Stress puts FOXO1 in the nucleus; Stressed for Life

[Guest guest]

All the new age gurus and Harpo Productions have endeavored to keep you "stressed out about being stressed out", but just "go with the flow", and realize we have running from tigers for a long time now.

The basic story from the literature is this. Adrenergic signalling, or "stress", can dephosphorlate your FOXO1. That is half of the requirement for "longevity". After this has happened, FOXO1 needs to be deacetylated by SIRT1 in humans. This is best accomplished by some form of mild oxidative or metabolic stress that will activate the redox-regulated sirtuin, SIRT1, to do its "thang", and and finish the modifications to the FOXO1 protein so that it is "functionalized".

After these two distinct modifications are made, FOXO1 can translocate into the nucleus, and modify transcriptional activity. The specific transcripts that then proceed to emerge from the nucleus are conducive to longevity.

So, "neurotransmitter-mediated stress" plus "energy deficit", or "neurotransmitter-mediated stress" plus "mild oxidative stress" equals "longevity, in this nascent calculus of longevity manipulation.

However, one "without" the other may be deleterious. That is something that is going to confuse the research community for probably at least a year, unless someone really smart figures out a way to instantly convince everyone that such a subtle distinction is necessary.

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Endocrinology. 2005 Jul 14; [Epub ahead of print]

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"Addition of epidermal growth factor (EGF) (10 nM) to neonatal rat cardiomyocytes caused rapid phosphorylation of Akt and slower FOXO1 phosphorylation. In contrast, the alpha1-adrenergic receptor agonist, phenylephrine (50 microM), did not phosphorylate Akt and caused

dephosphorylation of FOXO1 acutely and increased FOXO1 expression with chronic exposure. Phenylephrine, but not EGF, caused nuclear translocation of FOXO1, a response that is associated with dephosphorylation. " - PMID: 16020479

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Proc Natl Acad Sci U S A. 2004 Jul 6;101(27):10042-7. Epub 2004 Jun 25.

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Silent information regulator 2 potentiates Foxo1-mediated transcription through its deacetylase activity.

".....we show that reversible acetylation of Foxo1 (also known as FKHR), the mouse DAF-16 ortholog, modulates its transactivation function. cAMP-response element-binding protein (CREB)-binding protein binds and acetylates Foxo1 at the K242, K245, and K262 residues, the modification of which is involved in the attenuation of Foxo1 as a transcription factor. Conversely, Sir2 binds and deacetylates Foxo1.." - PMID: 15220471

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J Pharmacol Sci. 2005 Jul 9; [Epub ahead of print]

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Transcriptional Regulation of Neuronal Genes and Its Effect on Neural Functions: NAD-Dependent Histone Deacetylase SIRT1 (Sir2alpha).

" SIRT1 was shown to interact with various transcription factors such as p53, forkhead transcription factor (FOXO)...." - PMID: 16006743

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J Hypertens. 2005 Jul;23(7):1285-309.

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A forkhead in the road to longevity: the molecular basis of lifespan becomes clearer.

"Just like caloric restriction, lifespan can be increased in various species by plant-derived polyphenols, such as resveratrol, via activation of sirtuins in cells. Sirtuins, such as SIRT1 in mammals, utilize FOXO and other pathways to achieve their beneficial effects on health and lifespan. CONCLUSION: Lifespan is tractable and basic mechanisms are now known. Longevity research complements and overlaps research in most major medical disciplines. Current progress bodes well for an ever-increasing length of healthy life for those who adapt emerging knowledge personally (so-called 'longevitarians')." - PMID: 15942449

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve & db=pubmed & dopt=Abstract & list_uids=15942449

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T.

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