Aging is accompanied by a decline in the healthy function of multiple organ systems, leading to increased incidence and mortality from diseases such as type II diabetes mellitus, neurodegenerative diseases, cancer, and cardiovascular disease. Historically, researchers have focused on investigating individual pathways in isolated organs as a strategy to identify the root cause of a disease, with hopes of designing better drugs. Studies of aging in yeast led to the discovery of a family of conserved enzymes known as the sirtuins, which affect multiple pathways that increase the life span and the overall health of organisms. Since the discovery of the first known mammalian sirtuin, SIRT1, 10 years ago, there have been major advances in our understanding of the enzymology of sirtuins, their regulation, and their ability to broadly improve mammalian physiology and health span. This review summarizes and discusses the advances of the past decade and the challenges that will confront the field in the coming years.

/pdf/mammalian-sirtuins-biological-insights-and-disease-relevance-195sikg6e7.pdf

Mammalian sirtuins: biological insights and disease relevance.

Sirtuins are a conserved family of proteins found in all domains of life. The first known sirtuin, Sir2 (silent information regulator 2) of Saccharomyces cerevisiae, from which the family derives its name, regulates ribosomal DNA recombination, gene silencing, DNA repair, chromosomal stability and longevity. Sir2 homologues also modulate lifespan in worms and flies, and may underlie the beneficial effects of caloric restriction, the only regimen that slows aging and extends lifespan of most classes of organism, including mammals. Sirtuins have gained considerable attention for their impact on mammalian physiology, since they may provide novel targets for treating diseases associated with aging and perhaps extend human lifespan. In this review we describe our current understanding of the biological function of the seven mammalian sirtuins, SIRT1-7, and we will also discuss their potential as mediators of caloric restriction and as pharmacological targets to delay and treat human age-related diseases.

/pdf/sirtuins-in-mammals-insights-into-their-biological-function-4n0wwh14ol.pdf

Sirtuins in mammals: insights into their biological function

PURPOSE OF REVIEW: Peroxisome proliferator-activated receptor gamma coactivator-1-alpha (PGC-1alpha) has been extensively described as a master regulator of mitochondrial biogenesis. However, PGC-1alpha activity is not constant and can be finely tuned in response to different metabolic situations. From this point of view, PGC-1alpha could be described as a mediator of the transcriptional outputs triggered by metabolic sensors, providing the idea that these sensors, together with PGC-1alpha, might be weaving a network controlling cellular energy expenditure. In this review, we will focus on how disorders such as type 2 diabetes and the metabolic syndrome might be related to an abnormal and improper function of this network. RECENT FINDINGS: Two metabolic sensors, AMP-activated protein kinase (AMPK) and SIRT1 have been described to directly affect PGC-1alpha activity through phosphorylation and deacetylation, respectively. Although the physiological relevance of these modifications and their molecular consequences are still largely unknown, recent insight from different in-vivo transgenic models clearly suggests that AMPK, SIRT1 and PGC-1alpha might act as an orchestrated network to improve metabolic fitness. SUMMARY: Metabolic sensors such as AMPK and SIRT1, gatekeepers of the activity of the master regulator of mitochondria, PGC-1alpha, are vital links in a regulatory network for metabolic homeostasis. Together, these players explain many of the beneficial effects of physical activity and dietary interventions in our battle against type 2 diabetes and related metabolic disorders. Hence, understanding the mechanisms by which they act could guide us to identify and improve preventive and therapeutic strategies for metabolic diseases.

/pdf/pgc-1alpha-sirt1-and-ampk-an-energy-sensing-network-that-2nn4usli5m.pdf

PGC-1alpha, SIRT1 and AMPK, an energy sensing network that controls energy expenditure.

