Molecular pathology of aging and its implications for senescent coronary atherosclerosis

University of Arkansas at Little Rock, Little Rock, Arkansas, United States
Current Opinion in Cardiology (Impact Factor: 2.7). 10/2005; 20(5):399-406. DOI: 10.1097/01.hco.0000175517.50181.89
Source: PubMed


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.

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    • "The normal aging human brain is known to accumulate AGEmodified CNS components within neurons and glial cells [236] [237] as well as in senile plaques [238], 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 [239] [240]. There are much data to support the "
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    • "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). "
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    • "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. "
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