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Extramural Papers of the Month

April 2010

Aging Protein Function Revealed

An NIEHS-funded research team has discovered that the protein sestrin plays a key role in regulating aging and metabolism.

The work was carried out in fruit flies bred with an inactivated sestrin gene. The fruit flies began showing signs of premature aging at 20 days of age, which is roughly equivalent to 20 years in humans. The flies began accumulating high levels of triglycerides, showed signs of muscle degeneration, and had a high percentage of defective mitochondria in their muscle cells. Much of this damage was prevented by providing vitamin E as a source of antioxidants, replacing one of the natural functions of sestrin.

Sestrin is known to inhibit an enzyme called TOR, or target of rapamycin, an immunosuppressant drug used in organ transplant patients that has been shown to extend the lifespan of healthy mice up to 14 percent. However, the effects of the long-term use of rapamycin are not well known. The team also found that sestrin activates another protein called AMPK that is also activated by caloric restriction, which has been shown to increase the life span of several animals.

Mammals have three types of sestrin proteins, all very similar. The team plans additional research with mice aimed at determining whether sestrins or molecules that activate sestrin production could be useful in preventing or treating mitochondrial dysfunctions that lead to a number of chronic diseases and dysfunctions.

Citation: Lee JH, Budanov AV, Park EJ, Birse R, Kim TE, Perkins GA, et al. ( NIEHS 2010. Sestrin as a feedback inhibitor of TOR that prevents age-related pathologies. Science 327(5970):1223-8.

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Living Near a Major Roadway Linked with Atherosclerosis

NIEHS grantees presented the first epidemiologic evidence supporting the idea of a chronic vascular response to exposure to particulate matter air pollution. They found that the progression of atherosclerosis was more than twice as fast for people living within 100 meters of a major highway in Southern California.

The team used data from five Los Angeles-based double-blind randomized clinical trials that assessed effects of various treatments on the change in carotid artery intima-media thickness (CIMT), a marker for sub-clinical atherosclerosis. They used models to estimate the home outdoor concentrations of particulate matter air pollution and classified the subjects' homes by proximity to traffic-related pollution. Particulate matter pollutions levels and traffic proximity were positively associated with CIMT progression.

The researchers warn that it may be premature to conclude that particulate matter pollution and its constituents are the sole cause of the progression of the arterial thickening. Atherosclerosis results from complex processes that may include a combination of various urban pollutants, host factors, and pathways that ultimately lead to the association.

Given the leading role of heart disease as a cause of death in most westernized countries and the growing contribution in developing countries, these findings may be of high public health relevance. Further investigations need to focus on susceptible groups and follow-up of cohorts to investigate the effect of air pollution on the progression of CIMT.

Citation: Künzli N, Jerrett M, Garcia-Esteban R, Basagaña X, Beckermann B, Gilliland F, et al. ( NIEHS 2010. Ambient air pollution and the progression of atherosclerosis in adults. PLoS One 5(2):e9096.

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Blood Type and Pancreatic Cancer Linked

A new study funded in part by NIEHS reports novel findings related to the basic biology of pancreatic cancer, confirming that blood type is related to pancreatic cancer. More specifically, people with any blood type other than O are at a slightly increased risk for pancreatic cancer, a relatively rare, but usually fatal cancer.

The team determined ABO genotypes in about 1500 cases and controls from twelve cohorts of participants enrolled in the Pancreatic Cancer Cohort Consortium (PanScan).

These findings are important because they provide some insights into the biology of the disease. Previous research found that normal pancreas cells carry a different pattern of the blood-type antigens on their surface than do pancreatic cancer cells. This suggests that changes in the ABO gene activity may occur as the cells become cancerous, possibly by interfering with the cells' ability to signal and adhere to one another and with the immune system's ability to recognize them as abnormal cells. The researchers point out that the ABO gene could also merely be a marker for other nearby genes that are more directly involved in cancer development.

The association between blood type and pancreatic cancer risk provides a new line of investigation for understanding the mechanisms involved in pancreatic cancer development.

Citation: Wolpin BM, Kraft P, Gross M, Helzlsouer K, Bueno-de-Mesquita HB, Steplowski E, et al. ( NIEHS 2010. Pancreatic cancer risk and ABO blood group alleles: results from the pancreatic cancer cohort consortium. Cancer Res 70(3):1015-23.

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African Ancestry and Asthma

In the first genome-wide association study focused on populations of African descent, a multi-institutional team of researchers identified 3 single nucleotide polymorphisms (SNPs) that are biologically relevant to asthma and may help to explain at least part of the profound disparities in asthma observed in different populations.

Asthma is a biologically complex disease. It is affected by many non-biological issues as well as environmental, social, cultural, and economic factors; however, these factors have not proven to be the cause of the striking ethnic disparities. This study was designed to identify genes that might explain at least part of the racial disparity seen in the incidence of the disease.

Two populations of African descent were included in this study. One group consisted of 935 African-American and control subjects and the other consisted of 929 African Caribbean asthmatics and their family members. The study yielded three highly statistically significant SNPs for genes that are biologically relevant to asthma. Additional studies on groups from the U.K. and Germany did not find the same associations. Similar associations were also not found in four other case-control studies in African Americans.

The authors conclude that additional studies of these three candidate genes are warranted to confirm the possible uniqueness of the observed associations to populations of African descent. Because of the difficulty in finding SNP-for-SNP replication in all of the African populations, they suggest conducting fine-mapping studies around these three genes.

Citation: Mathias RA, Grant AV, Rafaels N, Hand T, Gao L, Vergara C, et al. ( NIEHS 2010. A genome-wide association study on African-ancestry populations for asthma. J Allergy Clin Immunol 125(2):336-346.e4.

(Jerry Phelps is a program analyst in the NIEHS Division of Extramural Research and Training.)

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