Sirtuins: The NAD+-Dependent Multifaceted Modulators of Inflammation.

Significance: Sirtuins are NAD+-dependent histone deacetylases regulating important processes in cellular biology such as inflammation, metabolism, oxidative stress, and apoptosis. Recent Advances: Despite initially being discovered to regulate transcription and life span via histone deacetylase activities, emerging data continually uncover new targets and propose additional roles. Due to the outstanding importance of the sirtuins in the control of the inflammatory response, their roles in the pathogenesis of several inflammatory-based diseases have become an area of intense research. Although sirtuins have been traditionally regarded as anti-inflammatory players, several recent findings suggest that their role in inflammation is complex and that in some cases sirtuins can indeed promote inflammation. Critical Issues: In this article, we provide an update on the latest findings concerning the new mechanisms of action and concepts about the role of sirtuins during inflammation. We focus on the impact that inflammatory-based processes exert on the liver, adipose tissue, and nervous system as well as on macrophage function and activation. Also, we discuss available data pointing to the dual role that, in particular contexts, sirtuins may have on inflammation control. Future Directions: Since the knowledge of sirtuin impact on metabolism is continually expanding, new venues of research arise. Besides become being regarded as candidates of therapeutic targets, posttranscriptional control of sirtuin expression by means of microRNAs challenges our traditional concepts of sirtuin regulation; importantly, the emerging role of NAD+ metabolism in aging and longevity has added a new dimension to the interest in sirtuin function. Antioxid. Redox Signal. 39, 1185-1208.

Impaired hippocampal neurogenesis and cognitive performance in adult DBC1-knock out mice.

The protein DBC1 is the main SIRT1 regulator known so far, and by doing so, it is involved in the regulation of energy metabolism, especially in liver and fat adipose tissue. DBC1 also has an important function in cell cycle progression and regulation in cancer cells, affecting tumorigenesis. We recently showed that during quiescence, non-transformed cells need DBC1 in order to re-enter and progress through the cell cycle. Moreover, we showed that deletion of DBC1 affects cell cycle progression during liver regeneration. This novel concept prompted us to evaluate the role of DBC1 during adult neurogenesis, where transition from quiescence to proliferation in neuronal progenitors is key and tightly regulated. Herein, we analyzed several markers of cell cycle expressed in the dentate gyrus of the hippocampus of controls and DBC1 KO adult mice. Our results suggest a reduced number of neuroblasts therein present, probably due to a decline of neuroblast generation or an impairment in neural differentiation. In agreement with this, we also found that adult DBC1 KO mice had a reduction in the volume of the granule cell layer of the dentate gyrus. Interestingly, behavioral analysis of KO and control mice revealed that deletion of DBC1 parallels to specific cognitive impairments, concerning learning and possibly memory formation. Our results show, for the first time, that DBC1 plays an active role in the nervous system. In particular, specific anatomical and behavioral changes are observed when is absent.