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
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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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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
CHINA
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24
16
08
14
23
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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 ???
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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 lives
For 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
2000
75 YEARS
1900
50 YEARS
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AVERAGE LIFE SPAN, EXPLANATION
• 100 HEALTHY PEOPLE
V75 – 95 y.
• 10 more Vin age 25 y.
• 10 moreVin 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
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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 SPAN
Biological constant but species specific
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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
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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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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 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)
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REPLICATIVE AGEING
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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 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%
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EVOLUTION OF AGEING
Mammals, primates, man
Very important role of neuroendocrine and
immune system
Economics (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 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
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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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