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UNIVERSITY OF PADUA ITALY
European Master in Gerontology Programme
Introductory Module BIOGERONTOLOGY IN A
DARWINIAN PERSPECTIVE What Natural History Can
Tell Us About Ageing Prof. Andrea G. Drusini, MD

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Charles Darwin Bicentenary February 12
1809 April 19 1882
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EVOLUTIONARY MEDICINE The darwinian model for the
study of ageing and diseases
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Name Andrea G. Drusini Date of Birth July 13,
1947 Nationality Italian Marital Status
celibate Education M.D., Full Professor of
Anthropology Institution University of Padua,
Italy Hobbies books, guitar, writing, travelling
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Nature is not God A hypothesis is not a fact Man
is not a machine (Denis Diderot) As other
natures sciences, biology today has lost many
illusions. Biology does not look at the truth,
rather it builds it. (François Jacob)
Denis Diderot (1713-1784)
Thinking in a biological perspective
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CRITICS TO REDUCTIONISM "Extreme analytical
reductionism is a failure because it cannot give
proper weight to the interaction of components of
a complex system. An isolated component almost
invariably has characteristics that are different
from those of the same component when it is part
of its ensemble, and does not reveal, when
isolated, its contribution to the interactions"
Ernst Mayr Mayr E., 1982a, The Growth of
Biological thought. Diversity, Evolution, and
Inheritance. The Belknap Press of Harvard
University Press, Cambridge, Mass., London,
England, p. 61.
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The basic biological processes (Ernst Mayr,
1982b) Teleological Processes All things are
directed toward an end and the intelligence that
governs them is God Teleomatic Processes They
depend on the natural laws the gravity, for
example, is a necessity. All these processes
reach their end when their potential is consumed
i.e. radioactive degradation and in living
organisms the metabolic processes, the blood
circulation and the immunitary response.
Teleonomic Processes Are based on the principle
"nothing does exist in nature which is not direct
to a target " (Mayr uses the term target,
different from purpose which implies a finality).
The best example is the fecundation and eggs
development. All these processes are under the
control of a program (reproduction, mating,
etc.)
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With cell, Biology discovered its atom (F.
Jacob)
Robert Hooke was a brilliant British experimental
and theoretical scientist who lived and worked in
London during the seventeenth century. In 1665
Robert Hooke coined the term cell.
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• General types of cellular construction
• EUKARYOTIC
• Complex organization
• Internal compartments
• Organelles
• Several chromosomes within a nucleus
• Tiny
• Plants, animals, fungi, protists
• PROKARYOTIC
• Simple in organization
• No
• - compartmentalization
• Organelles
• One chromosome within cytoplasm
• Tinier
• Bacteria, algae

CELL AS AN ISLAND
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DNA The genetic code
Any cell of our body contains a blueprint 60
millions of billions of cells 60 millions of
billions of blueprints
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With death we enter the game again (Paul
Valéry)
COLEOPTERA 40 years
FLY 1 month
THE ANIMAL LIFE-SPAN
DOG 10 years
TESTUDO 150 years
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METHUSALEH OPOSSUMS
The game of life and death
Opossums and other small mammals generally die in
nature from predators or cold temperatures.
Therefore, their most likely cause of death was
predators. The Steven N. Austads hypothesis for
opossums rapid ageing was that, given all these
predators, the high rate of accidental deaths
will make natural selection fade rapidly with
age. In these circumstances, an animals time
horizon is very short.
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Islands are of particular interest because they
are renowned among ecologists for their lack of
predators. As a consequence, island animals are
typically characterized by a lack of fear such
things as dogs, cats, or humans.
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By this logic, island environments should be less
hazardous than mainlands, and animals living on
islands should evolve slower ageing over an
evolutionarily significant amount of time.
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Sponges are multicellular organisms that can
reproduce themselves
The sorcerer apprentice
Dendrilla rosea
These organisms do not age at all
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The Dictyostelium discoideum world
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A transmission electron micrograph of Escherichia
coli (E.coli), negatively stained to enhance
contrast. Note the projecting pili, which may be
involved in mechanisms of infection.
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Wayson stain of Yersinia pestis. Note the
characteristic "safety pin" appearance of the
bacteria

