• Log in with Facebook Log in with Twitter Log In with Google      Sign In    
  • Create Account
  LongeCity
              Advocacy & Research for Unlimited Lifespans

Photo
* * * * * 1 votes

It's not Sirt1 or Sirt 2, its Sirt3!!

new research

  • Please log in to reply
49 replies to this topic

#31 niner

  • Guest
  • 16,276 posts
  • 2,000
  • Location:Philadelphia

Posted 05 February 2013 - 01:45 PM

Mike, the interlocking regulatory networks and the various Rube Goldberg apparati that are mammalian biochemistry are just so freaking complicated, they are shot full of apparent conflicts. I wouldn't even try to take a particular piece of the puzzle and try to make a clinical decision based on it. I'd stick to the observations of what actually happens when people fast or take metformin. That's really a better guide, imho.

#32 Logic

  • Guest
  • 2,646 posts
  • 559
  • Location:Kimberley, South Africa
  • NO

Posted 05 February 2013 - 03:44 PM

"...PQQ is not the only dietary supplement that can activate PGC-1alpha and therefore unleash its chain of beneficial results including enhanced SIRT3 expression and mitochondrial biogenesis. Resveratrol and quercetin and other substances in my anti-aging firewalls dietary supplement regimen, can also do this..."
http://www.anti-agin...ial-biogenesis/



Now this (quercetin) goes against other research linked here..?

sponsored ad

  • Advert
Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

#33 mikeinnaples

  • Guest
  • 1,846 posts
  • 276
  • Location:Florida

Posted 05 February 2013 - 04:22 PM

Mike, the interlocking regulatory networks and the various Rube Goldberg apparati that are mammalian biochemistry are just so freaking complicated, they are shot full of apparent conflicts. I wouldn't even try to take a particular piece of the puzzle and try to make a clinical decision based on it. I'd stick to the observations of what actually happens when people fast or take metformin. That's really a better guide, imho.


Fair enough. Just wanted to make some sense of it.

Regarding metformin, it looks from this like it is pro-aging?

#34 Logic

  • Guest
  • 2,646 posts
  • 559
  • Location:Kimberley, South Africa
  • NO

Posted 05 February 2013 - 05:02 PM

Icariin promotes expression of PGC-1alpha, PPARalpha, and NRF-1 during cardiomyocyte differentiation of murine ES cells in vitro
http://www.ncbi.nlm....pubmed/17883938


http://www.anti-agin...um-and-icariin/
Interesting!

#35 Mind

  • Life Member, Moderator, Secretary
  • 15,601 posts
  • 2,000
  • Location:Wausau, WI

Posted 05 February 2013 - 05:45 PM

Most research I have seen, plus Sven's article here at LongeCity, plus Josh Mitteldorf's learned opinion, all point toward metformin as definitively life-extending (or age-slowing).
  • like x 2

#36 zorba990

  • Guest
  • 1,305 posts
  • 179

Posted 06 February 2013 - 02:11 AM

Most research I have seen, plus Sven's article here at LongeCity, plus Josh Mitteldorf's learned opinion, all point toward metformin as definitively life-extending (or age-slowing).


Or Allantoin http://www.ncbi.nlm....pubmed/22147657

#37 xEva

  • Member
  • 1,239 posts
  • 79
  • Location:USA
  • NO

Posted 08 February 2013 - 02:55 AM

At one point it directly says that both fasting and calorie restricted mice display an increase in mitochondrial protein acetylation.


This must be a typo on your part. Fasting and CR decrease mitochondrial protein acetylation.

Then I read this up above: metformin downregulates SIRT3 exp<b></b>ression in the liver and this results in increased mitochondrial protein acetylation. Then knowing the research out there about metformin decreasing certain cancer risk, I see above that it reduces SIRT3 exp<b></b>ression and that SIRT3 is a tumor suppressor (and actual deletion is oncogenic).

This seems a little contradictory to me and I want to make sure I understand what this means in regards to metformin. As this isn't my field of expertise, can someone explain it to me in layman's terms? Thanks


Metformin downregulates SIRT3 in the liver resulting in increased mitochondrial protein acetylation, which leads to inhibition of ATP synthesis. On one hand, lower ATP causes mitochondiral biogeneses (=more mitochondria are needed to deal with perceived insufficient energy) and on the other hand, inhibits gluconeogenesis, which results in lower blood glucose levels. Lower blood glucose definitely decreases certain cancer risks (and has many other benefits).

