This review highlights common mechanisms of organismal aging and inflammatory coronary atherosclerosis.
A substantial body of evidence now indicates that aging is largely due to molecular damage inflicted by reactive oxygen species, electrophiles, and other reactive endobiotic and xenobiotic metabolites. Our understanding of genetic pathways regulating longevity began 12 years ago with the discovery that a developmental-arrest program in the nematode Caenorhabditis elegans also has marked effects on adult lifespan. This pathway, closely related to the insulin and insulinlike growth factor-signaling pathways of mammals, modulates longevity and stress resistance in several model organisms. Insulin-like signaling also has an impact on redox signaling, antioxidant defenses, and metabolic generation of oxidative stress. Recently, additional signaling pathways--involving Sirtuins, AMP kinase, Jun N-terminal kinase 1, and other master regulatory proteins--have been implicated in longevity and stress-resistance mechanisms. The inflammatory process involves acute production of reactive oxygen species by specialized cells responding to infection, exposure to toxins or allergens, cell damage, hypoxia, ischemia/reperfusion, and other factors, initiating signaling through several of these pathways. Free radical chain reactions arise from lipid oxidation and generate oxidized low-density lipoprotein, a powerful inflammatory signal and potentiator of atherosclerosis. Oxidized low-density lipoprotein accumulates in atherosclerotic arteries, particularly in rupture-prone regions. Inflammation involving oxidative stress, by way of the production of reactive oxygen species, is a hallmark of coronary atherosclerosis.
Common pathways underlie both organismal aging and tissue-autonomous senescent pathologic processes, such as coronary atherosclerosis. The mechanisms discovered in model organisms may lead to pharmacotherapeutic interventions.
"The normal aging human brain is known to accumulate AGEmodified CNS components within neurons and glial cells   as well as in senile plaques , and these are normally removed by a glial AGE-receptor system. However, while the rate of formation of AGE/ALEs and oxidative processes is relatively low in normal physiological conditions it increases with age in concert with decreased activity of endogenous antioxidant mechanisms  . There are much data to support the "
[Show abstract][Hide abstract] ABSTRACT: The nervous system is a unique network of different cell types and comprises a variety of proteins, lipids, and carbohydrates that have an important interplay with all major organs in the body. Homeostatic regulation of nervous tissue turnover must be carefully controlled, taking into account interactions of the nervous, endocrine, and immune systems. Clinical conditions affecting the nervous system range from mild cognitive perturbations such as headache, to life-threatening acute courses such as meningitis and glioblastoma, and to chronic neurodegenerative diseases such as multiple sclerosis. One unifying feature in normal developmental or homeostatic functions and clinical dysfunctions within the nervous system is redox regulation, with an imbalance in oxidative/carbonyl stress versus antioxidants being characteristic of pathological conditions. In this review we consider the state of current knowledge regarding structural, genetic, proteomic, histopathological, clinical, and therapeutic perspectives of oxidative and carbonyl stress within the nervous system.
"Reactive oxygen species (ROS), such as the superoxide anion ( ), hydrogen peroxide (H 2 O 2 ), and the hydroxyl radical @BULLETϪ O 2 (OH@BULLET), are produced as by-products of aerobic metabolism in mitochondria and can cause damage to DNA, lipids, and proteins (Harman 1956; Tyler 1975; Davies et al. 1982; Beckman and Ames 1998; Mecocci et al. 1999). This damage to macromolecules can accumulate with age (Barja 2004) and may contribute to senescence and degenerative diseases associated with aging (e.g., cardiovascular disorders, Parkinson's disease; Melov et al. 1999; McEwen et al. 2005; Wallace 2005). An elaborate defense system consisting of endogenous antioxidant enzymes such as catalase (CAT), superoxide dismutase (SOD), glutathione peroxidase (GPx), and numerous nonenzymatic antioxidants, including vitamins A, E, and C, glutathione (GSH), ubiquinone, melatonin, and flavonoids, exists to scavenge ROS and thereby prevent deleterious effects (Beckman and Ames 1998). "
[Show abstract][Hide abstract] ABSTRACT: Exercise increases metabolic rate and the production of reactive oxygen species (ROS) but also elevates protein turnover. ROS cause damage to macromolecules (e.g., proteins) and thereby contribute to aging. Protein turnover removes and replaces damaged proteins. The balance between these two responses may underlie beneficial effects of physical activity on aging. Effects of lifelong exercise on antioxidant enzyme activities and fractional synthesis rate of protein (FSRP) were examined at various ages (2-26 mo) in heart, liver, and muscle of mice that had been selectively bred for high wheel-running activity, housed with (S+) or without (S-) a running wheel, and their random-bred controls (C+) housed with running wheels. FSRP decreased with age and increased in muscle of young, but not old, activity-selected mice. Enzyme activity of superoxide dismutase and glutathione peroxidase decreased with age and showed a peak at 10 mo of age in liver. Selection for wheel-running activity did not affect antioxidant enzyme activity. Daily energy expenditure correlated positively with antioxidant levels in liver. This might indicate that oxidative stress (ROS production) increases with metabolic rate, driving upregulation of antioxidant enzymes. Alternatively, the elevated energy expenditure may reflect the energetic cost of elevated protection, consistent with the disposable-soma hypothesis and with other studies showing positive links between energy expenditure and life span. Long-term elevations in voluntary exercise did not result in elevations in antioxidant enzyme activities or protein synthesis rates.
"Integrating the two lines of reasoning, we proposed an extension to the oxidative damage theory of aging. This hypothesis (Ayyadevara et al., 2005a; Ayyadevara et al., 2005b; McEwen et al., 2005) postulates that the lipid peroxidation chain reaction, initiated by a reaction of ROS (reactive oxygen species) with lipids, amplifies an original oxidative insult. The end products of lipid peroxidation, in particular electrophilic aldehydes exemplified by 4-HNE (4- hydroxynon-2-enal) are the effectors which act in parallel with ROS to cause molecular damage, and ultimately aging. "
[Show abstract][Hide abstract] ABSTRACT: The lipid peroxidation product 4-hydroxynon-2-enal (4-HNE) forms as a consequence of oxidative stress, and acts as a signaling molecule or, at superphysiological levels, as a toxicant. The steady-state concentration of the compound reflects the balance between its generation and its metabolism, primarily through glutathione conjugation. Using an RNAi-based screen, we identified in Caenorhabditis elegans five glutathione transferases (GSTs) capable of catalyzing 4-HNE conjugation. RNAi knock-down of these GSTs (products of the gst-5, gst-6, gst-8, gst-10, and gst-24 genes) sensitized the nematode to electrophilic stress elicited by exposure to 4-HNE. However, interference with the expression of only two of these genes (gst-5 and gst-10) significantly shortened the life span of the organism. RNAi knock-down of the other GSTs resulted in at least as much 4-HNE adducts, suggesting tissue specificity of effects on longevity. Our results are consistent with the oxidative stress theory of organismal aging, broadened by considering electrophilic stress as a contributing factor. According to this extended hypothesis, peroxidation of lipids leads to the formation of 4-HNE in a chain reaction which amplifies the original damage. 4-HNE then acts as an "aging effector" via the formation of 4-HNE-protein adducts, and a resulting change in protein function.
Mechanisms of Ageing and Development 03/2007; 128(2):196-205. DOI:10.1016/j.mad.2006.11.025 · 3.40 Impact Factor
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