Accumulating evidence has suggested that NAD (including NAD+ and NADH) and NADP (including NADP+ and NADPH) could belong to the fundamental common mediators of various biological processes, including energy metabolism, mitochondrial functions, calcium homeostasis, antioxidation/generation of oxidative stress, gene expression, immunological functions, aging, and cell death: First, it is established that NAD mediates energy metabolism and mitochondrial functions; second, NADPH is a key component in cellular antioxidation systems; and NADH-dependent reactive oxygen species (ROS) generation from mitochondria and NADPH oxidase-dependent ROS generation are two critical mechanisms of ROS generation; third, cyclic ADP-ribose and several other molecules that are generated from NAD and NADP could mediate calcium homeostasis; fourth, NAD and NADP modulate multiple key factors in cell death, such as mitochondrial permeability transition, energy state, poly(ADP-ribose) polymerase-1, and apoptosis-inducing factor; and fifth, NAD and NADP profoundly affect aging-influencing factors such as oxidative stress and mitochondrial activities, and NAD-dependent sirtuins also mediate the aging process. Moreover, many recent studies have suggested novel paradigms of NAD and NADP metabolism. Future investigation into the metabolism and biological functions of NAD and NADP may expose fundamental properties of life, and suggest new strategies for treating diseases and slowing the aging process.

NAD+/NADH and NADP+/NADPH in Cellular Functions and Cell Death: Regulation and Biological Consequences

Hepatocyte-Specific Deletion of SIRT1 Alters Fatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation

The human immunodeficiency virus (HIV) Tat protein is acetylated by the transcriptional coactivator p300, a necessary step in Tat-mediated transactivation. We report here that Tat is deacetylated by human sirtuin 1 (SIRT1), a nicotinamide adenine dinucleotide-dependent class III protein deacetylase in vitro and in vivo. Tat and SIRT1 coimmunoprecipitate and synergistically activate the HIV promoter. Conversely, knockdown of SIRT1 via small interfering RNAs or treatment with a novel small molecule inhibitor of the SIRT1 deacetylase activity inhibit Tat-mediated transactivation of the HIV long terminal repeat. Tat transactivation is defective in SIRT1-null mouse embryonic fibroblasts and can be rescued by expression of SIRT1. These results support a model in which cycles of Tat acetylation and deacetylation regulate HIV transcription. SIRT1 recycles Tat to its unacetylated form and acts as a transcriptional coactivator during Tat transactivation.

/pdf/sirt1-regulates-hiv-transcription-via-tat-deacetylation-1wf0c8f5r7.pdf

SIRT1 regulates HIV transcription via Tat deacetylation.

The HIV transcriptional activator Tat enhances the processivity of RNA polymerase II by recruiting the CyclinT1/CDK9 complex to the TAR RNA element. In addition, Tat synergizes with the histone acetyltransferase p300 and is acetylated by p300 at a single lysine residue (K50) in the TAR RNA binding domain. We have recently reported that this post-translational modification is necessary for the interaction and transcriptional synergy of Tat with the transcriptional coactivator PCAF. We have further studied the relevance of Tat acetylation during HIV transcription and generated antibodies specific for acetylated Tat (AcTat). Microinjection of anti-AcTat antibodies inhibited Tat-mediated transactivation in cells. Similarly, the specific p300 inhibitor Lys-CoA and short inhibitory RNAs specific for p300 suppressed Tat transcriptional activity. Full-length synthetic AcTat bound to TAR RNA and CyclinT1 with high affinity, but formation of the Tat-TAR-CyclinT1 ternary complex was inhibited when K50 was acetylated. Our data collectively show that Tat acetylation by p300 defines a critical step in Tat transactivation that serves to disrupt the Tat/TAR/CyclinT1 complex and helps in recruiting PCAF to the elongating RNA polymerase II.

Tat acetylation: a regulatory switch between early and late phases in HIV transcription elongation.

Acetylation of Tat Defines a CyclinT1-Independent Step in HIV Transactivation

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SIRT1 regulates HIV transcription via Tat deacetylation.

Tat acetylation: a regulatory switch between early and late phases in HIV transcription elongation.

Acetylation of Tat Defines a CyclinT1-Independent Step in HIV Transactivation