It is not entirely clear to me if metformin downregulates SIRT3 in tissues other than liver. But it certainly acts in the liver. It lowers energy available to hepatocytes, which causes them to produce less glucose.

Also, even though metformin downregulates SIRT3, it upregulates SIRT1, just llike resveratrol does.


As for SIRT3, it suppresses tumors by upregulating mitochondrial metabolism. Tumors mainly rely on glycolysis, whose intermediaries feed their growth and proliferation. SIRT3 turns glycolysis off, which forces the cells to use their mitochondria and stops their proliferation. Also, active mitochondria can initiate apoptosis in damaged cells.

I hope this helps :)


PS
what's up with exp<b></b>ression again? I thought it was fixed

Edited by xEva, 08 February 2013 - 03:00 AM.


#38 Logic

  • Guest
  • 2,646 posts
  • 559
  • Location:Kimberley, South Africa
  • NO

Posted 08 February 2013 - 11:45 AM

I looked for practical and available supps for increasing the expression of SIRT3.
The PQQ and Horny Goat Weed (in vitro) linked above seem to be able to do so by upregulating PGC-1alpha.
Surely people here are interested and have opinions and advice on using these 2 supps!??

I realise that the icariin is only in vitro, but when you look at the other advantages, dont you think its worth looking at?:

By Vince Giuliano
Icariin is the active flavinoid substance in the traditional Chinese medicinal herb Epimedium brevicornum Maxim. Icariin can be derived from several species of plants in the Epimedium family. These plants are known most popularly as Horny Goat Weed or Yin Yang Huo.[1] Although known and marketed widely in the United States as an aphrodisiac(ref), icariin and its sister epimedium-derived flavinoids have been subect to extensive research, mainly in China and elsewhere in Asia, and have been shown to exhibit amazing health-producing properties. A series of in-vitro and animal model studies have shown that icariin can promote the differentiation and proliferation of cardiomyocyte s and otherstem cells in multiple organ systems, act as an antidepressant, be protective of neural cells, inhibit the breakdown of bone tissue, stimulate the development of new bone tissue, inhibit the actions of several toxic substances, attenuate unwanted microglial activation, stimulate angiogenesis, have a powerful effect in regulating the immune response, inhibit the inflammatory response in arthritis and other inflammatory disease conditions, and reduce or reverse bone loss due to injury or arthritis. Icariin administration extends the lifespan and healthspan of nematodes. It affects expression in numerous signaling pathways including MAPK, IGF-1, BMP, AMPK, NF-kappaB, MEK/ERK- and PI3K/Akt/eNOS, and, potentially could be the basis for new treatments addressing cancers, arthritis, osteoarthritis, asthma, acne, Alzheimer’s disease — and the list goes on. Finally, yes: older rats systematically administered icariin do exhibit accelerated sexual activity.
http://www.anti-agin...um-and-icariin/

Some studies:

Icariin attenuates lipopolysaccharide-induced microglial activation and resultant death of neurons by inhibiting TAK1/IKK/NF-kappaB and JNK/p38 MAPK pathways.
http://www.ncbi.nlm....pubmed/20347053

Icariin enhances neuronal survival after oxygen and glucose deprivation by increasing SIRT1.
http://www.ncbi.nlm....pubmed/19303870

Icariin and its derivative icariside II extend healthspan via insulin/IGF-1 pathway in C. elegans.
http://www.ncbi.nlm....pubmed/22216122

Effects of Epimedium flavonoids on proliferation and differentiation of neural stem cells in vitro.
http://www.ncbi.nlm....pubmed/19703337

Icariin induces the expression of toll-like receptor 9 in ana-1 murine macrophages.
http://www.ncbi.nlm....pubmed/21538629
"...Stimulation of Ana-1 murine macrophages with icariin induced a significant dose-dependent expression of TLR9, and its mRNA expression which increased from 3 h post-treatment was approximately five-fold that of DMSO-treated cells. Several molecules, such as myeloid differentiation factor 88, tumor necrosis factor-α and interleukin 6, which are involved in the TLR9 downstream signaling pathway.."
MS???

