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SIRT6 activation for countering age-related metabolic diseases

Final Report Summary - SIRAID (SIRT6 activation for countering age-related metabolic diseases)

Ageing is considered an inevitable process. However, the rate and the magnitude of the appearance of the physiological damages associated with ageing can be slowed. Thus, one can distinguish between lifespan and healthspan. Whereas the first is the number of years from birth to death, the second describes the period of a person’s life during which they are generally healthy and free from serious or chronic illness. Since the 19th century, the life expectancy of an individual in the Western population almost doubled. This significant increase in human longevity has created great opportunities for society by increasing the proportion of experienced individuals, yet at the same time has created great sociological, economical, and mostly medical challenges. To answer these challenges, one must understand and control the mechanisms that determine the rate of ageing. Having this knowledge, we could extend the length of healthspan and tip the balance from these challenges into opportunities. One family of proteins that have been implicated in ageing and the regulation of metabolism and genome stability are the sirtuins. The sirtuins are highly conserved enzyme homologues of the yeast Sir2, with NAD+ dependent deacetylase and/or mono ADP ribosyltransferase activitiy. Studies in several organisms have indicated that sirtuins are pivotal in the regulation of longevity and in thel effect of a dietary restriction (DR) diet, a procedure that delays ageing and reduces ageing related diseases. However, the role of mammalian sirtuins in lifespan and healthspan was elusive. In SIRAID we focused on SIRT6, one of the seven mammalian sirtuins SIRT1-7. SIRT6 is a protein deacylase with specific deacetylase and mono ADP ribosyl-transferase activities.
To explore SIRT6 role in ageing and metabolism we first showed an induction of SIRT6 by DR, which suggests a role for SIRT6 in the positive effects of DR on lifespan. Next, we generated transgenic mice over-expressing exogenous SIRT6 (MOSES) and showed that these mice are protected against the physiological damages of diet induced obesity. When fed with high fat diet (HFD), MOSES mice were protected against the accumulation of triglycerides and LDL cholesterol in the serum, increased body fat, and reduced glucose tolerance. This protection against obesity-related reduced glucose tolerance was partially due to improved insulin secretion upon glucose stimulation. Importantly, in support of our findings, the Alt group recently showed that brain specific SIRT6 knockout mice become obese with adulthood. In MOSES mice, the protective effect of SIRT6 in fat homeostasis was due to inhibition of a specific set of PPAR regulated genes and of DGAT1, a key enzyme in triglyceride synthesis. In normal animals, obesity related metabolic defects become apparent by middle age, and their appearance is delayed in animals fed with DR4. Thus, our findings suggested that over-expressing SIRT6 might mimic part of the DR phenotype. We therefore wished to determine whether MOSES mice have an increased healthspan and extended lifespan.
Indeed, recently we published that MOSES males, but not females, have a significant increase in lifespan. These groundbreaking results resolved the heated debate in the ageing field regarding the role of sirtuins in mammalian ageing. The lifespan was examined in comparison to their control wild type (wt) littermates. A glucose tolerance test (GTT) revealed that old male MOSES mice (26 months) but not wt littermates maintain proper glucose homeostasis. To better understand the gender specific effect of SIRT6 on life span and metabolic healthspan, we performed gene expression analysis on liver taken from four genotypes: wt male and female, and MOSES male and female. Differential expression (DE) analysis using Statistical Analysis of Microarrays showed that MOSES males display an expression profile similar to that of female animals in major components of the insulin like growth factor 1 (IGF-1) pathway, a key factor in the regulation of lifespan. Furthermore, biochemical analysis showed that transgenic males display lower serum IGF-1 levels and increased levels of IGFBP-1, a major short-term modulator of IGF-1 bioavailability. Surprisingly, within the three major metabolic tissues, liver, muscle and white adipose tissue (WAT), the most significant effects on IGF-1 signalling as determined by decreased phosphorylation levels of various components of the IGF-1 cascade, were observed in perigonadal WAT of MOSES male mice. IGF-1 is mainly generated by the liver, suggesting that SIRT6 plays a role in liver IGF-1 production or secretion as well as in WAT IGF-1 signalling. Interestingly, similar effects were reported in male mice fed DR diet. Thus, our findings show that SIRT6 indeed mimics part of the spectrum of DR phenotypes, including improved metabolism and increased healthy lifespan.