The pestilence, or the Great Death, as it was
also called, influenced art during the period. As
expected, most artwork of the time dealt with
death and the plague. The painting shown here is
of the city of Marseilles, devastated by an
outbreak of plague.
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The Measles virus
Atomic resolution in mica
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Octopus
..have sex, and eventually die..
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TRICONYMPHA (Zoomastigophora)
Mors tua. Mors mea
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Mitochondria are the cells' power sources. They
are distinct organelles with two membranes.
Usually they are rod-shaped, however they can be
round. The outer membrane limits the organelle.
The inner membrane is thrown into folds or
shelves that project inward. These are called
"cristae mitochondriales". This electron
micrograph taken from Fawcett, A Textbook of
Histology, Chapman and Hall, 12th edition, 1994,
shows the organization of the two membranes.
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THE AGEING CHARACTERISTICS
- ageing is deleterious it reduces the
functional capacity of an organism - ageing is
progressive it goes on gradually - ageing is
intrinsic it does not depend exclusively on
environmental factors - ageing is universal it
involves all living organisms.
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THEORIES ON AGEING A REVIEW
The speed of life hypothesis (Pearl 1928)
The free radicals theory (Harmon 1956) The
DNA damage hypothesis (Szilard 1959) The
catastrophic error hypothesis (Orgel 1963)
The cells finite number of cycles theory
(Hayflick (1965) The glucocorticoids
hypothesis (Sapolsky, Krey and McEwan 1986) The
glycosilation theory (Monnier 1990) The
telomere loss theory ( Lindsey and coll. 1991)

