Awards

Drs. Schmidt, Ramasamy and Yan Awarded $8M NIA Grant to Investigate Biology of Aging.

The Division of Surgical Science in the Department of Surgery of the Columbia University College of Physicians and Surgeons, which has been studying the biological pathways of degeneration in the human body for nearly 15 years, has recently received more than $8M from the National Institute on Aging (NIA) to study age-related cardiovascular disease.

The U.S. census tells us the number of Americans over 65 is expected to reach 21 percent of the total population by the year 2050—compared to the 12 percent reported by the Census in 2005. A proportionate increase of age-related cardiovascular disease and an accompanying crisis in public health will likely accompany this spike in the population of older Americans.

Ann Marie Schmidt, MD, Principal Investigator of the program project awarded to the Columbia University research team says the process of natural aging is the chief contributor to cardiovascular disease. "The major factor underlying enhanced propensity to cardiovascular diseases is advancing age itself," she says. It is this process of innate aging that is accelerated and greatly modified by superimposed factors such as diabetes, hypertension, obesity and hyperlipidemia.

The focus of the newly-funded grant is to dissect the molecular mechanisms that cause blood vessels and the heart itself to age.

The research will comprise a series of three distinct projects probing the aging effects on heart and endothelial cells arising from two biological pathways, that of the enzyme aldose reductase and that of advanced glycation endproducts (AGEs) and the RAGE cell-surface receptor. Researchers participating in the protocol are Drs. Ann Marie Schmidt, Ravi Ramasamy and Shi-Fang Yan. Using multiple mouse models and heart and vascular cells retrieved from old and young rats and mice, the team's goal will be to answer the question of whether the damage caused by two pathways prime the aged heart for increased cardiovascular dysfunction.

The project abstract follows below.

Research Abstract for NIA-Funded Program Project Investigating of Age-Related Cardiovascular Disease

Even after accounting for the major aging-associated diseases, the major factor underlying the enhanced propensity to cardiovascular diseases in human subjects is advancing age itself.

Findings uncovered by this program project team highlight new concepts in the biology of aging:

First, the level and activity of the polyol pathway enzyme aldose reductase (AR) is increased in heart, particularly in endothelial cells and cardiomyocytes. Multiple consequences ensue from upregulation of AR, including generation of diacylglycerol (DAG) and activation of Protein Kinase C (PKC); and production of 3 deoxyglucosone (3-DG) and methylglyoxal (MG), precursors of Advanced Glycation Endproducts (AGEs).

Second, accumulation of AGEs and expression of Receptor for Advanced Glycation Endproducts (RAGE) is increased in healthy aged vs. young human and Fischer 344 rat hearts, especially in endothelial cells and cardiomyocytes. The interaction of AGE with RAGE is linked intimately to cellular and tissue perturbation and tissue injury.

Our Program is built on the hypothesis that AR primes aged tissues for amplified cardiovascular dysfunction in the basal state. Upon superimposed I/R stress, at least in part via enhanced AGE generation and RAGE expression, increased biochemical and molecular signals amplify injury in the aged heart. We will dissect the influence and intersection of these pathways in aging and I/R stress, and determine the key signaling pathways that modulate expression of pro-inflammatory and prothrombotic genes in basal aging and I/R-stressed cardiovasculature.

This proposed program will consist of three independent but highly integrated projects, led by a team of project leaders with a long history of collaboration in cardiovascular biology. Projects 1 & 2 will probe the role of AR pathway and RAGE in the intact heart, respectively. Project 3 will probe AR and RAGE in isolated EC and cardiomyocytes.

These studies will address the questions: does basal modulation of AR and RAGE in aging prime the aged heart and, particularly, in endothelial cells and cardiomyocytes, for magnified injury upon I/R stress? Are these pathways, alone, or in combination, novel targets for cardiovascular protection in aging?

The proposed program project will be supported by three cores: Administrative and Biostatistics; Animal Experimentation and Analysis; and Transgenic Mouse and Animal Management. These endeavors will shed light on mechanisms linking aging to enhanced vulnerability to I/R stress, and, potentially, uncover new therapeutic interventions to suppress I/R injury in the aging cardiovascular system.