Aging is associated with a decline in physiological functions and a major incidence of several diseases. Among them, the risk of suffering from cancer dramatically increases with age. In fact, together with heart diseases, it represents the first cause of death in elder people. Besides the gradual accumulation of mutations with age, very little is known about the molecular mechanisms involved in the increased cancer incidence during aging. A prominent feature of cancer cells is their increased glucose uptake and reliance on aerobic glycolytic metabolism, a phenomenon described by Otto Warburg decades ago. Though it is a potential candidate for targeting against tumors, little is known about the mechanisms controlling it. Interestingly, such change in energy metabolism has been observed in several tissues during aging. However, the molecular pathways linking cancer, aging and metabolic reprogramming remain poorly characterized. Remarkably, we have recently identified the SIRT6 histone deacetylase as a central regulator of glycolytic metabolism: cells lacking SIRT6 undergo a dramatic metabolic switch, increasing lactate production while reducing mitochondrial respiration (Mostoslavsky et al., Cell 2006;Zhong et al., Cell 2010). More recently, we have found that SIRT6 is a potent tumor suppressor that inhibits cancer metabolism (Sebastian et al, Cell 2012). Inactivation of SIRT6 in cells leads to their transformation without the activation of a major oncogenic pathway and, in a mouse model of colorectal cancer, lack of SIRT6 increases the number, size and aggressiveness of tumors. Importantly, all these phenotypes are reversed by genetically or chemically inhibiting glycolysis, highlighting the driving role of glucose metabolism reprogramming in tumorigenesis. In this context, overexpression of SIRT6 in mice extends lifespan, a phenotype that is likely due to its tumor suppressor activity. Based on these findings, we hypothesize that decreased expression of SIRT6 during aging could switch glucose metabolism in tissues, favoring glycolytic-dependent tumorigenesis and tumor growth. In this grant, we will specifically: 1- Study the role of SIRT6 in metabolic reprogramming during aging. 2- Determine the role of SIRT6 as a tumor suppressor in aging-associated cancers by regulating glucose metabolism. Modulation of SIRT6 activity could provide us in the future with a potential therapeutic approach to reduce cancer incidence in the age population.

Public Health Relevance

Cancer is the leading cause of mortality in the aging population in the US. One hallmark of cancer cells is their particular metabolism, where sugars are utilized mainly to produce lactate instead of energy through mitochondria (Warburg Effect), with recent studies arguing that such dependency on sugars represents a potential Achilles'heel for tumors. We have found that a protein from the sirtuin deacetylase family, SIRT6, is a critical regulator of energy metabolism, specifically controlling glucose utilization in cells. In his proposal, we will investigate whether during aging, metabolism in tissues shift toward lactate production due to decreased expression of SIRT6, in turn predisposing to tumor development;notably, our preliminary results suggest that SIRT6 levels indeed go down with age, providing a putative therapeutic approach to tackle metabolism in order to reduce the incidence of cancer in the elder population.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Exploratory/Developmental Grants (R21)
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Special Emphasis Panel (ZCA1-SRLB-U (J1))
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Spalholz, Barbara A
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Massachusetts General Hospital
United States
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