Cardiovascular disease is the leading cause of morbidity and mortality in western countries. Advanced glycation end products (AGEs) are bioactive molecules implicated in the pathogenesis of atherosclerosis and cardiovascular disease. Major sources of systemic AGEs are endogenous AGEs generated in the body and exogenous AGEs found in foods. The western diet is rich in AGEs that are formed when food is processed at high temperatures. AGEs play a role in atherosclerosis by cross-linking collagen in vessel walls, increasing oxidation of low-density lipoprotein, and increasing inflammation through activation of the receptor for AGE (RAGE). Circulating isoforms of RAGE include endogenous secretory RAGE (esRAGE), a splice variant of RAGE that is secreted into blood and lacks the transmembrane and cytoplasmic portion of the receptor, and truncated forms of RAGE that have been cleaved from the cell surface. Based upon knowledge of the AGE-RAGE pathway and our preliminary data, we hypothesize that older people with elevated serum AGEs, sRAGE, and esRAGE are at greater risk of developing adverse cardiovascular outcomes, such as coronary heart disease, heart failure, stroke, and cardiovascular disease mortality. We propose to characterize the relationship between AGEs and circulating RAGE with cardiovascular outcomes in the NIH-supported Health, Aging and Body Composition (Health ABC) Study, a community-based prospective study of aging. Serum AGEs and circulating RAGE will be measured at enrollment and examined in relation to prevalent cardiovascular disease and to incident cardiovascular diseases that have been assessed over ten years of follow-up. Serum AGEs and circulating RAGE will also be examined in relation to aortic pulse wave velocity, abnormal glucose metabolism, and markers of inflammation. The proposed study will determine whether or not serum AGEs are a major risk factor for cardiovascular disease and will provide insight into the biological mechanisms by which serum AGEs and their circulating receptors may be involved in the pathogenesis of cardiovascular disease. AGEs are a potentially modifiable risk factor, as circulating AGEs can be lowered by dietary modification and by pharmacological intervention with AGE inhibitors or AGE-breakers.

Public Health Relevance

This project is relevant to public health as it aims to characterize the relationship between advanced glycation end products, bioactive compounds found in high amounts in the western diet, and cardiovascular disease in older adults.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL094507-03
Application #
8100250
Study Section
Cardiovascular and Sleep Epidemiology (CASE)
Program Officer
Hasan, Ahmed AK
Project Start
2009-07-15
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$410,000
Indirect Cost
Name
Johns Hopkins University
Department
Ophthalmology
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Semba, Richard D; Ferrucci, Luigi; Sun, Kai et al. (2016) Low Plasma Klotho Concentrations and Decline of Knee Strength in Older Adults. J Gerontol A Biol Sci Med Sci 71:103-8
Chalhoub, Didier; Marques, Elisa; Meirelles, Osorio et al. (2016) Association of Serum Klotho with Loss of Bone Mineral Density and Fracture Risk in Older Adults. J Am Geriatr Soc 64:e304-e308
Shardell, Michelle; Semba, Richard D; Kalyani, Rita R et al. (2015) Serum 25-Hydroxyvitamin D, Plasma Klotho, and Lower-Extremity Physical Performance Among Older Adults: Findings From the InCHIANTI Study. J Gerontol A Biol Sci Med Sci 70:1156-62
Semba, Richard D; Ferrucci, Luigi; Bartali, Benedetta et al. (2014) Resveratrol levels and all-cause mortality in older community-dwelling adults. JAMA Intern Med 174:1077-84
Semba, Richard D; Gebauer, Sarah K; Baer, David J et al. (2014) Dietary intake of advanced glycation end products did not affect endothelial function and inflammation in healthy adults in a randomized controlled trial. J Nutr 144:1037-42
Semba, Richard D; Moghekar, Abhay R; Hu, Jason et al. (2014) Klotho in the cerebrospinal fluid of adults with and without Alzheimer's disease. Neurosci Lett 558:37-40
Semba, R D; Crasto, C; Strait, J et al. (2013) Elevated serum fibroblast growth factor 21 is associated with hypertension in community-dwelling adults. J Hum Hypertens 27:397-9
Semba, R D; Ang, A; Talegawkar, S et al. (2012) Dietary intake associated with serum versus urinary carboxymethyl-lysine, a major advanced glycation end product, in adults: the Energetics Study. Eur J Clin Nutr 66:3-9
Semba, Richard D; Sun, Kai; Egan, Josephine M et al. (2012) Relationship of serum fibroblast growth factor 21 with abnormal glucose metabolism and insulin resistance: the Baltimore Longitudinal Study of Aging. J Clin Endocrinol Metab 97:1375-82
Crasto, Candace L; Semba, Richard D; Sun, Kai et al. (2012) Relationship of low-circulating ""anti-aging"" klotho hormone with disability in activities of daily living among older community-dwelling adults. Rejuvenation Res 15:295-301

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