Glancing to biogerontology: Biology of aging - Johannes Grillari Aging and Immortalization Research (A.I.R.) Vienna Institute of BioTechnology ...
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Glancing to biogerontology:
Biology of aging
Johannes Grillari
Aging and Immortalization Research (A.I.R.)
Vienna Institute of BioTechnology
Universität für Bodenkultur, Wien
Definition of Aging
Biological aging is a progressive,
generalized impairment of function
resulting in an increasing
probability of death.
John Maynard Smith, 1956
Survival curves
Successful aging:
“More life into the years”
% survival
Time
Jeanne Calment, Arles, 122 years
(1875-1997)
• Learns fencing
at the age of 85
• Bicycle till 100
• Stopped
smoking at 120
• Rap CD at 121
Harriet,
1830-2006
• Sydney - In einem Tiergarten im australischen Brisbane hat am Montag die vermutlich
älteste noch lebende Riesenschildkröte der Welt ihren 175. Geburtstag gefeiert. Zur Feier
des Tages gab es für die Schildkröte Harriet, die 1835 im zarten Alter von geschätzten fünf
Jahren vom britischen Naturforscher und Begründer der Evolutionstheorie, Charles Darwin,
von den Galapagos-Inseln mit nach England genommen wurde, einen Geburtstagskuchen
und ihr Leibgericht: Hibiskusblüten. "Uns geht's gut und wir hoffen wirklich, dass Harriet
noch viel älter wird", sagte Krötenpflegerin Laura Campbell. Harriet lebt seit Mitte des 19.
Jahrhunderts in Australien.
• Langlebigkeits-Rekord liegt bei 188 Jahren
• Der "Langlebigkeitsrekord" liegt bei 188 Jahren, gehalten ebenfalls von einer Galapagos-
Riesenschildkröte, die vor ihrem Tod dem König von Tonga gehörte. Darwin hatte bei einer
seiner Forschungsreisen zu den Galapagos- Inseln drei Riesenschildkröten mitgenommen
und sie - da er sie allesamt für männliche Exemplare hielt - Tom, Dick und Harry genannt.
Erst in den 50er Jahren des letzten Jahrhunderts wurde der kleine Irrtum festgestellt, und
aus Harry wurde Harriet. (APA/dpa)
Do all organisms age?
• Animals that stop growing, do age
– All mammals
– All birds
• Animals that do not stop growing, do not show
signs of aging (or only very slowly)
– Lobster, sturgeon und shark, reptiles
– Sturgeon (82), Galapagos turtle (175)
– Plaice: females continue growing, males do not (and
age)
• However: eternal life? You cannot observe it…
fairy tales (vampires, lost horizon, orlando)
• accidents and diseases
Why – the nasty question
• Aging is necessary: we have to wear out (2nd
law of thermodynamics)
– BUT: we are closed systems
• Aging is necessary as overcrowding control
– BUT: Evolution does not select on the population
level but on the individual
• But then, why??
Many - more or less - funny theories • Yoghurt (Metchnikoff – Nobel with Ehrlich) • Testicles • Rate of living theory • Oxidative stress (Denham Harman) • Death hormones.... (Denckla et al.)
The Baltimore Longitudinal Study
• 1958, Nathan Shock (NIA)
• 1400 men and women at the age of 18-100
• Check-up every 18-24 months
– Clinical, physiological, biochemical, psychological
tests
• Study is still ongoing, however: We do age
differently (creatinine clearance)Criteria for a “biomarker”
• predict a person's physiological, cognitive, and physical function in
an age-related way independent of chronological age.
• It must be able to be tested repeatedly without harming the person.
• Preferably, it should work in laboratory animals as well as humans.
• Biomarkers need to be simple and inexpensive to use. They should
cause little or no pain and stress. And they must measure aging
accurately.How can you measure biological age?
• Hair greying
• Length of ear lobes
• Strength of fist
• Fuction of heart
• Sports
• Lung capacity
There is no parameter…What are the mechanisms
of Aging?
Aging is very heterogenous, large
differences between chronological and
biological ageWhat are the mechanisms
Tina Turner, 68 Keith Richards, 65
of
Aging?
Aging is very heterogenous, large
differences between chronological and
biological ageWhat might determine the rate of aging
(1) Accumulation of stochastic damage
counteracted by
(2) genetically determined repair capacity
and
(3) environmentally regulated repair
Disposable Soma Theory
Tom KirkwoodDisposable Soma Theory
(Tom Kirkwood, 1977)
In the wild life:
• Limited energy intake
• Allocation of energy
– Maintenance
– Reproduction
N. Tavernarakis, 2007The stochastic damage
component
• Overexpression of antioxidative proteins and
decreasing ROS prolongs life span
• Life span of species is correlated with repair
activity of their cells
• Progeroid syndromes arise, if repair enzymes
(especially DNA repair) are mutated or if stem
and progenitor cells can not repair tissues
anymore
• Nutrition
• „Life style“Genetic component of aging • Twin studies: longevity more similar than fraternal twins • Children of parents who lived beyond 80 themselves live on average 6 years longer than children of parents who died before 60 • 87% of the 90-100 years old have at least one parent that was older than 70
Environmental regulation of repair • Calorie restriction • Hormesis? • Mutations in transcription coupled repair – signals back to „organism level“ – by IGF repression (Niedernhofer et al. 2007) – relocating energy to repair?
