cron-web.org

[MR]

All:

A CRONie recently wrote:

> Increased activity of the enzyme
> pyrazinamidase/nicotinamidase 1 (PNC1), which converts
> the nicotinamide form of vitamin B3 to the nicotinic
> form of vitamin B3, is associated with life extension
> at some cost to the ability of cells to survive stress
> (1). This is one of the mechanisms of CR.

That is WAY too strong a statement, and I would in fact incline to say
that it is false. *In yeast*, PNC1 *may* have something to do with the
ability of CR to extend REPLICATIVE lifespan (ie, to determine how long
a yeast cell continues to bud off daughter cells, perpetuating the LINE)
via Sir2 -- that's Sinclair's/Sirtris' story -- but:

(a) even that much has been disputed both by Guarente/Elixir
Pharmaceuticals (who say that it's the rate of use, not salvage) and by
Kaeberlein's group (who say that Sir2 doesn't even play the central role
in the CR replicative "life extending" effect);

(b) we don't know whether mammalian cells even HAVE a PNC1 homologue,
let alone whether it's involved in the activity of the human sirtuin
homologue, SIRT1;

(c) most importantly, as has been reported on the List before, when
Valter Longo's group at USC looked at CHRONOLOGICAL lifespan in yeast --
ie, how long an INDIVIDUAL YEAST ORGANISM can live, which would
certainly SEEM to be a more reasonable analogy to mammalian lifespan --
they found that KNOCKING OUT Sir2 *extends* it, and that the effects are
additive to those of CR, so that by this measure Sir2 not only doesn't
play into a REAL CR "life extension" effect but actually inhibits it
(10); and on a related point,

(d) Frederick Alt's lab has found that SIRT1 actually *limits* human
cells' ability to avoid senescence in response to genotoxic stressors (11).

When you consider recent evidence supporting the already-intuitive
notion that SIRT1 might promote cancer (12), I think that asserting that
PNC1 "is associated with life extension at some cost to the ability of
cells to survive stress[, which] one of the mechanisms of CR" is pretty
darned dubious.

>
> Since the lifespan of a cell will not be enhanced by
> CR if it dies in the meantime due to stress this shows
> dramatically my often posted observation that we can
> only push CR to the limits if we reduce stress of many
> types.

I don't think that that follows at all, even if we accepted your initial
statements, both because you're engaged in an ambiguity fallacy (the
'stress' that you talk about is normally endocrine/psychological stress,
while the stressors being tested in sirtuin research are genotoxic
agents like dehydration, solute stress, or gamma radiation), and because
in any case very few people will actually suffer much harm over a
lifetime from such 'stressors,' while aging will certainly kill us if
simple bad diet, deadly genes, or imprudent driving don't first.

> 1. Curr Neurovasc Res. 2005 Oct;2(4):271-85
> The sirtuin inhibitor nicotinamide enhances neuronal
> cell survival during acute anoxic injury through AKT,
> BAD, PARP, and mitochondrial associated
> "anti-apoptotic" pathways.
> Chong ZZ, Lin SH, Li F, Maiese K.
> PMID: 16181120
>
> 2. Mol Cell. 2005 Feb 18;17(4):595-601
> Chemical activation of Sir2-dependent silencing by
> relief of nicotinamide inhibition.
> Sauve AA, Moir RD, Schramm VL, Willis IM.
> PMID: 15721262
>
> 3. Nature. 2003 May 8;423(6936):181-5
> Nicotinamide and PNC1 govern lifespan extension by
> calorie restriction in Saccharomyces cerevisiae.
> Anderson RM, Bitterman KJ, Wood JG, Medvedik O,
> Sinclair DA.
> PMID: 12736687
>
> 4. Mol Cell Biol. 2004 Feb;24(3):1301-12
> Nicotinamide clearance by Pnc1 directly regulates
> Sir2-mediated silencing and longevity.
> Gallo CM, Smith DL Jr, Smith JS.
> PMID: 14729974
>
> 5. J Biol Chem. 2002 May 24;277(21):18881-90
> Manipulation of a nuclear NAD+ salvage pathway delays
> aging without altering steady-state NAD+ levels.
> Anderson RM, Bitterman KJ, Wood JG, Medvedik O, Cohen
> H, Lin SS, Manchester JK, Gordon JI, Sinclair DA.
> PMID: 11884393
>
> 6. Yeast. 2002 Feb;19(3):215-24
> Identification and functional analysis of the
> Saccharomyces cerevisiae nicotinamidase gene, PNC1.
> Ghislain M, Talla E, Francois JM.
> PMID: 11816029
>
> 7. Microbiology. 1999 Jun;145 ( Pt 6):1359-67
> Mechanisms of pyrazinamide resistance in mycobacteria:
> importance of lack of uptake in addition to lack of
> pyrazinamidase activity.
> Raynaud C, Laneelle MA, Senaratne RH, Draper P,
> Laneelle G, Daffe M.
> PMID: 10411262
>
> 8. Blood. 1990 Apr 15;75(8):1705-10
> Increased nicotinamide adenine dinucleotide content
> and synthesis in Plasmodium falciparum-infected human
> erythrocytes.
> Zerez CR, Roth EF Jr, Schulman S, Tanaka KR.
> PMID: 2183889
>
> 9. Zentralbl Bakteriol [Orig A]. 1979
> Jul;244(2-3):302-8
> [Nicotinamidase and the so-called pyrazinamidase in
> mycobacteria; the simultaneous occurrence of both
> activites (author's transl)]
> [Article in German]
> Tarnok I, Pechmann H, Krallmann-Wenzel U, Rohrscheidt
> E, Tarnok Z.
> PMID: 506551
>

10: Fabrizio P, Gattazzo C, Battistella L, Wei M, Cheng C, McGrew K,
Longo VD.
Sir2 blocks extreme life-span extension.
Cell. 2005 Nov 18;123(4):655-67.
PMID: 16286010 [PubMed - indexed for MEDLINE]

11: Chua KF, Mostoslavsky R, Lombard DB, Pang WW, Saito S, Franco S,
Kaushal D, Cheng HL, Fischer MR, Stokes N, Murphy MM, Appella E, Alt FW.
Mammalian SIRT1 limits replicative life span in response to chronic
genotoxic stress.
Cell Metab. 2005 Jul;2(1):67-76. Erratum in: Cell Metab. 2006 Jan;3(1):75.
PMID: 16054100 [PubMed - indexed for MEDLINE]

> 12. Pruitt K, Zinn RL, Ohm JE, McGarvey KM, Kang SH, Watkins DN,
Herman JG,
> Baylin SB.
> Inhibition of SIRT1 Reactivates Silenced Cancer Genes without Loss of
> Promoter DNA Hypermethylation.
> PLoS Genet. 2006 Mar;2(3):e40. Epub 2006 Mar 31.
> PMID: 16596166
http://genetics.plosjournals.org/perlserv/?request=get-document&doi=10.1371/journal.pgen.0020040