
50 % probability to live so long Variable – short time changes are possible, too Does not depend on old generation !!! Continuous rise in the past – luring menace of
decrease (AIDS, obesity)
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GOMPERTZ CURVE
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LIFE EXPECTANCY AT BIRTH, XXth CENTURY - USA
19001900
50 YEARS50 YEARS
20002000
75 YEARS75 YEARS
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AVERAGE LIFE SPAN, EXPLANATION
• 100 HEALTHY PEOPLE
75 – 95 y. (average = 85 y) • 10 more in age 25 y. (average = 79 y)• 10 morein age 70 y. (average = 84 y)
IN PAST – PERINATAL AND INFANT MORTALITY, PANDEMIES (PEST XVI-XVII cent., FLU 1918), WARS
TODAY: CHD, OBESITY, MALIGNANCIES, ACCIDENTS, AIDS
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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.
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AGE PYRAMID
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MAXIMUM LIFE SPANBiological constant but species specific
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THE NUMBER OF CENTENARIANS IN GERMANY
• 1938 4
– 37/37
• 1975 146
– 15/9,7
• 1990 1416
– 5/1,65
• 1995 2333
– 7/1,66
• 2002 3883
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VARIATION IN MAXIMUM LIFE SPAN ACROSS SPECIES
SPECIES• MAYFLY• C. ELEGANS• DROSOPHILA• ZEBRAFISH,
MOUSE• DOG, CAT• MAN, GIANT
TORTOISE
RANGE• < 1 DAY• WEEK – MONTH• MONTH – YEAR• YEAR – DECADE
• DECADE• CENTURY
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THE ECONOMICAL DIMENSION OF AGING(% of people > 60 y)
• REGION 1990 2030• OECD 19 33
• POSTSOC COUNTRIES 16 24
• SOUTH AMERICA 07 16
• AFRICA 05 08
• ASIA WITHOUT CHINA 07 14
• CHINA 09 23
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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 ?
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TEAR AND WEAR OR PROGRAMME ?
AGING IS NOT LIKELY TO BE REGULATED IN THE SAME
PROGRAMMED WAY AS DEVELOPMENT
Kirkwood, 1982, 1996
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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
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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
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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
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EVOLUTION OF AGEINGUNICELLULAR
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)
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REPLICATIVE AGEING
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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
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TELOMERES IN AGEING AND CANCER
Germ lineGerm line
SomaticSomatic
ProgeriaProgeria
CancerCancer
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Germ lineGerm line
SomaticSomatic
Acceleration of telomere loss:Acceleration of telomere loss:
Stress, smoking, obesity and ???Stress, smoking, obesity and ???
TELOMERES IN AGEING AND CANCER
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PROGERIA AND CANCER – A PARADOX
• Werner sy (WRN)
• Ataxia teleangiectasia (ATM)
• Bloom sy (BLM)
• Dyskeratosis congenita (DKC1)
• Aplastic anaemia (TERC)
• Fanconi anaemia (Fanc genes)
Germ lineGerm line
SomaticSomatic
ProgeriaProgeria
CancerCancer
Progeric syndromes are Progeric syndromes are associated with associated with increased occurence of increased occurence of malignant tumorsmalignant tumors
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EVOLUTION OF AGEING
Caenorhabditis elegans (simple multicellular) age1 – 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 spe26 (gamete production), clk1 (internal rytmus)
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EVOLUTION OF AGEING
Drosophila melanogasterDifferent 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%
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EVOLUTION OF AGEING
Mammals, primates, manVery important role of neuroendocrine and
immune systemEconomics (cost/benefit) of complex system
In very complicated systems the „costs“ of maintenance are inappropriate high („STK“ system of cars)
Nakano - lipofuscin begins to accumulate after reproductive period
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EVOLUTION OF AGEING
• Caloric restriction and longevity• Works in rats, mice... (different life cycle) • Okinawa • CALERIE = Comprehensive assesment of Long-
term 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
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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 ?
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THE OLDEST OLD
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)
JOHN GLENN, 1922 (1962, 1999 and his 96 years old friend)
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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
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Nature collections - Ageing
• Spinney L: Eat your cake and have it N441, 2006, 807-809
• Finkel T et al: The common biology of cancer and aging N448, 2007, 767-774
• Rando TA Stem cells, ageing and the quest for immortality N441, 2006, 1080-1086
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