nicotinic acid and CR

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Al's post about nicotinamide and Sirt1-mediated unsilencing got me concerned whetherniacin (nicotinic acid) therapy to raise HDL levels might be CR-unfriendly. Happily,that appears to not be the case, per the following:http://www.jbc.org/cgi/content/full/277/47/45099#SEC2specifically:We have shown that the potency of nicotinamide rivals that of the most effectivesynthetic Sir2 inhibitors identified thus far. The fact that SIRT1 is inhibited by such low concentrations of nicotinamide in vitro raises the possibility that this mode of inhibition may be physiologically relevant. Levels of nicotinamide in mammalian tissues have been reported to lie in the range of 11-400 µM (41, 58-60).More recently, levels of nicotinamide in cerebrospinal fluid were determined withhigh accuracy to be 54.2 µM (61), a value that is similar to the IC50 for nicotinamidereported here. We propose that fluctuations in cellular nicotinamide levels may directly control the activity of Sir2 proteins in vivo. These fluctuations may inturn be regulated by enzymes involved in nicotinamide metabolism, including Pnc1.The yeast PNC1 gene encodes a nicotinamidase that is situated in a key position to regulate NAD+-dependent deacetylases. By converting nicotinamide into nicotinicacid as part of the NAD+ salvage pathway, Pnc1 may reduce levels of this inhibitorand simultaneously increase the availability of NAD+ to Sir2 (see Fig. 1). Interestingly,PNC1 is one of the most highly induced genes in response to stress and conditionsthat resemble calorie restriction (62, 63), both of which have been shown to extendreplicative life span (64, 32). This raises the possibility that high levels of Pnc1 induce silencing under conditions of stress or nutrient limitation, by removingthe inhibitory effects of nicotinamide and increasing NAD+ production. Our previousfinding that a single extra copy of PNC1 increases Sir2-dependent silencing (33)adds further support to this model. It will be interesting to determine whether intracellular nicotinamide levels vary in response to such conditions.Nicotinamide and nicotinic acid are used at high doses (up to 10 g/day) to self-treata wide variety of ailments (43). Both are considered forms of vitamin B3 and areoften used interchangeably, although nicotinamide has become preferred in many casesbecause of an apparent lack of side effects. We have shown that these two relatedcompounds have drastically different effects at the molecular level. In addition,nicotinamide is currently in trials as a therapy to prevent cancer recurrence andinsulin-dependent (type I) diabetes (42). Our results clearly demonstrate that nicotinamidecan inhibit Sir2 enzymes, even in noncycling cells, and raise the concern that theremay be deleterious consequences of long term nicotinamide therapy in humans. and thenhttp://www.pdrhealth.com/drug_info/nmdrugprofiles/nutsupdrugs/nia_0184.shtmlRecently, it has been found that NAD+ plays a key role in life-span extension bycalorie restriction in the yeast Saccharomyces cerevisiae. It does so by servingas the cofactor for an NAD+-dependent histone deacetylase, an enzyme that removesacetyl groups from the lysine residues of histone proteins, thus promoting genomicsilencing. Maintenance of genomic silencing may be critical to longevity either by repressing genomic instability or by preventing inappropriate gene expression.A similar mechanism may operate in metazoans, including humans.As mentioned above, niacin is used either to refer to both nicotinic acid and nicotinamideor to nicotinic acid itself. Nicotinic AcidACTIONS AND PHARMACOLOGYACTIONSNicotinic acid has antihyperlipidemic activity and may have anti-atherogenic activity.MECHANISM OF ACTIONNicotinic acid in gram doses, but not nicotinamide, lowers serum levels of totalcholesterol, low-density lipoprotein cholesterol (LDL-C), very low-density lipoprotein(VLDL) and triglycerides. High-dose nicotinic acid also increases serum levels ofhigh-density lipoprotein cholesterol (HDL-C) and decreases serum levels of lipoprotein(a) [Lp(a)] and apolipoprotein B-100 (Apo . The mechanism of the antihyperlipidemicaction of nicotinic acid is not well understood. It is thought that this effect is mediated, in part, via decreases in the release of free fatty acids from adiposetissue, thereby decreasing the influx of free fatty acids into the liver, the hepaticreesterification of free fatty acids and the rate of production of hepatic very low-density lipoprotein (VLDL). A decrease in the hepatic production of VLDL reducesthe level of circulating VLDL available for conversion to LDL. Another hypothesisholds that nicotinic acid directly inhibits hepatic synthesis or secretion of apolipoproteinB-containing lipoproteins. Still another hypothesis holds that nicotinic acid hasthe potential to cause a generalized inhibition of synthetic function in the liver.This mechanism may be considered a manifestation of nicotinic acid hepatotoxicityresulting in decreased LDL-cholesterol. However, this liver-damaging hypothesis would not explain the HDL-elevating effect of nicotinic acid. The mechanism by whichnicotinic acid elevates HDL is unknown.High dose nicotinic acid has been found to significantly decrease cardiovascularand cerebrovascular events in those with coronary heart disease. It is thought thatthis effect is due, in part, to nicotinic acid's antihyperlipidemic activity.PHARMACOKINETICSBoth nicotinic acid and nicotinamide are efficiently absorbed from the stomach andsmall intestine. At low amounts, absorption is mediated by sodium-dependent facilitateddiffusion. Passive diffusion is the principal mechanism of absorption at higher doses. Doses of up to three to four grams of nicotinic acid and niacinamide are almost completely absorbed. Nicotinic acid and nicotinamide are transported via the portal circulation to the liver and via the systemic circulation to the varioustissues of the body. Nicotinic acid and nicotinamide enter most cells by passivediffusion and enter erythrocytes by facilitated transport.Nicotinic and nicotinamide are metabolized through different pathways. Nicotinicacid is not directly metabolized to nicotinamide. It undergoes a number of metabolicsteps to yield NAD+ which in turn can be converted to nicotinamide. <snip>In the liver, the principal catabolic product of high doses of nicotinic acid isthe glycine conjugate of nicotinic acid called nicotinuric acid. The principal catabolicproducts of nicotinamide are N'-methylnicotinamide, N' -methyl-5-carboxamide-2-pyridone,N'-methyl-5-carboxamide-4-pyridone and nicotinamide-N-oxide.High doses of nicotinic acid are excreted in the urine as unchanged nicotinic acidand the glycine conjugate of nicotinic acid nicotinuric acid. High doses of nicotinamideare excreted in the urine as unchanged nicotinamide, N'-methylnicotinamide, N'-methyl-5-carboxamide-2-pyridone,N'-methyl-5-carboxamide-4-pyridone and nicotinamide-N-oxide.--So it looks as though one can take niacin (nicotinic acid) without, to use thetechnical term, screwing up one's CR.Maco