Cellular Senescence, Vascular Disease, and Aging

Abstract

Longevity is a vascular question, which has been well expressed in the axiom that man is only as old as his arteries. To a majority of men death comes primarilyn 2030, when all of the baby boomer generation will be Ն65 years of age, nearly 1 in 5 US residents is expected to be Ͼ65 years of age. By 2050, this age group is projected to more than double in number, from 38.7 million in 2008 to an estimated 88.5 million (Figure 1). 2 Similarly, the population Ն85 years of age is expected to more than triple, from 5.4 million in 2008 to 19 million by 2050. 2 With this aging of the population, the number of people at risk for adverse cardiovascular events, in particular atherothrombosis, stroke, myocardial infarction, and heart failure, will increase dramatically. The importance of these projections is underscored by the fact that currently, although octogenarians represent only 5% of the US population, they account for 20% of all hospitalizations for myocardial infarction and 30% of all myocardial infarction-related deaths. 3 A Looming Aging EpidemicDespite their increased risk of adverse cardiac events, elderly patients are less likely to receive appropriate therapy. This paradox is perhaps related to the fact that elderly patients with cardiovascular disease are more likely to be frail. 4 Heightened concerns that frail older patients may be more susceptible to adverse side effects, particularly in the setting of complex pharmacotherapy, can lead to efficacious therapies being withheld. [5][6][7] As an example, although the relative risk reduction of cholesterol-lowering therapy may be equivalent in the young and elderly, the absolute risk reduction, or number of adverse cardiovascular events prevented, may be significantly greater in elderly patients. 8 This serves as a sobering reminder that even though many exciting advances that might help fight the ravages of old age appear to be at the point of clinical translation, at the present time, clinicians must remain vigilant to ensure the delivery of best medical care to all elderly patients.In this 2-part review, we discuss important pathobiological changes that occur with aging in the cardiovascular system and how they relate to clinical outcomes. Furthermore, we explore areas of scientific progress that may, optimistically, be translatable into targeted clinical strategies to help offset the looming impact of the aging epidemic on morbidity, mortality, and healthcare resource use. Readers should be aware that we do not propose to exhaustively discuss all potential biological players in this complex arena. Rather, we will attempt to selectively highlight novel and important broad aspects of basic and cellular biology and clinical medicine that are of significant relevance to this field. In this first installment, we focus at the basic-science level on key advances in our understanding of the cellular aging process and look to extend these observations to the aging adult vasculature. Telomere Shortening and Cellular Senescence Mechanisms of Telomere-Telomerase Fun...

Molecular Biology of Atherosclerosis

“…Careful examination of the coronary arteries in humans with this syndrome show that there are atherosclerotic lesions with cholesterol crystals and activated macrophages, but the degree of lipid accumulation is less and there is more fibrous tissue and calcium in the intima compared with usual plaques. There was also a unique adventitial thickening with pronounced fibrosis that may have contributed to the stenosis (942,1344). Whether impaired endothelial repair leads to this remarkably premature atherosclerosis or some other mechanism is the underlying cause remains unknown.…”

Testosterone delays vascular smooth muscle cell senescence and inhibits collagen synthesis via the Gas6/Axl signaling pathway

“…Cellular senescence is considered to play a causal role in the pathogenesis and development of vascular aging (Kovacic et al 2011a, b;Minamino and Komuro 2007). Cellular senescence causes disorders of ECM metabolism, initiates vascular remodeling, and finally results in a reduction in compliance and an increase in stiffness (Kovacic et al 2011a;Minamino and Komuro 2007). The circulating level of testosterone decreases with age gradually.…”

Preterm Birth and Hypertension Risk

“…Like other mitotic cells, vascular cells may undergo replicative senescence driven by telomere shortening or stressinduced premature senescence 98,99 ; senescent vascular cells have decreased proliferative and angiogenic capacity. Importantly, oxidative stress has been linked to accelerated telomere shortening, DNA damage, senescence of endothelial and vascular smooth muscle cells, and atherosclerosis.…”

“…Importantly, oxidative stress has been linked to accelerated telomere shortening, DNA damage, senescence of endothelial and vascular smooth muscle cells, and atherosclerosis. [99][100][101] Telomere length has been shown to be similar in low birth weight versus control infants assessed at birth 102 ; however, another study demonstrated that telomere length was decreased in 5-year olds that were born with low birth weight, 103 which together suggests accelerated attrition. To our knowledge, the effect of preterm birth on telomere shortening, however, has not been reported.…”