Molecular mechanisms of anti-ageing hormetic effects of mild stress….
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Transcript of Molecular mechanisms of anti-ageing hormetic effects of mild stress….
Suresh Rattan
Editor-in-Chief, Biogerontology
Danish Centre for Molecular Gerontology
Department of Molecular BiologyUniversity of AarhusDenmark
Molecular mechanisms of anti-ageing hormetic effects of mild
stress….
Approaching ageing/anti-ageing scientifically....
• Describing the phenomenon
• Explanation/conceptualisation
• Intervention
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
Describing the phenomenon…
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 termedVIRTUAL GERONTOGENES (Rattan, 1995: FASEB J.)
Smoking
Oxygen Metabolism
Cell
UV- lightRadiation
Molecular struggle for survival against constant onslaught...
Pollution
Mitochondria
Positive correlations withspecies lifespan
DNA repairAntioxidant levelsCell proliferation potentialCellular 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/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.
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.
Induction of defence and repair pathways by mild stress has beneficial effects for cells and organisms.
This effect is known as
HORMESIS.
Mild stress...
Exercise as a paradigm for hormesisBiochemically, 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.
Inactive HSF1
HSP
Refolding
Proteasome
DNA binding
Translation
Functional protein
Activation &
translocation
Degradation
Degradation
Denatured protein Substrate binding
Transcription
Lysosome
Intracellular stress
Extracellular stressHSF1
Heat shock response in a cell
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 oxidatively-
and 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?
Technical backboneGunhild 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,......
Aging hormetically Brian ClarkAnuresh & Suresh Rattan