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A study in the Journal of the National Cancer
Institute showed an association between telomere
length and cancer development. The impact of
genetic and environmental factors on telomere
length is unknown.
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ANTAGONISTIC PLEIOTROPY
In the 50s, Williams (1957) introduced the
concept of antagonistic pleiotropy. Pleiotropy
is a biological term indicating the multiple
effects of a single gene on several components of
the phenotype (p?e??? to increase ??ep? to
turn)
As Mayr stated, no gene has a constant fitness
value, because the very same gene will manifest
itself differently, depending on the complex of
other genes in which it finds itself
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THE DISPOSABLE SOMA THEORY
Tom Kirkwood - a major figure in the field of
ageing evolution - in 1998 developed what is
currently known as the Disposable Soma Theory
(DST)
DST is in analogy to the industrial habit to
invest very little on the endurance of objects
that are destined to a limited time use
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PALE
DARK
NATURAL SELECTION AT WORK the moth Biston
betularia
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Microcebus murinus
..both can undergo Alzheimers disease
Macaca mulatta
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LONGEVITY AWARDS
Rockfish (Sebastes aleutianus)
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The Old Car Theory of Ageing
Why after some years do cars go out of use?
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DAPHNIA This animal may be more common than ants
and it probably lives in your neighborhood. It's
a fascinating animal, and you can even view its
heart beating inside the body
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HUNTINGTONS DISEASE
The CT scan is of a patient with advanced
Huntington disease. Note the diffuse cortical
atrophy and the selective atrophy of the caudate
nuclei as shown by the excessive width of the
lateral ventricles.
Chorea from the greek khoreutes, a dancer in the
choir (from which the term choreography was
derived)
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Welcome to the Absent-Mind Scientists Lab
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PROGERIA (WERNERS SYNDROME) Pathogenesis
unknown linked to deficits in cellular helicase
function Locus short arm of chromosome 8
(p21-p12)
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DROSOPHILAND
Teen-ager
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THE BIONIC DROSOPHILA
Catalase and superoxide dismutase are two enzymes
that destroy ROS (Reactive Oxygen Species). If
these enzymes are inserted into embryonic fruit
flies, their life span would be extended by 33
when compared to controls.
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The Extraordinary deeds of Caenorhabditis elegans
NEMATODA (ROUNDWORMS)
Caenorhabditis elegans is a small (about 1 mm
long) soil nematode found in temperate regions,
used worldwide for genetic ageing experiments
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sheep talesand reductivism
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PAPUA NEW GUINEA
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PAPUA NEW GUINEA MAN
In Papua New Guinea the worlds highest frequency
of e4 was found
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IN THE WAKE OF ODYSSEUSA Mythological Journey
" at any rate, that some of them put the Sirens
on Cape Pelorias Cape Faro, Sicily, while
others put them more than two thousand stadia
distant on the Sirenussae, which is the name
given to a three-peaked rock that separates the
Gulf of Cumae Bay of Naples from the Gulf of
Peseidonia Gulf of Salerno..
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The most dangerous moment comes with victory
Napoleon IEmperor of the French 1769 - 1821
Was his death programmed?
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The two fundamental ageing
theories
(Medina, 1997) Errors storage (wear and
tear) as cells age, they accumulate errors (the
ravages of environment). Ageing is simply the
incapacity to repair such ravages  Activation of
a genetic programme (the molecular clock of age)
presence of suicide genes" which favours
cellular death through apoptosis (programmed
ageing / programmed death )
APOPTOSIS the programmed cell death
Napoleon Bonaparte 1769-1821
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TWO AGEING THEORIES) 1)Errors storage (wear
and tear) as cells age, they accumulate errors
(the ravages of environment). Ageing is simply
the incapacity to repair such ravages 2)
Activation of a genetic programme (the molecular
clock of age) presence of suicide genes" which
favour cell death (programmed ageing/ programmed
death ).
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A telomere is a region on the very tip of
chromosomes. They are composed of a repeating
series of six nucleotides (TTAGGG). A typical
human telomere may have more than 15000 such
repeats in it. Their relevance to the ageing
process is being investigated. (Source Medina,
1997, p. 276, with permission of the Editor)
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CELL CULTURE A FIBROBLAST
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CELL CULTURE
A Petri dish
Human cells, placed in a Petri dish, can survive
outside the body After a while cells refuse to
duplicate themselves Such microscopic menopause
is called replicative senescence
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THE HAYFLICK LIMIT
Leonard Hayflick is Professor of Anatomy at the
University of California, San Francisco, School
of Medicine
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The life and death genes
Senstatin proteins. Can reverse the ageing
process in the cells of skin, brain and some
