A Sirtain Regulator of Longevity & Metabolism It has long been known that caloric restriction increases lifespan in numerous organisms from yeast to mammals1,2. I know you are thinking, “Mind and Muscle readers aren’t interested in calorie restriction as a means of life extension.” That may be true, however I encourage you to continue reading as this article will articulate the relationship between life extension and metabolic regulation as well as body composition. Studies in yeast identified as class of genes which are critical in caloric restriction induced life extension known as Sirtuins3. Recent genetic screens identified seven mammalian orthologs, Sirt1-7 of which only Sirt1 has been extensively studied. Sirt1 is an NAD+ dependent nuclear deacetylase involved both in chromatin remodeling and the regulation of a variety of critical transcription factors, including but not limited to HNFa, p53, Fox01, and NF-kB4.
So why do we care? While it is true that Sirt1 was originally implicated in life extension, recent data has shown that it has a critical role in glucose homeostasis, insulin sensitivity, lipolysis, as well as the prevention of fat storage. What is potentially most interesting to readers of M&M is that Sirt1 has tissue specific effects, and can be activated using small molecules in the absence of caloric restriction in vitro. There is data to indicate that Sirt1 is a master metabolic regulator, which promotes the lean phenotype through diverse pathways in multiple tissues.
White Adipose Tissue
The activation of Sirt1 in white adipose tissue (WAT) represses PPARg transcriptional activity5. In WAT, PPARg activates transcription of genes involved in fat storage . Sirt1 binds to PPARg and PPARg corepressors NcoR and SMRT. The Sirt1/PPARg/NcoR complex binds to PPARg response elements (PPRE) which are specific DNA sequences found in the promoter region of PPARg target genes. The binding of this complex prevents the transcription of a number of genes involved in fat storage and in turn increases lipolysis. Though supplementation is outside the scope of this article, it should be noted that in vitro a number of natural products including resveratrol and quercitin have shown to be potent activators of Sirt16. Lipolysis in white adipocytes is potentiated by treatment with resveratrol, but only in the presence of catecholamines. This is suggestive of a role for sympathetic nervous system signaling in Sirt1 activation.
Who cares about hepatocytes, you ask? Frankly, everyone should be but we won’t get into that just now. Rogers et. al. using an ingenious series of experiments demonstrated that Sirt1 physically associates with PPARg coactivator 1 (PGC-1a), a transcriptional coactivator that controls metabolism at the level of gene transcription7. Sirt1 deacetylates PGC-1a, which in turn upregulates the transcription of genes involved in gluconeogenesis and suppresses the transcription of genes involved in glycolysis. Rogers et. al. went on to show that the increased activity of PGC-1a mediated by Sirt1 deacetylase activity is dependent on changes in pyruvate and NAD+ concentration. Sirt1 in the liver is thought to function as a sensor interpreting flux of NAD+ concentration within the hepatocyte. Though it has long been known that sirtuins were dependent on NAD+ for their activity, this work established a firm connection between these genes known to be involved in longevity, and the ability to regulated cellular metabolism in response to changes in nutrient status.
Pancreatic Beta Cells
Pancreatic beta cells for the uninitiated are the insulin producing cells contained in the pancreas. Recently, Moynihan et. al. developed a transgenic mouse model known as BESTO mice which overexpress Sirt1 specifically in beta cells8. These mice show improved glucose tolerance as a function of increased glucose stimulated insulin secretion. This may seem surprising when we consider the role of Sirt1 in hepatocytes described above. As one may expect, overexpression of PGC-1a in pancreatic beta cells results in the transcription of gluconeogenic genes and repression of genes involved in glucose uptake and glycolysis. This leads to a decrease in ATP levels and inhibits glucose stimulated secretion of insulin. Given the interaction of Sirt1 and PGC-1a in hepatocytes, one would expect the BESTO phenotype to be similar to that of PGC-1a overexpressing beta cells. However Moynihan et. al., found an increase of ATP levels in glucose stimulated beta cell from BESTO mice instead of a decrease. They also found a concomitant down regulation of uncoupling protein (UCP) 2 in BESTO beta cells in which Sirt1 is activated.
Strangely enough this casts a monkey wrench in to the role of reactive oxygen species (ROS) and SIRT1 in aging and longevity. UCPs uncouple oxygen consumption from ATP production, thus reducing the formation of ROS. Both ROS and SIRT1 appear to have a strong role in aging but as of yet no connection between the two has been made. In theory downregulation of UCPs would increase the amount of ROS produced thereby promoting the aging process, while upregulation of UCPs would decrease ROS production leading to enhanced longevity. Unfortunately, there is no data beyond what I have just told you to reconcile this apparent discrepancy so we will simply have to wait and see.
Taken together the findings indicate that Sirt1 maybe a master regulator of both metabolism and aging. Unfortunately for the M&M crowd the role of Sirt1 in the brain and muscle tissue is yet to be described, though there is a known neuroprotective effect for Sirt19. It is very tempting to hypothesize that Sirt1 will have similar functions in these tissues as it does to liver, but that of course needs to be determined experimentally. I do predict that in the next few years Sirt1 will become the topic of much discussion both in the scientific world and in the health and fitness community, given its clear role in supporting the lean phenotype as well as longevity.
1. Weindruch R & Walford RL. The retardation of aging and diseases by dietary restriction Thomas, CC: Springfield, IL 1998
2. Koubova J & Guarente L. How does calorie restriction work? Genes Dev 2003; 17: 313?321.
3. Kaeberlein M, McVey M & Guarente L. The SIR2/3/4 complex and SIR2 alone promote longevity in Saccharomyces cerevisiae by two different mechanisms. Genes Dev 1999; 13: 2570?2580.
4. Leibiger B & Berggren P. Sirt1: a metabolic master switch that modulates lifespan. Nature Medicine 12, 34 – 36 (2006)
5. Picard F et. al. SIRT1 promotes fat mobilization in white adipocytes by repressing PPAR. Nature 2004; 429: 771?776.
6. Howitz KT et. al. Small molecule activators of sirtuins extend Saccharomyces cerevisiae lifespan. Nature. 2003 Sep 11;425(6954):191-6.
7. Rodgers JT et. al.Nutrient control of glucose homeostasis through a complex of PGC-1alpha and SIRT1. Nature. 2005 Mar 3;434(7029):113-8.
8. Moynihan KA et. al. Increased dosage of mammalian Sir2 in pancreatic beta cells enhances glucose-stimulated insulin secretion in mice. Cell Metab. 2005 Aug;2(2):105-17
9. Raval AP, Dave KR, Perez-Pinzon MA. Resveratrol mimics ischemic preconditioning in the brain. J Cereb Blood Flow Metab. 2005 Dec 14; [Epub ahead of print]