Icariin attenuates LPS-induced acute inflammatory responses: involvement of PI3K/Akt and NF-kappaB signaling pathway.
http://www.ncbi.nlm....pubmed/20519138

Attenuation of LPS-induced inflammation by ICT, a derivate of icariin, via inhibition of the CD14/TLR4 signaling pathway in human monocytes
http://www.ncbi.nlm....pubmed/22056950

Molecular mechanism of icariin on rat asthmatic model
http://www.ncbi.nlm....pubmed/22040500
"...Icariin could regulate the imbalance of Th1/Th2 cytokines..."

Inducible effects of icariin, icaritin, and desmethylicaritin on directional differentiation of embryonic stem cells into cardiomyocytes in vitro.
http://www.ncbi.nlm....pubmed/15780198
"...The promoting effect of icariin on cardiac differentiation was related to increasing and accelerating gene expression of a-cardiac MHC and MLC-2v, as well as regulating the cell cycles and inducing apoptosis..."

Activating effect and mechanism of epimedium on endogenous stem cells
http://www.ncbi.nlm....pubmed/19548445
Stem cells are the cells with capacities of self-renovation, multiplication and differentiation. By activating endogenous stem cells to promote regeneration response has provided a new thinking for the treatment of degenerative diseases. The authors found that epimedium flavonoids (EF) can promote the proliferation and migration of adrenocortical stem cells in corticosterone-treated rats (as a model of Shen-yang deficiency); and through gene-chip test it was showed that EF could significantly up-regulate the growth hormone (GH), growth hormone releasing hormone (GHRH) and other growth factors such as insulin-like growth factor binding protein (IGFBP) and nerve growth factor (NGF) in the model rats. In natural aging rats (as model for Shen deficiency), EF could make the gene expression of multiple tissues youthening, and up-regulate the lowered expressions of GH, GHRH, IGFBP and NGF, etc. Further study on the in vitro isolated and cultivated neuro-stem cells proved that EF and its components have direct promoting actions on stem cell proliferation. All the above-mentioned outcomes indicated that the actions of EF and its extracts on stem cells are possibly the cytological basis for their effects on counteracting the suppression of glucocorticoids on hypothalamus-pituitary-adrenal (HPA) axis and retarding aging; also illustrated that TCM could treat diseases by a way of activating endogenous stem cells through mobilizing and elevating hormones and cytokines levels, and bringing the reserved potential of organism into full play.

Icariin, a flavonoid from the herb Epimedium enhances the osteogenic differentiation of rat primary bone marrow stromal cells.
http://www.ncbi.nlm....d?term=16398272

Icariin protects murine chondrocytes from lipopolysaccharide-induced inflammatory responses and extracellular matrix degradation.
http://www.ncbi.nlm....pubmed/20116661

SIRT3 research – tying together knowledge of aging:
http://www.anti-agin...ledge-of-aging/
  • like x 2

#39 mikeinnaples

  • Guest
  • 1,846 posts
  • 276
  • Location:Florida

Posted 08 February 2013 - 04:32 PM

At one point it directly says that both fasting and calorie restricted mice display an increase in mitochondrial protein acetylation.


This must be a typo on your part. Fasting and CR decrease mitochondrial protein acetylation.


No, not a typo on my behalf. Perhaps a typo in the article I linked, but they seemed very specific about it. It could be they were being liver specific, but the last line used the word 'globally'. Hmm. Anyways, I cant CnP from the page simply, so I attached a screenshot of what I was referring to. (click on it to make it readable)

[attachment=10816:Untitled.png]

Edited by mikeinnaples, 08 February 2013 - 04:34 PM.


#40 xEva

  • Member
  • 1,239 posts
  • 79
  • Location:USA
  • NO

Posted 08 February 2013 - 05:48 PM

At one point it directly says that both fasting and calorie restricted mice display an increase in mitochondrial protein acetylation.


This must be a typo on your part. Fasting and CR decrease mitochondrial protein acetylation.


