ABSTRACT
Aging process is accompanied by hormonal changes characterized by an imbalance between catabolic hormones, such as cortisol and thyroid hormones which remain stable and hormones with anabolic effects (testosterone, insulin like growth factor-1 (IGF-1) and dehydroepiandrosterone sulphate (DHEAS), that decrease with age. Deficiencies in multiple anabolic hormones have been shown to predict health status and longevity in older persons.Unlike female menopause, which is accompanied by an abrupt and permanent cessation of ovarian function (both folliculogenesis and estradiol production), male aging does not result in either cessation of testosterone production nor infertility. Although the circulating serum testosterone concentration does decline with aging, in most men this decrease is small, resulting in levels that are generally within the normal range. Hormone therapy (HT) trials have caused both apprehension and confusion about the overall risks and benefits associated with HT treatment. Stress-response hormesis from a molecular genetic perspective corresponds to the induction by stressors of an adaptive, defensive response, particularly through alteration of gene expression. Increased longevity can be associated with greater resistance to a range of stressors. During aging, a gradual decline in potency of the heat shock response occur and this may prevent repair of protein damage. Conversely, thermal stress or pharmacological agents capable of inducing stress responses, by promoting increased expression of heat-shock proteins, confer protection against denaturation of proteins and restoration of proteome function. If induction of stress resistance increases life span and hormesis induces stress resistance, hormesis most likely result in increased life span. Hormesis describes an adaptive response to continuous cellular stresses, representing a phenomenon where exposure to a mild stressor confers resistance to subsequent, otherwise harmful, conditions of increased stress. This biphasic dose-response relationship, displaying low-dose stimulation and a high-dose inhibition, as adaptive response to detrimental lifestyle factors determines the extent of protection from progression to metabolic diseases such as diabetes and more in general to hormonal dysregulation and age-related pathologies. Integrated responses exist to detect and control diverse forms of stress. This is accomplished by a complex network of the so-called longevity assurance processes, which are composed of several genes termed vitagenes. Vitagenes encode for heat shock proteins (Hsps), thioredoxin and sirtuin protein systems. Nutritional antioxidants, have recently been demonstrated to be neuroprotective through the activation of hormetic pathways under control of Vitagene protein network. Here we focus on possible signaling mechanisms involved in the activation of vitagenes resulting in enhanced defense against functional defects leading to degeneration and cell death with consequent impact on longevity processes.
ABSTRACT
Multiple sclerosis (MS) is an autoimmune-mediated neurodegenerative disease with characteristic foci of inflammatory demyelination in the brain, spinal cord, and optic nerves. Recent studies have demonstrated not only that axonal damage and neuronal loss are significant pathologic components of MS, but that this neuronal damage is thought to cause the permanent neurologic disability often seen in MS patients. Emerging finding suggests that altered redox homeostasis and increased oxidative stress, primarily implicated in the pathogenesis of MS, are a trigger for activation of a brain stress response. Relevant to maintenance of redox homeostasis, integrated mechanisms controlled by vitagenes operate in brain in preserving neuronal survival during stressful conditions. Vitagenes encode for heat shock proteins (Hsp) Hsp32, Hsp70, the thioredoxin and the sirtuin protein systems. In the present study we assess stress response mechanisms in the CSF, plasma and lymphocytes of control patients compared to MS patients. We found that the levels of vitagenes Hsp72, Hsc70, HO-1, as well as oxidative stress markers carbonyls and hydroxynonenals were significantly higher in the blood and CSF of MS patients than in control patients. In addition, an increased expression of Trx and sirtuin 1, together with a decrease in the expression of TrxR were observed. Our data strongly support a pivotal role for redox homeostasis disruption in the pathogenesis of MS and, consistently with the notion that new therapies that prevent neurodegeneration through nonimmunomodulatory mechanisms can have a tremendous potential to work synergistically with current MS therapies, unravel important targets for new cytoprotective strategies.
