Cellular Stress Response: A Novel Target for Chemoprevention and Nutritional Neuroprotection in Aging, Neurodegenerative Disorders and Longevity

Abstract

The predominant molecular symptom of aging is the accumulation of altered gene products. Moreover, several conditions including protein, lipid or glucose oxidation disrupt redox homeostasis and lead to accumulation of unfolded or misfolded proteins in the aging brain. Alzheimer's and Parkinson's diseases or Friedreich ataxia are neurological diseases sharing, as a common denominator, production of abnormal proteins, mitochondrial dysfunction and oxidative stress, which contribute to the pathogenesis of these so called "protein conformational diseases". The central nervous system has evolved the conserved mechanism of unfolded protein response to cope with the accumulation of misfolded proteins. As one of the main intracellular redox systems involved in neuroprotection, the vitagene system is emerging as a neurohormetic potential target for novel cytoprotective interventions. Vitagenes encode for cytoprotective heat shock proteins (Hsp) Hsp70 and heme oxygenase-1, as well as thioredoxin reductase and sirtuins. Nutritional studies show that ageing in animals can be significantly influenced by dietary restriction. Thus, the impact of dietary factors on health and longevity is an increasingly appreciated area of research. Reducing energy intake by controlled caloric restriction or intermittent fasting increases lifespan and protects various tissues against disease. Genetics has revealed that ageing may be controlled by changes in intracellular NAD/NADH ratio regulating sirtuin, a group of proteins linked to aging, metabolism and stress tolerance in several organisms. Recent findings suggest that several phytochemicals exhibit biphasic dose responses on cells with low doses activating signaling pathways that result in increased expression of vitagenes encoding survival proteins, as in the case of the Keap1/Nrf2/ARE pathway activated by curcumin and NAD/NADH-sirtuin-1 activated by resveratrol. Consistently, the neuroprotective roles of dietary antioxidants including curcumin, acetyl-L-carnitine and carnosine have been demonstrated through the activation of these redox-sensitive intracellular pathways. Although the notion that stress proteins are neuroprotective is broadly accepted, still much work needs to be done in order to associate neuroprotection with specific pattern of stress responses. In this review the importance of vitagenes in the cellular stress response and the potential use of dietary antioxidants in the prevention and treatment of neurodegenerative disorders is discussed.

Redox regulation of cellular stress response in multiple sclerosis

“…After a CNS injury, Hsp70 is synthesized at high levels and is present in the cytosol, nucleus, and endoplasmic reticulum [52]. Hsp60 chaperone proteins within mitochondria and, also, protect brain cells against ischemia and seizures in vivo, after viral-induced overexpression [18]. Hsp60 is encoded in the nucleus and resides mainly in the mitochondria [53].…”

“…To date this is the first report demonstrating changes in thioredoxin/thioredoxin reductase protein levels in MS patients. Thioredoxin (TRX) represents an intracellular redox regulator that has been shown to be important for the regulation of redox-sensitive transcription factors [18]. In its reduced state TRX can oxidatively reactivate inactive transcription factors such as Jun, Fos, AP-1, redox factor-1 (ref-1), and Nrf-2 [59].…”

“…The most studied is the SIRT1, a NAD+ dependent enzyme, involved in deacetylation of different proteins and in the regulation of energy metabolism and redox state. Sirtuins are involved in the regulation of important biological processes, such as apoptosis, cell differentiation, energy transduction, glucose homeostasis [18,65], as well as in mediating enhancement of synaptic plasticity and neurogenesis in response to exercise, dietary energy restriction, and other hormetic environmental factors [15,66]. Because of their roles in cellular stress responses, sirtuins would be expected to play particularly important roles in adaptive responses of neural cells to stress, such as that associated with the MS pathogenesis.…”

“…Neuroprotection mediated by SIRT1 activation has been demonstrated in axotomized dorsal root ganglion neurons and in neurons containing the Huntingtin gene mutation responsible for neurodegeneration in Huntington disease. Thus, pharmacological modulation of cellular stress pathways has emerging implications for the treatment of human diseases, including cardiovascular disease, cancer and neurodegenerative disorders [17,18].…”

Neuroprotective role of intermittent fasting in senescence-accelerated mice P8 (SAMP8)

“…Moreover, experimental rodent models of myocardial infarction and stroke on an intermittent fasting (IF) regimen exhibit increased resistance of heart and brain cells to ischemic injury. The beneficial effects of IF and caloric restriction (CR) result from at least two mechanisms, namely reduced oxidative damage and increased cellular stress resistance (Calabrese et al, 2008). In the epidemiology of neurodegenerative diseases, the incidence of sporadic Parkinson's disease (PD) and suggested that restriction of calorie intake is crucial for the prevention of learning and memory deficits in different animal models (Komatsu et al, 2008).…”