LEZIONE 7 Anno Accademico 2010/11 BIOTECNOLOGIE FARMACOLOGICHE
CORSO DI LAUREA SPECIALISTICA IN BIOTECNOLOGIE DEL FARMACO
Slide 2
LE BASI BIOLOGICHE DELLINVECCHIAMENTO Invecchiamento e genetica
Regolazione endocrina dellinvecchiamento Invecchiamento e
ambiente
Slide 3
Non-Programmed Passive Aging Theories Aging is a passive result
of an organisms 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)
Slide 4
Programmed Active Aging Theories 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.
Slide 5
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
Glycosylation Theory of Aging (The cell waste accumulation) Aging
Theories Immune system alterations
Slide 6
Aging Theory Status 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. Some relatively recent discoveries appear to
favor aging-by-design theories. 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.
Slide 7
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.
Slide 8
Hutchinson-Guilford Progeria and Werner syndrome
Hutchinson-Guilford Progeria, a very rare human genetic disease,
accelerates many symptoms of aging including atherosclerotic heart
disease. Victims usually die by age 13. 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. 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
Slide 9
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 in
GGT nel codone 608 della laminina A (LMNA). Questo determina
linsorgenza 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.
Hutchinson-Gilford progeria syndrome
Slide 10
Figure 1. Processing of lamin A in normal and HGPS cells
Meshorer E., Gruenbaum Y. J. Cell Biol. 2008:181:9-13
Invecchiamento e genetica
Slide 11
La presenza di laminina mutata (progerin)altera le funzione
della membrana nucleare, la sua permeabilit e la trascrizione
genica.
Slide 12
Slide 13
La laminina A 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; lintervento 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 attivit intranucleare.
Slide 14
Capell and Collins, Nature Reviews Genetics 2006.
Slide 15
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.
Slide 16
Slide 17
Slide 18
Sindrome di Werner Una patologia autosomica recessiva La
mutazione genica a carico della DNA elicasi (cromosoma 8 braccio
corto) che accorcia la lunghezza dei telomeri. La malattia si
manifesta alla pubert e i portatori della mutazione vivono fino
circa 40 anni di et.
Slide 19
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
Slide 20
When replication forks stall, the stable maintenance of
replisome components requires the ATR kinase Mec1/Ddc2 and the RecQ
helicase Sgs1.
Slide 21
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.
Slide 22
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.
Slide 23
STUDIARE VERMI E INSETTI PER CAPIRE LUOMO Drosophila
melanogaster Coenorabditis elegans
Slide 24
adulto L4 embrioni L1 L2 L3 Circa 3 giorni a 22C CICLO VITALE
DI C.ELEGANS
Slide 25
adulto L4 embrioni L1 MANCANZA DI ALIMENTI CICLO VITALE DI
C.ELEGANS STADIO DAUER
Slide 26
LARVALARVA DAUER
Slide 27
Slide 28
Studio di processi biologici legati a una maggiore morbidit
lesempio dellinvecchiamento DAF1 (IGF-R) AGE 1 (IP3-K) DAF 16* DAF
12 DAUER DAF 7 ( TGF ligand) DAF 4 (Type II TGF R) DAF 3, DAF 5
(SMAD prot) DAF9 (cytochrome C CYP27A1 ) * Proteine della famiglia
FOXO coinvolte nel metab del glucosio SIR2 (deacetilasi attiva di
DAF 16) 3-keto-cholestenoic acid metabolite
SEXUAL REPRODUCTION REGULATORS NUTRIMENT AGE EFFECTOR
EVOLUTION: LAND OF BIOLOGICAL EQUAL OPPORTUNITIES
Slide 32
SEXUAL REPRODUCTION FECUNDITY SHOULD BE DIRECTLY PROPORTIONAL
TO NUTRIENT AVAILABILITY, HIGH NUTRIENT AVAILABILITY, FAVORING
FECUNDITY, SHOULD SHORTEN THE LIFE SPAN DEATH: A TOOL INDISPENSABLE
TO ENSURE THE CONTINUATION OF THE SPECIE but EVOLUTION: LAND OF
BIOLOGICAL EQUAL OPPORTUNITIES
Slide 33
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) Fertility-driven Extrinsic factors nutrition
adaptable environment 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
