Transcript Let evolution improve it... (from Olshansky et al, Scientific American

Molecular mechanisms of antiageing hormetic effects of mild
stress….
Suresh Rattan
Editor-in-Chief, Biogerontology
Danish Centre for Molecular Gerontology
Department of Molecular Biology
University of Aarhus
Denmark
Approaching ageing/anti-ageing
scientifically....
• Describing the phenomenon
• Explanation/conceptualisation
• Intervention
Describing the phenomenon…
Species/populations: fungi, insects, worms, fish, bird, mammals
Individuals rats, mice, Drosophila, C. elegans, Humans
Systems immune, nervous, cardiovascular, endocrine, reproductive, skeletal
Organs and tissues brain, heart, liver, lungs, skin, kidney,
Cells fibroblasts, keratinocytes, epithelial cells, osteoblasts, T cells, glial cells
Organelles nucleus, mitochondria, lysosomes, ER
Macromolecules DNA, RNA, proteins, carbohydrates, lipids
Understanding ageing
1: Functional principle
Ageing is the progressive
impairment in functional ability,
(making us more prone to diseases and
death).
Genetic principle of ageing
There are no
real gerontogenes
which have evolved to
specifically cause ageing.
Nature of genes in ageing
Of course, genes can influence lifespan, and several
gene mutations have been reported which increase or
decrease lifespan through a wide range of molecular
pathways.
None of these genes had evolved to specifically cause
ageing or terminate life.
So, at best, these genes can be termed
VIRTUAL GERONTOGENES (Rattan, 1995: FASEB J.)
Molecular struggle for survival
against constant onslaught...
Radiation
UV- light
Cell
Pollution
Smoking
Oxygen Metabolism
Mitochondria
Positive correlations with
species lifespan
DNA repair
Antioxidant levels
Cell proliferation potential
Cellular responsiveness to stress
other correlations which may or may not always hold true
are: body mass, brain mass, genome size, ribosome
number etc..
Biochemical failure of
maintenance and repair
causes ageing.
Strategies to slow down and/or
to prevent the failure of maintenance:
• Chemical interventions for damage control/removal.
• Chemical interventions to stimulate maintenance and
repair pathways.
• Chemical mimetics of maintenance and repair
pathways.
• Replenishing lost hormones and other macromolecules,
micronutrients.
• Nutritional supplements, functional foods.
Slowing down ageing from
within
By making use of the
homeodynamic characteristic
of living beings.
Homeostasis/Homeodynamics
Living systems have the ability to
counteract and adapt in response
to any disturbance, challenge and
stress.
As a result of homeodynamic
ability, a challenge is
counteracted, damage repaired,
and a new adapted state for
survival is achieved.
(if not, the system is dead!!).
Stress response and
longevity...
Cells and organisms selected for
resistance to severe stress have
enhanced survival and longevity.
Genetically engineered cells and
organisms with overexpressing stress
response genes have increased longevity.
Mild stress...
Induction of defence and repair
pathways by mild stress has
beneficial effects for cells and
organisms.
This effect is known as
HORMESIS.
Exercise as a paradigm for
hormesis
Biochemically, exercise
is damaging.
But, biologically, it is
generally good -
HORMETICALLY
Hormesis could be a way to
improve maintenance and
repair processes, and to
slow down the progression
of ageing.
Heat shock response in a cell
Extracellular stress
HSF1
DNA binding
Inactive HSF1
Transcription
Activation &
translocation
Translation
Intracellular stress
Denatured protein
Degradation
Substrate binding
Refolding
Degradation
Proteasome
Lysosome
HSP
Functional
protein
Repated mild heat shock and
cellular ageing
 Mild heat shock at 41° C,
twice a week, throughout
replicative lifespan of human
skin fibroblasts has no
negative effects on:
Cell survival
Cell attachment
Growth rates and PD rates
Cell yield
CPDL
Biological effects of repeated mild
heat stress on human fibroblasts
 Reduced cell enlargement.
 Redued irregularization.
 Reduced lipofuscin-containing residual
bodies.
 Reduction in the level of oxidativelyand glycoxidatively-damaged proteins.
 Increased resistance to other stresses:
UV-A, ethanol, hydrogen-peroxide.
Mechanisms of hormesis - 1
 2 to 3-fold increase in the level of reduced
glutathione (GSH).

2-fold reduction in oxidized glutathione
(GSSG).

Increased levels of Hsp27, Hsc70 and
Hsp70.

Decreased levels of Hsp90.
Mechanisms of hormesis - 2:
Improved protein degradation
machinery - proteasome
Proteasomal activities
are stimulated by mild
heat stress.
Proteasomal content
is not affected by mild
heat stress.
Mechanisms of hormesis - 3:
Stimulation of proteasome via
its activators
The content of the 11S,
but not of the 19S,
activator is increased.
The binding of the 11S
activator is enhanced in
young cells.
Hormetic questions yet to be
resolved......
1. How do cells sense stress and how quickly?
2. What are the molecular differences between mild and
severe stress-response?
3. What are the differences in hormetic-response of different
cells, organs, tissues, individuals...?
4. Can different stresses be combined, and to what extent?
5. What is the ideal hormetic regime - intensity, frequency?
Anuresh & Suresh Rattan
Aging hormetically
Brian Clark
 Technical backbone
Gunhild Siboska, Helle
Jacobsen, Anne Gylling
 Students and post-docs
Rasmus Beedholm,
Lakshman Sodagam,
Regina Gonzalez,
Ripudaman Singh,
Elise Nielsen, David
Kraft and Yvonne
Eskildsen-Helmond.
Financial support from:
Danish Medical and
Science Research
Councils SSVF & SNF,
EU-Biomed Programmes
and Senetek PLC,......