blood vessels. Some BioTech Companies try to
inhibit the skin ageing and delay
ageing. Mortality 1 (M1) and Mortality 2 (M2)
gene programs. Such genes work in tandem. They
can cause cancer (retinoblastoma gene and p53).
M1 originates the ageing process and M2 finishes
to kill the cell. Longevity assurance genes (LAG
genes). These genes were studied in yeast and
man. They can extend the yeast cells life by
30. Miscellanea. Genes which press the
trigger of ageing in man can be found in
chromosomes 1 and 4 and in other sites. Among
them there are the Werner Syndrome genes.
Heat-shock genes. A response of genes to
stress.
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THE IMMORTALS
Aphrodite, Ares, Apollon, Artemis. Jupiter, etc.
Hesiodus wrote that in the so called Gold Age,
humans were living without any trouble and free
of disease. In that time humans were as gods,
then they became bad and Zeus, in the bronze age,
created the poor mortals. Only Gods remain
immortal.
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Cellular senescence is inevitable, and every cell
has a more or less determined life span. Such
destiny cell death does happen in all types
of normal cells. Except one type the cancer
cell..
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The ageing paradox Why are men and especially
women more and more longeval? To reply to this
question we might consider correctly the causes
of ageing, in other words we must define and
measure ageing.
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The Kebaras cave site Neanderthal skeleton
(Mount Carmel, Israel Middle-Upper Palaeolithic
transition)
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BONE REMODELING DYNAMICS
CORTICAL SECTIONE OF HUMAN FEMUR (100x)
F
OS
PRIMARY OSTEONSgt SECONDARY OSTEONS lt FRAGMENTS OF
OSTEONS lt r 0.86 plt0.01 E.S. ?3.92 years
BONE microstructures of cortical bone undergo
some modifications with age
(Cera Drusini, 1985 Drusini, 1987 Drusini,
1988 Drusini Businaro, 1990 Alciati, Drusini,
Di Bacco Pezzulli, 1994)
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Histological section of human male femur (100x).
N of secondary osteons/mm2.
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CANCER THE EVOLUTIONARY LEGACY
Most of Neanderthals the Stone Age mankind
buried their dead sometimes anthropologists
found graves with the dead belongings, or offers
as antelope-horns. Most Neanderthals diedat a
middle age 47 years or so, as anthropological
research have demonstrated calculating the
relationship and correlation between age at death
and bone remodeling. We suppose that the
Neanderthal life was more difficult and
hazardous compared to our modern life. Now,
getting back to the cancer, is is very rare to
find cancer in the prehistoric time the reason
is simply that first, prehistoric man was living
in a free of pollution environment, and second,
he was die too young to get cancer. This simple
explanation fits well with the Darwinian theory.
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The Disposable soma theory The biologist
Thomas Kirkwood sees the organism as a black
box in which the two principal aims are to
obtain energy from the environment and to produce
an offspring. The organism needs energy also to
perform other functions to grow, develop, and
protect itself. Moreover, it might convert energy
to preserve intact its genetic code and its germ
cells. Energy is not infinite, so what happens?
That energy converted in some benefit is not
disposable for another.
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KILLER WHALE (Orcinus orca)
LIFE SPAN Male 50-60 years Female 90
years Female undergo menopause
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Menopause is a many-faceted event Following the
disposable soma theory of Tom Kirkwood, woman
is genetically programmed to live longer than
man. Women pay their long life with menopause
men instead pay their continuous reproductive
capacity with a shorter life.
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The menopause a Darwinian- adaptive value It
is rather rare that zoologists who work in the
field would find animals which continue to live
even after they stopped their reproductive
period. From an evolutionary point of view, this
is quite trivial if fertility coincided with the
life span, it would be catastrophic for the
natural environment and for the biological
species balance.
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Longevity of the Doges in the XVI century Venice
  Leonardo Loredan (1436-1521) 1501-1520 ?
65-85 Antonio Grimani (1434-1523) 1521-1523 ?
87-89 Andrea Gritti (1455-1538) 1523-1538 ?
68-83 Pietro Lando (1462-1545) 1539-1545 ?
77-83 Francesco Donà (1468-1553) 1545-1553 ?
77-85 Marcantonio Trevisan (1475-1554)
1553-1554 ? 78-79 Francesco Venier (1489-1556)
1554-1556 ? 65-67 Lorenzo Priuli (1489-1559)
1556-1559 ? 67-70 Girolamo Priuli (1486-1567)
1559-1567 ? 73-81 Pietro Loredan (1482-1570)
1567-1570 ? 85-88 Alvise I Mocenigo (1507-1577)
1570-1577 ? 63-70 Sebastiano Venier
(1496-1578) 1577-1578 ? 81-82 Nicolò da Ponte
(1491-1585) 1578-1585 ? 87-94 Pasquale Cicogna
(1509-1595) 1585-1595 ? 76-86 Marino Grimani
(1538-1605) 1595-1506 ? 63-73 Mean age at
election 74 Mean age at death 81 Mean
duration of the 15 Doges 6.66 years
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THE EXPENSIVE TISSUE HYPOTHESIS (Aiello and
Wheeler, 1995)
log10E 0.76log10P 1.77,  E brain mass
(mg) P body mass (g) Modern humans have an
encephalization quotient ratio of observed to
expected brain size EQ of 4.6 while other
primates average 1.9 0.6. This means that the
average human has a brain that is 4.6 times the
size expected for the average mammal and the
average non-human primate anthropoid has a brain
almost twice as large as that of the average
mammal.
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Neural aspects of ageing (Dani, 1998)

