A critical component of the homeodynamic property of living systems is their capacity to respond to stress. In this context, the term â��stressâ�� is defined as a signal generated by any physical, chemical or biological factor (stressor), which in a living system initiates a series of events in order to counteract, adapt and survive. While successful and compensatory responses to low doses of stressors improve the overall homeodynamics of cells and organisms, an incomplete or failed homeodynamic response leads to the damaging and harmful effects of stress, including death.
Therefore, the idea is that if biological systems are intentionally exposed to mild stress, so that their homeodynamic pathways of maintenance and repair get challenged, and in response become activated, this should lead to achieving beneficial hormetic effects, including health- and longevity-promoting effects. Thus hormesis in aging is defined as the life supporting beneficial effects resulting from the cellular responses to single or multiple rounds of mild stress.
HORMETINS AS MODULATORS OF AGEING, DIFFERENTIATION AND WOUND HEALING
Various natural or synthetic compounds which can bring about biologically beneficial hormetic effects by activating one or more pathways of stress response, are termed as hormetins. Actually, hormetin can be any condition which challenges one or more stress response pathways in the cells, and is potentially hormetic in strenghÂ´thening the homeodynamic space. Three main categories of hormetins can be:
-Physical hormetins - exercise (running, walking, weight lifting etc), temperature (hot sauna or cold baths), irradiation (sunlight, solar-treatments)
- Nutritional hormetins - food restriction (fasting, low calorie diet), spices (turmeric, clove), zinger, garlic, onion, and micronutrients (zinc). There are many many more nutritional hormetins yet to be identified, and synthetic hormetins yet to be synthesized.
- Mental hormetins - mental activity (reading, puzzle solving, chess), public speaking/performance, focussed attention (meditation), "falling" in love....
Accordingly, several dietary components, such as resveratrol, vitamins, and trace elements and minerals including iron, iodine, fluorine, selenium and copper and zinc are potential hormetins. Other potential hormetins are the so-called antioxidants such as alpha lipoic acid and coenzyme Q10 which, owing to their pro-oxidant activities in producing hydrogen peroxide, induce antioxidative defensive responses and ultimately may bring about beneficial effects. Another hormetin is a plant growth factor kinetin, which we have snown to have several anti-ageing effects in human skin cells, promotes the differentiation of keratinocytes by inducing stress response pathways.
Similarly, some components of certain medicinal plants used frequently in the traditional Chinese medicine and in the Indian Ayurvedic system of medicine are claimed to have anti-aging effects, which appear to be achieved through hormetic pathways. For example, celasterols and paeoniflorin present in some medicinal herbs have cytoprotective effects and induce HSP in human cells. Leaf extracts of Ashwagandha (Withania somnifera) also induce HSP synthesis in mammalian cells, which may be one of the reasons for its observed beneficial medicinal effects.
Curcumin: Another potential hormetin being tested for its biological effects is curcumin or diferuloylmethane. It is the active component in the commonly used food spice turmeric, and is derived from the roots of Curcuma longa. Curcumin is a co-inducer of HSP and has wide ranging biological effects depending on its dosage. We have undertaken studies to check the hormetic effects of curcumin on human keratinocytes and fibroblasts. We have previously reported that at lower doses (0.3 and 1 Î¼M) curcumin stimulates proteasome activity, enhances HSP induction after HS, and stimulates sodium pump activity. We are now extending these studies to find out long term effects of curcumin treatment on cellular aging, differentiation and angiogenesis.
Rosmarinic acid: Another potential hormetin that we are testing is the rosmarinic acid (RA), which is a phenolic compound present in several medicinal plants such as those from the Labiatae family, for example Salvia officinalis (common sage) and Rosmarinus officinalis. We are now in the process of testing further the short term and the long terms effects of the hormetin RA on aging, wound healing, angiogenesis and differentiation of human cells. Our preliminary results show that human skin fibroblast cultures grown continuously in the presence of 20 Î¼M RA for 50 days have a significant (33%) reduction in the number of cells showing senescence-specific Î²-galactosidase marker. Furthermore, there was 50% reduction in the proportion of enlarged cell population with high levels of green autofluorescence in RA-treated cultures, as measured by flow cytometery.
In conclusion, using human fibroblasts, keratinocytes, endothelial cells and bone marrow mesenchymal stem cells we have provided evidence in support of the view that hormesis can be applied successfully to aging research and intervention. This includes the effects of mild HS on various parameters of cellular aging and other functional characteristics, such as differentiation, wound healing and angiogenesis.
Therefore, it is important to determine how various components of the homeodynamic machinery respond and interact during stress-induced hormesis, and how relatively small individual hormetic effects lead to a significant biological amplification that results in an overall improvement of the living system. Such understanding will be essential for developing effective means of slowing down ageing and preventing the onset of age-related diseases.
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