No, not a typo on my behalf. Perhaps a typo in the article I linked, but they seemed very specific about it. It could be they were being liver specific, but the last line used the word 'globally'. Hmm. Anyways, I cant CnP from the page simply, so I attached a screenshot of what I was referring to. (click on it to make it readable)

[attachment=10816:Untitled.png]


Wow. indeed but this is in complete contradiction to all the other studies. Namely, fasting upregulates SIRT3, which in turn ups mitochondrial energy production by removing mitochondria protein acetylation.

For example, here is the quote from the metformin article http://www.plosone.o...al.pone.0049863 : "We show that metformin downregulates SIRT3 exp<b></b>ression and that this results in increased mitochondrial protein acetylation." So, SIRT3 down = acetylation up and visa versa. Fasting ups SIRT3 => it decreases acetylation.

Or another article http://www.ncbi.nlm....les/PMC2841477/: "We demonstrate that increased SIRT3 expression and activity deacetylates and enzymatically activates the fatty acid oxidation enzyme LCAD*"

"...the upregulation of SIRT3 expression and the increase in cellular NAD+ that both occur during the transition to fasting could work in synergy to maximally induce SIRT3 deacetylation of LCAD..."

*LCAD = long-chain acyl CoA dehydrogenase (aids in long-chain FA metabolism)

Or take just the title of this one: SIRT3 Deacetylates Mitochondrial 3-Hydroxy-3-Methylglutaryl CoA Synthase 2 and Regulates Ketone Body Production. http://www.cell.com/...4131(10)00395-5

Or this http://www.cell.com/...4131(10)00395-5 :
"The mitochondrial sirtuin SIRT3 is a mitochondrial deacetylase and is emerging as an important regulator protein acetylation and metabolic regulation during fasting. SIRT3 exp<b></b>ression is enhanced during fasting, deacetylates long-chain acyl-CoA dehydrogenase (LCAD), and increases fatty acid oxidation in the liver (Hirschey et al., 2010). In extrahepatic tissue, SIRT3 also deacetylates and activates mitochondrial acetylCoA synthase 2 (AceCS2) (Hallows et al., 2006 and Schwer et al., 2006), an enzyme required in the fasting response (Sakakibara et al., 2009). Additionally, SIRT3 deacetylates a subunit of the electron transport chain and regulates ATP production (Ahn et al., 2008). In this study, we identify HMGCS2 as a substrate of SIRT3, further supporting a role for SIRT3 in adaptive response to fasting."

Or this http://www.ncbi.nlm....les/PMC3065720/ SIRT3 opposes reprogramming of cancer cell metabolism through HIF1a destabilization. 2011:

"SIRT3 is a major mitochondrial deacetylase that targets many enzymes involved in central metabolism, resulting in the activation of many oxidative pathways. For example, SIRT3 deacetylates complex I and complex II to activate electron transport. SIRT3 induces fatty acid oxidation during fasting in hepatocytes via deacetylation of LCAD. "

"SIRT3 is a mitochondrial deacetylase that activates multiple metabolic enzymes and promotes mitochondrial substrate oxidation and ATP production. Our study shows that SIRT3 additionally controls glycolytic metabolism by regulating the stability and activity of HIF1a."
____________________________

My understanding is that mitochondrial proteins are rendered inactive by acetylation. When demand for energy rises, they are deacetylated by SIRT3, which kicks mitochondria in high gear, increasing the metabolic efficiency.
  • like x 1

#41 mikeinnaples

  • Guest
  • 1,846 posts
  • 276
  • Location:Florida

Posted 08 February 2013 - 06:40 PM

http://www.ncbi.nlm....les/PMC2752488/

This is the actual source they were citing for that. Looks like they were referring to the liver specifically. Still though, this shows CR increasing it in the liver.

#42 xEva

  • Member
  • 1,239 posts
  • 79
  • Location:USA
  • NO

Posted 08 February 2013 - 08:25 PM

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2752488/

This is the actual source they were citing for that. Looks like they were referring to the liver specifically. Still though, this shows CR increasing it in the liver.


Yes, this is [28] ref in that article. I found it here http://www.sciencedi...97276506004540. Their other ref is [2], which is this: http://onlinelibrary...09.00503.x/full

In [2] the only phrase in this regard is this:
  • "Proteomics analysis identified 277 unique acetylation sites in 133 proteins from two fractions of mouse liver mitochondria, one from fed mice and the other from fasted mice... Among the acetylated proteins, 62% were identified in both fractions, 14% were specific to fed mice, and 24% were specific to fasted mice."

