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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 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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