AGEING Basic terms, epidemiology, theories of ageing and the genetic background of ageing

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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 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

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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 Swifts 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 gt 90 y.
• PRACTICE
• Old age gt 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. (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

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LIFE 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.

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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
• lt 1 DAY
• WEEK MONTH
• MONTH YEAR
• YEAR DECADE
• DECADE
• CENTURY

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THE 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

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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) gtgt mouse (30 g) but
• 1 g mouse tissue gtgt 1 g human tissue
• Maximum life span
• Man gtgt 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 line
Cancer
Somatic
Progeria
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TELOMERES IN AGEING AND CANCER
Germ line
Somatic
Acceleration of telomere loss Stress, smoking,
obesity and ???
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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)

Progeric syndromes are associated with increased
occurence of malignant 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 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 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 lt 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, KNAZOVICKÝ...
• 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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