BIOTECNOLOGIE FARMACOLOGICHE
CORSO DI LAUREA SPECIALISTICA IN BIOTECNOLOGIE DEL FARMACO
LEZIONE 7
Anno Accademico 2010/11
LE BASI BIOLOGICHE
DELL’INVECCHIAMENTO
Invecchiamento
e genetica
Invecchiamento
e ambiente
Regolazione endocrina
dell’invecchiamento
Non-Programmed Passive Aging Theories
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Aging is a passive result of an organism’s inability to better resist fundamental
deteriorative processes.
Aging serves no purpose, is not an adaptation, is not programmed.
Compatible with traditional evolutionary mechanics theory.
Mammals needing more time for development needed a longer life span and
therefore developed better maintenance and repair mechanisms that
consequently delayed onset of age-related symptoms and diseases relative to
shorter-lived mammals.
Poor fit to many other observations of humans, other mammals, and other
organisms particularly those that die suddenly from apparent biological suicide
following reproduction rather than from gradual deterioration (e.g. Octopus,
salmon)
Programmed Active Aging Theories
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Organisms are purposely designed and genetically programmed to age or
otherwise limit life span because the deterioration and life span limitation serves
an evolutionary purpose.
Aging is an adaptation, a purposeful design feature resulting from the evolution
process.
Aging is the result of a potentially complex active aging mechanism or “life span
management system.” The mechanism could sense external conditions in order
to adapt life span to local or temporary conditions and could operate by
manipulating the maintenance and repair functions.
Provides excellent fit to observations in humans, mammals, and other
organisms.
Incompatible with traditional “survival of the fittest” individual benefit requirement;
requires an alternative mechanics theory.
Supported and predicted by several alternative mechanics theories.
Aging Theories
Planned Obsolescence Theory
Telomerase Theory of Aging
The Neuroendocrine Theory
The Free Radical Theory
Mitochondrial Theory of Aging
The Membrane Theory of Aging
The Hayflick Limit Theory (The cell waste accumulation)
Glycosylation Theory of Aging
Immune system alterations
Aging Theory Status
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“Main line” consensus of current gerontologists favors the passive theories.
Earlier simple deterioration theories have little current scientific credibility in
the biology community while still popular in the human-oriented (physician)
community.
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Some relatively recent discoveries appear to favor aging-by-design theories.
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Efforts to explain aging based on traditional mechanics and efforts to explain
other discrepancies with alternative mechanics cannot be simultaneously
valid. Eventually there will be a unified theory.
“Non-Aging” Species
• Some species have been identified that apparently do not age or have
negligible senescence. Older individuals do not appear to be weaker, less agile,
less reproductive, more susceptible to disease, or otherwise less fit than
younger animals. (Ages of some wild animals can be determined by annual
marks in scales or bones similar to tree rings.)
• Some species with age of oldest recorded specimen:
Rougheye Rockfish 205 Years
Lake Sturgeon152 Years
Aldabra Tortise152 Years
• Common U.S. Eastern Box Turtle is also long-lived (~100 years).
• Non-aging species tend to defeat simple deterioration theories and suggest
dramatically longer human life spans are possible.
Hutchinson-Guilford Progeria and Werner syndrome
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Hutchinson-Guilford Progeria, a very rare human genetic disease,
accelerates many symptoms of aging including atherosclerotic heart disease.
Victims usually die by age 13.
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Werner syndrome, another genetic disease, involves acceleration of most
symptoms of aging including baldness, hair and skin conditions, heart
disease, calcification of blood vessels, some cancers, cataracts, arthritis,
diabetes, etc. Victims usually die by age 50.
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These conditions suggest aging is centrally controlled such that a single
genetic defect could result in proportionally accelerating all of the expressed
symptoms. Central control suggests aging-by-design
Hutchinson-Gilford progeria syndrome
Una malattia autosomica dominante e sporadica e rara che
determina invecchiamento precoce: in genere il paziente muore a 13
anni circa per patologie cardiache
La base genetica per molti casi di questa patologia consiste
nella mutazione della tripletta GGC
della laminina A (LMNA) .
in GGT nel codone 608
Questo determina l’insorgenza di un sito di splicing criptico porta
alla sintesi di una proteina con una delezione di 50 aa. La regione
deleta ha in se la sequenza riconosciuta da enzimi proteolitici che
fanno maturare la Laminina. In mancanza di questa parte della
proteina, questa viene carbossifarnesilata e si accumula a livello
endocellulare e soprattutto a causa della farnesilazione, nella
membrana nucleare.
Invecchiamento e genetica
Figure 1. Processing of lamin A in normal and HGPS cells
Meshorer E., Gruenbaum Y. J. Cell Biol. 2008:181:9-13
La presenza di laminina mutata (progerin)altera le
funzione della membrana nucleare, la sua
permeabilità e la trascrizione genica.
La laminina A è una proteina della membrana nucleare che si
posizione nella porzione intranucleare e partecipa alla
organizzazione dei processi che presiedono la biosintesi di
RNA e DNA.
