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