Molecular pathology of aging and its implications for senescent coronary atherosclerosis.
OBJECTIVE
This review highlights common mechanisms of organismal aging and inflammatory coronary atherosclerosis.


RESULTS
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.


CONCLUSIONS
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.
McEwen
Joan E
JE
Geriatric Research and Education Clinical Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
Zimniak
Piotr
P
Mehta
Jawahar L
JL
Shmookler Reis
Robert J
RJ
D000375:Aging / Q000378:metabolism / Q000473:pathology*; D000818:Animals; D003324:Coronary Artery Disease / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008954:Models, Biological; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
D007328:Insulin; D017382:Reactive Oxygen Species; D007334:Insulin-Like Growth Factor I