Title: AGEING Basic terms, epidemiology, theories of ageing and the genetic background of ageing
1AGEINGBasic 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
2WHAT IS AGEING ?
- 1973 my first assay on ageing
- 1987 you cant study aging, it just happens
- Tear and wear or a programme ?
- 1999, TIME - can I live to be 125 ? (or 300)
- Dont 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
3WHAT 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 Swifts Gulliver and a lot of other
literature, alchemy, etc.) - Or
- Henrietta Lacks, 33 y old mother of 5 children in
1951 ???
4WHAT 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 gt 90 y.
- PRACTICE
- Old age gt 65 y.
5THE 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
6THE MATHEMATICS OF AGEING
- MORTALITY (J)
- LIFE EXPECTANCY (AVERAGE OR MEDIAN LIFE SPAN,
Gompertz) - AGE PYRAMID
- MAXIMAL LIFE SPAN (MLSP)
7AVERAGE 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)
8GOMPERTZ CURVE
9LIFE EXPECTANCY AT BIRTH, XXth CENTURY - USA
2000 75 YEARS
1900 50 YEARS
10AVERAGE LIFE SPAN, EXPLANATION
- 100 HEALTHY PEOPLE
- V75 95 y. (average 85 y)
- 10 more Vin age 25 y. (average 79 y)
- 10 moreVin 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 -
11LIFE EXPECTANCY
- AT BIRTH (75) BUT ALSO LATER
- At 50, 75, 90
- Women gt men (also in nature, XX gt X)
- Social status
- Smokers lt nonsmokers, obese lt lean, etc.
12AGE PYRAMID
13MAXIMUM LIFE SPANBiological constant but species
specific
14THE 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
15VARIATION IN MAXIMUM LIFE SPAN ACROSS SPECIES
- SPECIES
- MAYFLY
- C. ELEGANS
- DROSOPHILA
- ZEBRAFISH, MOUSE
- DOG, CAT
- MAN, GIANT TORTOISE
- RANGE
- lt 1 DAY
- WEEK MONTH
- MONTH YEAR
- YEAR DECADE
- DECADE
- CENTURY
16THE ECONOMICAL DIMENSION OF AGING( of people gt
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
17AGEING 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 ?
18TEAR AND WEAR OR PROGRAMME ?
- AGING IS NOT LIKELY TO BE REGULATED IN THE SAME
PROGRAMMED WAY AS DEVELOPMENT - Kirkwood, 1982, 1996
19TEAR 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
20TEAR 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) gtgt mouse (30 g) but
- 1 g mouse tissue gtgt 1 g human tissue
- Maximum life span
- Man gtgt mouse
!!!
21TEAR 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
!!!
22EVOLUTION 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)
23REPLICATIVE AGEING
24Tissue 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
25TELOMERES IN AGEING AND CANCER
Germ line
Cancer
Somatic
Progeria
26TELOMERES IN AGEING AND CANCER
Germ line
Somatic
Acceleration of telomere loss Stress, smoking,
obesity and ???
27PROGERIA AND CANCER A PARADOX
- Werner sy (WRN)
- Ataxia teleangiectasia (ATM)
- Bloom sy (BLM)
- Dyskeratosis congenita (DKC1)
- Aplastic anaemia (TERC)
- Fanconi anaemia (Fanc genes)
Progeric syndromes are associated with increased
occurence of malignant tumors
28EVOLUTION 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)
29EVOLUTION 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
30EVOLUTION 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
31EVOLUTION 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
32THE OLDEST OLD
- SELECTIVE SURVIVAL ?
- Mortality over 90 turn on the curve
- men lt women
- Incidence of Alzheimer disease
- Short period before death
- Which genes? APO E ?, ACE ?
33THE OLDEST OLD
- TIZIANO V 1477 - 1576 98 PIETA
- VERDI G 1813 - 1902 80 FALSTAFF
- PICASSO P 1881 - 1973 86 LE COUPLE
- CHURCHILL, CASALS, KNAZOVICKÝ...
- QUEEN MOTHER, MOJSEJEV (102)
- JOHN GLENN, 1922 (1962, 1999 and his 96 years
old friend)
34PRIMARY 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
35Nature 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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