• Increasing brain size
• Increasing brains demands
• Nutrient restriction to the rest of the body

• Encephalization
• Neoteny
• Increased longevity

AGEINGthe evolutionary legacy
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Neural aspects of ageing (Dani, 1998)

• Retardation of growth and maturation
• Increased life span
• Nutrient surplus in modern societies

• Break of brain-metabolic adaptations
• Onset of age-related conditions (diabetes
  mellitus, Alzheimers disease)

AGEINGthe evolutionary legacy
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Ageing and the conquests of modern medicine

• According to the data by Olshansky1 if we
  consider the two major causes of death cancer
  and heart disease we shall notice how
• ? could cancer be defeated overnight, then the
  average age of the population would only increase
  by 2 years
•   ? by eliminating all heart disease the same
  would increase only by 3-4 years2
• 1 Olshansky S.J., Carnes B.A., 2001, Prospects
  for human longevity. Science 291 1491-1492.
• 2 Olshansky S.J., 1998, On the Biodemography of
  Aging A Review Essay. Population and Development
  Review 24(2) 381-393.

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WORLD RECORDS 10.000 m MEN

• First under 31 min 3058.8 Jean Bouin FRA
• 1911
• First under 30 min 2952.6 Taisto Mäki FIN 1939
• First under 29 min 2854.2 Emil Zátopek TCH 1954
  
• First under 28 min 2739.4 Ron Clarke AUS 1965
• First under 27 min 2658.38 Yobes Ondieki KEN
  1993

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World Records 10.000 m Men Linear Regression
Method with Projections Calculated on Real Times
from 1911 to 1993 (r 0.90)
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THE TERRESTRIAL PARADISE
WELCOME!
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CREATION VS EVOLUTION
A Question of Origins The creation vs. evolution
debate is a question of origins. How did we get
here? Were we created or did we evolve randomly?
Are we the product of purposeful intelligence or
are we merely the end result of countless cosmic
accidents? What does the evidence say? Are the
organisms the product of an Intelligent Design?
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The fight between the wasp and the spider
Animal tales
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The wasp attacks the spider with his sting and
paralizes it with eight bites at the nervous
ganglions level. Then, it lays the eggs on it.
The spider is then immobilized, but still alive.
Then, the larvae come out, beginning to eat the
living spider. The larvae pay attention to not
eat the vital organs the spider could die and
putrify, and thats not good.
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The moral of this tale WHERE IS GOD?
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ANOTHER ANIMAL TALE Take a coleopter, genus
Micromalthus. This animal is very bizarre it is
viviparous, like mammals. But the female lays
the eggs, and she keeps them inside. The larvae
come out and oh my God! They begin to eat the
mother!!! Incredible but true!
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AND AGAIN WHERE IS GOD?
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AGEINGhow do we manage theuncertainty?
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AGEING IN A TECHNOLOGICAL WORLD

• The three questions on the table
• Did science and technique improve the quality of
  life of elderly people?
• It Is it true that the  faith in the future  -
  that is the utopian research of biotechnologies
  holds back the solution of some major problems
  such as ageing, handicap and malaise?
• What shall gerontologists do in order to correct
  this direction toward a science and technique
  profitable to everybody?

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The Ageing GameAnywhere something lives,
there is, open in some place, a register in which
time is inscribed (Henri Bergson)
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Great Things About Getting Older

• THE ALTERNATIVE IS WORSE...

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Great Things About Getting Older

• You can stop upgrading your software

The end