Molecular mechanisms of antiageing hormetic effects of mild stress.

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Molecular mechanisms of anti-ageing hormetic
effects of mild stress.
Suresh Rattan Editor-in-Chief,
Biogerontology Danish Centre for Molecular
Gerontology Department of Molecular
Biology University of Aarhus Denmark
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Approaching ageing/anti-ageing scientifically....

• Describing the phenomenon

• Explanation/conceptualisation

• Intervention

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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

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Understanding ageing1 Functional principle

• Ageing is the progressive impairment in
  functional ability,
• (making us more prone to diseases and death).

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Genetic principle of ageing

• There are no
• real gerontogenes
• which have evolved to specifically cause ageing.

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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.)
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Molecular struggle for survival against constant
onslaught...
UV- light
Radiation
Cell
Pollution
Smoking
Oxygen Metabolism
Mitochondria
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Positive correlations withspecies 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..

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Biochemical failure of maintenance and repair
causes ageing.
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Strategies to slow down and/orto 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.

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Slowing down ageing from within

• By making use of the homeodynamic characteristic
  of living beings.

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Homeostasis/Homeodynamics

• Living systems have the ability to counteract and
  adapt in response to any disturbance, challenge
  and stress.

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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!!).
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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.

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Induction of defence and repair pathways by
mild stress has beneficial effects for cells and
organisms.
Mild stress...

• This effect is known as
• HORMESIS.

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Exercise as a paradigm for hormesis

• Biochemically, exercise is damaging.
• But, biologically, it is generally good -
• HORMETICALLY

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Hormesis could be a way to improve maintenance
and repair processes, and to slow down the
progression of ageing.
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Heat shock response in a cell

Extracellular stress
HSF1
DNA binding
Transcription
Activation translocation
Inactive HSF1
Translation
Intracellular stress
Substrate binding
Denatured protein
HSP
Degradation
Refolding
Functional protein
Degradation
Proteasome
Lysosome
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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

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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 oxidatively- and
  glycoxidatively-damaged proteins.
• Increased resistance to other stresses UV-A,
  ethanol, hydrogen-peroxide.

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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.

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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.
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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.
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Hormetic questions yet to be resolved......

• How do cells sense stress and how quickly?
• What are the molecular differences between mild
  and severe stress-response?
• What are the differences in hormetic-response of
  different cells, organs, tissues, individuals...?
• Can different stresses be combined, and to what
  extent?
• What is the ideal hormetic regime - intensity,
  frequency?

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Aging hormetically
Brian Clark
Anuresh Suresh Rattan

• 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,......