Highlights d PPARa mediates various SIRT6-regulated metabolic pathways d PPARa binds to and is activated by SIRT6 to promote fatty acid beta oxidation d SIRT6 decreases NCOA2 acetylation and induces its coactivation of PPARa d Coordinated SIRT6-PPARa activities control energy production under limited nutrients

SIRT6, a member of the mammalian sirtuins family, functions as a mono-ADP-ribosyl transferase and NAD(+)-dependent deacylase of both acetyl groups and long-chain fatty acyl groups. SIRT6 regulates diverse cellular functions such as transcription, genome stability, telomere integrity, DNA repair, inflammation and metabolic related diseases such as diabetes, obesity and cancer. In this review, we will discuss the implication of SIRT6 in the biology of cancer and the relevance to organism homeostasis and lifespan.

Sirtuins are NAD(+) dependent deacylases enzymes. There are seven mammalian sirtuins, SIRT1-SIRT7, which are localized to different cellular compartments and are capable of diverse catalytic activities. SIRT6 is a key regulator of healthy ageing. In the past decade our understanding of SIRT6 significantly increased in many different aspects. We know its cellular localization, catalytic activities, substrates and the pathways it is involved in. This review discusses the recent discoveries regarding the SIRT6 enzyme.

The histone deacetylase, SIRT1, plays a major role in glucose regulation and lipid metabolism. Ammonium Trichloro (dioxoethylene-o,o') Tellurate, AS101, is a potent in vitro and in vivo immunomodulator, with several potential therapeutic applications. AS101 administration resulted in upregulation of SIRT1 protein expression and activity. These effects were associated with decreased levels of serum insulin like growth factor-1 (IGF-1) and of insulin. The properties of AS101 prompted us to investigate its potential therapeutic role in rats with type 2 diabetes (T2D). T2D was induced by a high fat diet combined with a low dose of Streptozotocin (STZ). Treatment with AS101 before manifestation of hyperglycemia, resulted in increased insulin sensitivity, and decreased blood glucose levels, and prevented symptoms of diabetes including defective glucose clearance, fatty liver, and abnormal distribution of insulin-producing beta cells in the pancreas. Treatment after disease emergence resulted in partial restoration of normal glucose homeostasis. Diabetic rats showed a reduction in liver SIRT1 levels. In both treatment regimens the reduction in SIRT1 levels in the liver were blocked by AS101 consumption. Together, these findings demonstrate the therapeutic potential of AS101 for treating T2D, and for reversing impaired fat and glucose metabolism.

Imbalanced homeostasis and oligomerization of the amyloid-β (Aβ) peptide in the brain are hallmarks of Alzheimer's disease (AD). Microglia and macrophages play a critical role in the etiology of AD either by clearing Aβ from the brain or inducing inflammation. Recent evidence suggests that clearance of Aβ by microglia/macrophages via the phagocytic pathway is defective in AD, which can contribute to the accumulation of Aβ in the brain. We have recently demonstrated that protein microspheres modified at their surface with multiple copies of an Aβ-recognition motif can strongly bind Aβ, inhibit its aggregation, and directly reduce its toxicity by sequestering it from the medium. Here, we describe how microsphere-bound Aβ can stimulate microglial cells and be phagocytosed through a mechanism that is distinct from that of Aβ removal and, thus, contribute to the clearance of Aβ, even by defective microglial cells. The phagocytosis was most effective, with microspheres having a diameter of <1 μm. The introduction of polyethylene glycol to the surface of the microspheres changed the kinetics of the phagocytosis. Moreover, while aggregated Aβ induced a significant inflammatory response that was manifested by the release of TNF-α, the microsphere-bound Aβ dramatically reduced the amount of cytokine released from microglial cells.