SIRT1, SIRT2, SIRT3, up to SIRT7 in humans

[Guest guest]

Humans have at least 7 "sirtuin" proteins, and some of them go to the nucleus, others to the mitochondria, and so on. "Only" SirT1 seems to deacetylate cellular p53 in vivo.

But the "sensational" finding here I suppose is that over-expression of any of the SIRT proteins does not extend replicative lifespan. It doesn't even enhance resistance to "moderate" oxidative stress!

There are, of course, multiple interpretations. For one thing, they conducted this experiment in largely "standard" culture conditions. In other words, the cells are "fully fed". This will undoubtedly affect certain aspects of internal signal transduction that may significantly compromise the capacity of the overexpressed gene's physiologic role to be realized.

http://lists.calorierestriction.org/cgi-bin/wa?A2=ind0404 & L=crsociety & P=R61948 & X=0A356349AFB63133E2

[ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=15788402 ]

[ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=15205477 ]

In this particular case, I am referring to the deacetylase activity of Sirtuins on forkhead transcription factors that is presently associated with stress-resistant phenotypes and longevity.

However, there is the possibility that human longevity is not "directly correlated" to Sirtuin activity. I think the possibility for this "ambiguous" relationship in humans is stronger than most people [ alright, I guess "most people" = the 20 people on the planet following this... : ) ] realize. For one thing, numerous human cancer cell lines have been found to be sensitive to histone deacetylase antagonism. In other words, in humans, there may be a much more "guarded" reliance upon sirtuins and other such "histone deacetylases" for fear of unleashing the "Ubercell". When a cell "figures out a way" to abuse this survival programming, it may become invincible barring pharmacologic restoration of "histone acetylation".

If you think that the "deacetylation" associated with the sirtuin proteins is very "targeted" and specific, I believe that the evidence to date speaks to the opposite conclusion. [ PMID: 15640142 ]. The importance of this is that this [ PMID: 15640142 ] needs to be the case if you are going to begin to entertain the notion that the Sirtuins and the well-characterized family of histone deacetylase inhibitors really are inhabiting opposite ends of an axis of "histone acetylation".

[ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=12454781 ]

[ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=15940285 ]

[ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=15822187 ]

[ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=15778293 ]

[ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=15596714 ]

And, then you have the issue of differentiated cells versus stem cells. I am of the opinion that if they are differentiated, "screw 'em, I'll just make more". Of course, the one exception to this would be neurons, but, it is growing increasingly apparent that when things "hit the fan" systemically, they have their own "survival programming", mediated by agents such as BDNF and locally synthesized IGF-1 that can largely compensate for systemic decriments in insulinemic signalling.

However, what effect does histone acetylation have on stem cells? Interestingly, if you inhibit histone deacetylase activity, you get a more aggressive proliferation of stem cells. This could begin to generate a model where histone deacetylase activity is actually quite desireable in stem cells, as it keeps them from "overproliferating" and exhausting whatever replicative potential they began with [ PMID: 15805245 ], but undesirable in differentiated cells that may just turn malignant.

Additionally, it is growing increasingly apparent that histon deacetylation antagonizes stem cell differentiation. If stem cell differentiation negatively influences maximum lifespan, than it may be that histone deacetylase activity, such as that associated with the sirtuin family of proteins, may be quite desireable, at least in stem cells. [ PMID: 15705964 ]

To add to the complexity, you have stem cells, progenentior cells, and differentiated cells. All three of these may have unique contributions to longevity, and distinct influences from the sirtuins.

What can you to do to corroborate this perspective (or rambling, depending on your read) ? You can't, because it represents an original synthesis of evidence from the basic research and clinical oncology communities that will take several years to confirm. If I had my own lab, I would "assign" about 2 post-docs and 5-7 grad students on it. [ Sic 'em, boy! ]

[ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=15805245 ]

[ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=15705964 ]

[ http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=16081735 ]

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Mol Biol Cell. 2005 Aug 3; [Epub ahead of print]

Related Articles,

Links

Evolutionarily Conserved and Nonconserved Cellular Localizations and Functions of Human SIRT Proteins.Michishita E, Park JY, Burneskis JM, Barrett JC, Horikawa I.Laboratory of Biosystems and Cancer, Center for Cancer Research,

National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.Monitoring Editor: Cleveland Sir2 is a NAD(+)-dependent protein deacetylase that extends lifespan in yeast and worms. This study examines seven human proteins homologous to Sir2 (SIRT1 through SIRT7) for cellular localization, expression profiles, protein deacetylation activity, and effects on human cell lifespan. We found that: 1) three nuclear SIRT proteins (SIRT1, SIRT6 and SIRT7) show different subnuclear localizations: SIRT6 and SIRT7 are associated with heterochromatic regions and nucleoli, respectively, where yeast Sir2 functions; 2) SIRT3, SIRT4 and SIRT5 are localized in mitochondria, an organelle that links aging and energy metabolism; 3) cellular p53 is a major in vivo substrate of SIRT1 deacetylase, but not the other six SIRT proteins; 4) SIRT1, but not the other two nuclear SIRT proteins, shows an in vitro deacetylase activity on histone H4 and p53 peptides; and 5) overexpression

of any one of the seven SIRT proteins does not extend cellular replicative lifespan in normal human fibroblasts or prostate epithelial cells. This study supports the notion that multiple human SIRT proteins have evolutionarily conserved and nonconserved functions at different cellular locations and reveals that the lifespan of normal human cells, in contrast to that of lower eukaryotes, cannot be manipulated by increased expression of a single SIRT protein.PMID: 16079181 [PubMed - as supplied by publisher]

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