Environmental Factor, February 2010, National Institute of Environmental Health Sciences
Researcher Looks for Key to Longevity
By Thaddeus Schug
"Aging is one certainty in life that we can all count on, but not one that is particularly well understood by the scientific community," observed Xiaoling Li, Ph.D.(http://www.niehs.nih.gov/research/atniehs/labs/lst/mammalian/index.cfm), in her Jan. 7 talk at NIEHS. A principal investigator in the NIEHS Mammalian Aging Group, Li is hoping to shed light in this area of research by determining how environmental factors, such as nutrients, stresses, and hormones, impact the rate at which we age. Li presented some of her recent findings in a seminar titled "SIRT1 and Metabolic Diseases."
Li and her team study the sirtuin family of genes, which have been shown to extend the life span of yeast, worms, and flies in response to caloric restriction. The recent discovery that compounds such as resveratrol, a naturally occurring molecule found in the skin of grapes, activate sirtuins to extend lifespan has made headlines in popular television shows such as "60 Minutes" and in Newsweek magazine, noted event host Thomas Eling, Ph.D., a principal investigator in the NIEHS Laboratory of Molecular Carcinogenesis.
Looking at metabolism in SIRT1 knockout mice
Sirtuins are highly conserved NAD+-dependent protein deacetylases and/or ADP ribosyltransferases that function as master regulators of cellular metabolism. Li's research focuses primarily on SIRT1, which is the most conserved mammalian sirtuin. Knocking out SIRT1 completely in mice leads to severe developmental abnormalities and lethality, making it difficult to study the protein's true physiological functions. To bypass these issues, Li has created several tissue-specific SIRT1 knockout mouse models.
Li first created a liver-specific SIRT1 knockout (LKO) mouse because SIRT1 activity is dependent on nutritional status and the liver is a central metabolic organ. Li has utilized this model to define a new role for SIRT1 as a key regulator of lipid metabolism. Her team discovered that when LKO mice consume a high-fat diet, they display defective fatty acid metabolism, show signs of liver inflammation, and have altered insulin signaling. These metabolic abnormalities are indicative of a condition called metabolic syndrome. Li noted that nearly one in four adults in the U. S. suffers from metabolic syndrome, and worldwide estimates are over 2.1 billion.
Using microarray technology, Li's team determined that SIRT1 interacts with and regulates the lipid sensing nuclear receptor called the peroxisome proliferators-activated receptor alpha (PPAR∝). PPAR∝ signaling is responsible for regulating fatty acid metabolism. The researchers found that of 48 PPAR∝-regulated genes, 25 displayed lower expression in the knockout mouse livers. Li noted, "One mechanism by which SIRT1 regulates PPAR∝ in the liver appears to be through PGC-1 - a key coactivator for PPAR∝ and direct target of SIRT1." The study was recently published in the journal Cell Metabolism.
Li's group has found a similar metabolic profile in SIRT1 heterozygous mice challenged with a high-fat diet. These mice also have elevated steroid hormone levels and appear to age prematurely, which she demonstrated with a striking photograph comparing a heterozygous mouse to a liter-mate control.
Li concluded that gaining "a better understanding of the role of SIRT1 in specific tissues, will provide the molecular basis for development of novel anti-aging therapeutic targets."
Citation: Purushotham A, Schug TT, Xu Q, Surapureddi S, Guo X, Li X(http://www.ncbi.nlm.nih.gov/pubmed/19356714?ordinalpos=amp;=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DefaultReportPanel.Pubmed_RVDocSum) . 2009. Hepatocyte-specific deletion of SIRT1 alters fatty acid metabolism and results in hepatic steatosis and inflammation. Cell Metab 9(4):327-338. (See story(http://www.niehs.nih.gov/news/newsletter/2009/may/key-regulator.cfm))
(Thaddeus Schug, Ph.D., is a postdoctoral research fellow in the NIEHS Laboratory of Signal Transduction.)