http://www.klinikaikozpont.u-szeged.hu/pedia/images/pdf/CME_TEL/Full-Text/25.pdf

The Hallmarks of Aging

NAD(+) Metabolism and the Control of Energy Homeostasis: A Balancing Act between Mitochondria and the Nucleus.

NAD+ and sirtuins in aging and disease

Nicotinamide adenine dinucleotide (NAD + ) is a coenzyme found in all living cells. It serves both as a critical coenzyme for enzymes that fuel reduction-oxidation reactions, carrying electrons from one reaction to another, and as a cosubstrate for other enzymes such as the sirtuins and poly(adenosine diphosphate–ribose) polymerases. Cellular NAD + concentrations change during aging, and modulation of NAD + usage or production can prolong both health span and life span. Here we review factors that regulate NAD + and discuss how supplementation with NAD + precursors may represent a new therapeutic opportunity for aging and its associated disorders, particularly neurodegenerative diseases.

http://science.sciencemag.org/content/sci/350/6265/1208.full.pdf

NAD+ in aging, metabolism, and neurodegeneration

Sirtuins such as SIRT1 are conserved protein NAD(+)-dependent deacylases and thus their function is intrinsically linked to cellular metabolism. Over the past two decades, accumulating evidence has indicated that sirtuins are not only important energy status sensors but also protect cells against metabolic stresses. Sirtuins regulate the aging process and are themselves regulated by diet and environmental stress. The versatile functions of sirtuins including, more specifically, SIRT1 are supported by their diverse cellular location allowing cells to sense changes in energy levels in the nucleus, cytoplasm, and mitochondrion. SIRT1 plays a critical role in metabolic health by deacetylating many target proteins in numerous tissues, including liver, muscle, adipose tissue, heart, and endothelium. This sirtuin also exerts important systemic effects via the hypothalamus. This review will cover these topics and suggest that strategies to maintain sirtuin activity may be on the horizon to forestall diseases of aging.

/pdf/sirt1-and-other-sirtuins-in-metabolism-14osjdyabq.pdf

SIRT1 and other sirtuins in metabolism.

Regulation of meiosis and sporulation in Saccharomyces cerevisiae is a model for a highly regulated developmental process. Meiosis middle phase transcriptional regulation is governed by two transcription factors: the activator Ndt80 and the repressor Sum1. It has been suggested that the competition between Ndt80 and Sum1 determines the temporal expression of their targets during middle meiosis. Using a combination of ChIP-on-chip and expression profiling, we characterized a middle phase transcriptional network and studied the relationship between Ndt80 and Sum1 during middle and late meiosis. While finding a group of genes regulated by both factors in a feed forward loop regulatory motif, our data also revealed a large group of genes regulated solely by Ndt80. Measuring the expression of all Ndt80 target genes in various genetic backgrounds (WT, sum1Δ and MK-ER-Ndt80 strains), allowed us to dissect the exact transcriptional network regulating each gene, which was frequently different than the one inferred from the binding data alone. These results highlight the need to perform detailed genetic experiments to determine the relative contribution of interactions in transcriptional regulatory networks.

/pdf/combination-of-genomic-approaches-with-functional-genetic-2ob74whg1v.pdf

Combination of genomic approaches with functional genetic experiments reveals two modes of repression of yeast middle-phase meiosis genes

Identifying conserved and divergent response patterns in gene networks is becoming increasingly important A common approach is integrating expression information with gene association networks in order to find groups of connected genes that are activated or repressed In many cases, researchers are also interested in comparisons across species (or conditions) Finding an active sub-network is a hard problem and applying it across species requires further considerations (eg orthology information, expression data and networks from different sources) To address these challenges we devised ModuleBlast, which uses both expression and network topology to search for highly relevant sub-networks We have applied ModuleBlast to expression and interaction data from mouse, macaque and human to study immune response and aging The immune response analysis identified several relevant modules, consistent with recent findings on apoptosis and NFκB activation following infection Temporal analysis of these data revealed cascades of modules that are dynamically activated within and across species We have experimentally validated some of the novel hypotheses resulting from the analysis of the ModuleBlast results leading to new insights into the mechanisms used by a key mammalian aging protein

Guy Zinman

Papers

Combination of genomic approaches with functional genetic experiments reveals two modes of repression of yeast middle-phase meiosis genes

ModuleBlast: identifying activated sub-networks within and across species