La Prelaminina A contiene un CAAX box nella sua porzione
carbossiterminale che ne permette la farnesilazione ed il suo
legame con la membrana nucleare; l’intervento di una
metalloproteasi specifica taglia il frammento farnesilato
producendo la Laminina A che ha una legame meno forte con
la membrana nucleare e puo’ svolgere la propria attività
intranucleare.
The is a mouse model of progeria where the
prelamin A is not mutated. Instead, the
metallopeptidase ZMPSTE24, the specific
protease that is required to remove the C-terminus
of prelamin A, is missing.
Sindrome di Werner
Una patologia autosomica recessiva
La mutazione genica è a carico
della DNA elicasi (cromosoma 8
braccio corto) che accorcia la
lunghezza dei telomeri.
La malattia si manifesta alla
pubertà e i portatori della
mutazione vivono fino circa 40
anni di età.
A yeast protein similar to the human WRN protein,
called SGS1, has been found.
Mutations in SGS1 cause yeast to have a shorter
lifespan than yeast cells without the mutation, and
shown other signs typical of aging in yeast, such as an
enlarged and fragmented nucleolus. Using yeast as a
model for human aging in general, may give insight into
the mechanisms of Werner syndrome and related
diseases
When replication forks stall, the stable maintenance of replisome
components requires the ATR kinase Mec1/Ddc2 and the RecQ
helicase Sgs1.
A. Topo I usually found in eukaryotes
binds the 3’ end of the broken DNA
strand, and removes (+) or (-)
supercoils. As replicating DNA moves
through the structure, the two parental
strands (black) are separated by the
helicase, while positive supercoiling is
removed by the 3’ topoisomerase.
B. A machine able to separate the
daughter
molecules at the end of replication is
formed by a helicase (red) removing the
last turns of parental DNA and a type II
topoisomerase
(green) untangling the daughter
duplexes.
C. Nucleosome disruption.
The positive supercoiling produced by
the translocating helicase H (red)
destabilizes the nucleosome, while a
topoisomerase T (5’ or 3’ Topo I,
or eukaryotic topo II, green) efficiently
relaxes the negative supercoiling,
reforming the normal duplex behind
the helicase.
Drosophila melanogaster
STUDIARE VERMI E
INSETTI
PER CAPIRE L’UOMO
Coenorabditis elegans
CICLO VITALE DI C.ELEGANS
adulto
L4
Circa 3 giorni a
22°C
L3
embrioni
L1
L2
CICLO VITALE DI C.ELEGANS
adulto
embrioni
L4
MANCANZA DI
ALIMENTI
STADIO DAUER
L1
LARVA
LARVA DAUER
Studio di processi biologici legati
a una maggiore morbidità
l’esempio dell’invecchiamento
DAF 7 ( TGFb ligand)
DAF1 (IGF-R)
DAF 4 (Type II TGFbR)
AGE 1 (IP3-K)
DAF 3, DAF 5 (SMAD prot)
DAF 16*
DAF 12
3-keto-cholestenoic acid metabolite
DAUER
SIR2 (deacetilasi attiva di DAF 16)
DAF9 (cytochrome C
CYP27A1)
* Proteine della famiglia FOXO coinvolte nel metab del glucosio
GH
Insulin/IGF-1
Insulin/IGF-1
DAF 2 receptor
IGF-1R
dFOXO
DAF 16/FOXO (adip. Tissue)
TOR
LONGEVITY
germline
IGF-1
1R
TOR
LONGEVITY
germline
Insulin
LONGEVITY
Invecchiamento e ambiente
EVOLUTION:
LAND OF BIOLOGICAL EQUAL OPPORTUNITIES
“EFFECTOR”
SEXUAL REPRODUCTION
“REGULATORS”
NUTRIMENT
AGE
EVOLUTION:
LAND OF BIOLOGICAL
EQUAL OPPORTUNITIES
DEATH: A TOOL INDISPENSABLE
TO ENSURE THE CONTINUATION
OF THE SPECIE
• FECUNDITY SHOULD BE
DIRECTLY PROPORTIONAL
TO NUTRIENT AVAILABILITY,
but
• HIGH NUTRIENT AVAILABILITY,
FAVORING FECUNDITY, SHOULD
SHORTEN THE LIFE SPAN
SEXUAL REPRODUCTION
AGING
AS NECESSITY FOR THE CONTINUATION OF LIFE
and
AS A MEAN TO GIVE TO EACH INDIVIDUAL EQUAL
POSSIBILITIES TO GIVE HIS GENETIC CONTRIBUTION TO THE
NEXT GENERATION
Intrinsic program for aging aiming at increasing the
fraility of the organism:
a biological clock(telomers length, mitochondrial
viability; DNA replication errors, loss of immune
control and inflammation…)
sex-dependent (male fecundity cannot be limited as
well as in females)
Extrinsic factors
Fertility-driven
nutrition
adaptable environment