What „nature“ might have
intended:
• Under favourable environment conditions:
– Make love and babies
• Under non-favourable conditions:
– Extend life span and retard reproduction
– Increase the chance that the progeny meets
better conditions
• ?Pathways involved in increasing life
span of mammals
• Calorie restriction
– by higher efficiency of oxidative phosphorylation?
– suppress fertility and increase repair?
• Nutrient sensing
– Suppressing insulin and GH-IGF1 Axis
– 6 of 9 lifespan extended mice have defects in this pathway
– Centenarians show higher incidence of mutations in IGF1 receptor
– Klotho regulates IGF1 and Ca2+
– TOR?
• Increasing stress resistance / repair
– the other 3 of 9 are/might be involved in stress resistance: Surf1,
AC5, p66shc- Amino acids
Replicative
senescence as
model of aging
1 population doubling
Early PD HUVECs Senescent HUVECs
Number of doublings:
Age of donor
Life span of species
Premature aging syndromesCellular senescence contributes to age related functional decline
Tumorigenesis
8
DNA damage Decline of organ
ROS and tissue function -
stem cells
1 2 9
7
Replication
Aging
3
6
Oncogenic Altered cell
signalling physiology
4
5a
Altered
Cell
signalling
5b removal
function (Stem) cell
depletion
Grillari & Grillari, 2010Senescence contributes to age
associated diseases
• Baker
• Blasco
• dePinhoOur approach:
Which cells have we been looking at
• Endothelial cells
• Renal proximal tubular epithelial
cells
• Skin fibroblasts
• Fat derived adult stem cells
• Amnion derived adult stem cells
Side effect: Immortalized cell lines of all of these cellsThe screening:
differential gene expression
miRNA
C
mRNA and
miRNA Protein
µ-arrays 2D DIGE interactions
ElectrophoresisIdentified cellular aging related
factors
~ 1500 on mRNA level
~ 70 on protein level
~ 40 on miRNA levelmiR-31
The working hypothesis:
miR-31 is secreted within exosomes to the
blood decreases osteogenic differentiation
and promotes growth
Exosomes/ Osteogenic
supernatant Target mRNA FRZD3? differentiation
miRNA
Osteoporosis?
miRNA
Senescent mesenchymal stem cell
endothelial cell
(increased in atherosclerosis)
Thus miRNAs might be novel members of the senescent messaging secretome
Unpublished data, not for public disseminationHuman serum derived exosomes of elderly inhibits osteogenic
differentiation of ASCs
Alizarin Quantification
2.5
P =miR-31 levels are significantly increased in
serum of elderly donors
25 p = 0.028
20
relative miR-31 levels
15
10
5
0
old young
N=27 N=21
Mean age: 68.8 Mean age: 26.2
50-91 years 19-47 years
Unpublished data, not for public disseminationA novel cell source for model systems
and regenerative medicine?
Zhou et al. JASN, 2011Establishing cultures of
HEPTECs
20.01.2014 Confidential – for internal use onlyDifferentiation of UiPSCs
Cardiomyocytes
differention
Hepatocytes
Directed
Neurons
Tuj1 AFP cTNT
20.01.2014 Confidential – for internal use onlyCardiomyocyte differentiation of iPSCs
Further reading • Tom Kirkwood Zeit unseres Lebens: Warum altern biologisch unnötig ist 2000, ISBN: 3351025092 • Robert Arking Biology of Aging 2006, ISBN: 0195167392
The Grillari Labs (gio) The Grillari Labs (regina)
Elisabeth Schraml Matthias Wieser Medical University Vienna
Rossella Monteforte Rita Reynoso Erwin Tschachler
Markus Schosserer Sarah Dunzinger
Hanna Dellago Lukas Fliedl LBI für Traumatologie
Barbara Preschitz Matthias Gerstl Heinz Redl
Hameed Khan
Klemens Wassermann LUMC, Leiden
Sylvia Weilner Andrea B. Maier
Evercyte
Eva Fuchs Rudi Westendorp
Regina Grillari
Vaibhav Jadhav
Otto Kanzler
Matthias Hackl
Johannes Grillari
Jens Pontiller IBA, Innsbruck
Pidder Jansen-Dürr
Beatrix Grubeck-Loebenstein
University of Salzburg
Funding Johann Bauer
CDG
CERIES
FWF Chinese Academy of
GEN-AU Sciences
Austrian Academy of Sciences Miguel Esteban
Herzfelder’sche Familienstiftung Duanqing Pei
ACIB
AWS TU Graz
Marcel Scheideler
Title page of special issue DNA Aging in Nucl. Acids Res. 2007You can also read
