Fulltext:
http://www.jbc.org/c...nt/C700018200v1-
Thomas Carter replied in sci.life-extension:
(sci.life-extension is a must read IMVHO)
Hi RS and Iftikhar,
Resveratrol is the current hot supplement that enhances this pathway.
A lot of evidence is converging to strongly suggest life and health
extension by its enhancement. Supplementation of nicotineamide, the
substrate for
nicotinamide phosphoribosyltransferase, or NAD itself, the product of
the enzyme is indicated by this abstract. Resveratrol affects the
pathway downstream and its use is suggested by other evidence. NAD is
one of the purine dinucleotides (RDA). These are the double ring
nucleotides which are not absorbed well, and must be injected for
proven benefits. Such injection has been shown to increase the
lifespan of rodents in older studies, and the recent report of a mouse
lifespan increase by resveratrol supports these older papers. There is
also independant evidence for a lifespan increase by deacetylation of
the p53 gene product. This convergence of evidence from disparate
fields is very compelling for at least a small life extension in
humans. I wonder how great the effect might be? Five years, if started
late in life? Even two or three would be welcome.
I think I posted these two reports previously, but they fit in well
here.
Thomas
Nampt is the rate limiting enzyme for NAD synthesis, (1) depletion of
which causes stress related apoptosis. (2) RDA supplementation has
shown benefits in a few reports, but NAD is a purine dinucleotide and
the purines must be injected for proven benefits. Such injection
increased lifespan in at least two rodent studies. This area is now
being intensively studied with the intention of bringing a product to
market.
Thomas
1: J Biol Chem. 2004 Dec 3;279(49):50754-63. Epub 2004 Sep 20. Links
The NAD biosynthesis pathway mediated by nicotinamide
phosphoribosyltransferase regulates Sir2 activity in mammalian
cells.Revollo JR, Grimm AA, Imai S.
Department of Molecular Biology and Pharmacology, Washington
University School of Medicine, St. Louis, Missouri 63110, USA.
Recent studies have revealed new roles for NAD and its derivatives in
transcriptional regulation. The evolutionarily conserved Sir2 protein
family requires NAD for its deacetylase activity and regulates a
variety of biological processes, such as stress response,
differentiation, metabolism, and aging. Despite its absolute
requirement for NAD, the regulation of Sir2 function by NAD
biosynthesis pathways is poorly understood in mammals. In this study,
we determined the kinetics of the NAD biosynthesis mediated by
nicotinamide phosphoribosyltransferase (Nampt) and nicotinamide/
nicotinic acid mononucleotide adenylyltransferase (Nmnat), and we
examined its effects on the transcriptional regulatory function of the
mouse Sir2 ortholog, Sir2alpha, in mouse fibroblasts. We found that
Nampt was the rate-limiting component in this mammalian NAD
biosynthesis pathway. Increased dosage of Nampt, but not Nmnat,
increased the total cellular NAD level and enhanced the
transcriptional regulatory activity of the catalytic domain of
Sir2alpha recruited onto a reporter gene in mouse fibroblasts. Gene
expression profiling with oligonucleotide microarrays also
demonstrated a significant correlation between the expression profiles
of Nampt- and Sir2alpha-overexpressing cells. These findings suggest
that NAD biosynthesis mediated by Nampt regulates the function of
Sir2alpha and thereby plays an important role in controlling various
biological events in mammals.
PMID: 15381699
(2) J Biol Chem. 2005 Dec 30;280(52):43121-30. Epub 2005 Oct 5.
Related Articles, Links
Poly(ADP-ribose) polymerase-1-dependent cardiac myocyte cell death
during heart failure is mediated by NAD+ depletion and reduced
Sir2alpha deacetylase activity.
Pillai JB, Isbatan A, Imai S, Gupta MP.
Department of Cardiothoracic Surgery, University of Chicago, IL 60637,
USA.
Robust activation of poly(ADP-ribose) polymerase-1 (PARP) by oxidative
stress has been implicated as a major cause of caspase-independent
myocyte cell death contributing to heart failure. Here, we show that
depletion of myocyte NAD levels and the subsequent reduction of
Sir2alpha deacetylase activity are the sequential steps contributing
to PARP-mediated myocyte cell death. In both failing hearts and
cultured cardiac myocytes, the increased activity of PARP was
associated with depletion of cellular NAD levels and reduced Sir2alpha
deacetylase activity. Myocyte cell death induced by PARP activation
was prevented by repletion of cellular NAD levels either by adding NAD
directly to the culture medium or by overexpressing NAD biosynthetic
enzymes. The beneficial effect of NAD repletion was seen, however,
only when Sir2alpha was intact. Knocking down Sir2alpha levels by
small interfering RNA eliminated this benefit, indicating that
Sir2alpha is a downstream target of NAD replenishment leading to cell
protection. NAD repletion also prevented loss of the transcriptional
regulatory activity of the Sir2alpha catalytic core domain resulting
from PARP activation. We also show that PARP activation and the
concomitant reduction of Sir2alpha activity in failing hearts regulate
the post-translational acetylation of p53. These data demonstrate
that, in stressed cardiac myocytes, depletion of cellular NAD levels
forms a link between PARP activation and reduced Sir2alpha deacetylase
activity, contributing to myocyte cell death during heart failure.
PMID: 16207712