That's the only place where they specifically speak of increased acetylation. Also note that they had several CR groups of mice, from 10% to 40%, the results of which they pooled against one ad lib group. They also combined the results from mice liver cells with HELA cells which are immortalized cancer cells grown in vitro, known for their messed up metabolic responses.

In ref [28] of your article, they say:
  • "Of note, in contrast to our findings, a recent study reported that CPS1 acetylation is decreased in mice during CR (Nakagawa et al., 2009). ... The cause of the discrepancy between our findings and those of Nakagawa et al. is unclear."

To me this tells that dust has not settled yet in this field of research.

My understanding is that any metabolic changes deacetylate some proteins and acetylate others. All papers are in agreement that SIRT3 deacetylates "many mitochondrial proteins". <-- that quote is from [2] ref from the article you link. I don;t think that the gross quantity of acetylated proteins (the full number of which is unknown and likely to change in the future) matters that much. It's what those individuals proteins do that matters.

#43 APBT

  • Member
  • 769 posts
  • 309

Posted 26 September 2013 - 11:32 PM

Forever young: SIRT3 a shield against mitochondrial meltdown, aging, and neurodegenerationhttp://www.ncbi.nlm....les/PMC3764375/
  • like x 1

#44 DorianGrey

  • Guest
  • 152 posts
  • 15
  • Location:Canada

Posted 17 October 2013 - 08:19 PM

Icariin is a PDE5 inhibitor and PDE5 plays a role in vision. Testosterone production may be stimulated at high doses >1g. I don't think long-term consumption is advised, or would you take Sildenafil on a daily basis?

#45 tunt01

  • Guest, Advisor
  • 2,252 posts
  • 381
  • Location:NW

Posted 19 April 2014 - 03:33 AM

superb overview tying sirt3, sod2, CR and longevity together

 

https://www.youtube....h?v=pfa0hgwiPbI


  • like x 3

#46 HaloTeK

  • Guest
  • 253 posts
  • 7
  • Location:chicago

Posted 23 April 2014 - 09:00 PM

If SIRT3 is activated by cold, would using a sauna and activating heat shock proteins be a complimentary way to increase health benefits?  Or do we wanna stay away from too much heat?


Edited by HaloTeK, 23 April 2014 - 09:00 PM.


#47 Aditya Kumar

  • Guest
  • 11 posts
  • 3
  • Location:Ann Arbor

Posted 27 April 2014 - 04:29 AM

One activator mentioned in literature is : oroxylin A


Edited by Aditya Kumar, 27 April 2014 - 04:29 AM.


#48 DorianGrey

  • Guest
  • 152 posts
  • 15
  • Location:Canada

Posted 01 May 2014 - 01:54 PM

So I found and read this while trying to understand this a little better: http://lab.hirschey....cetylation.html

At one point it directly says that both fasting and calorie restricted mice display an increase in mitochondrial protein acetylation. Then I read this up above: metformin downregulates SIRT3 expression in the liver and this results in increased mitochondrial protein acetylation. Then knowing the research out there about metformin decreasing certain cancer risk, I see above that it reduces SIRT3 expression and that SIRT3 is a tumor suppressor (and actual deletion is oncogenic).

This seems a little contradictory to me and I want to make sure I understand what this means in regards to metformin. As this isn't my field of expertise, can someone explain it to me in layman's terms? Thanks

I guess reducing blood sugar decreases the cancer risk in general as cancer cells feast on sugar. The SIRT3 effect is less pronounced and becomes background noise in this particular experimental setting.



#49 Logic

  • Guest
  • 2,646 posts
  • 559
  • Location:Kimberley, South Africa
  • NO

Posted 13 September 2014 - 04:51 PM

Interaction of Sirt3 with OGG1 contributes to repair of mitochondrial DNA and protects from apoptotic cell death under oxidative stress
http://www.nature.co...is2013254a.html


  • like x 1

sponsored ad

  • Advert
Click HERE to rent this advertising spot for SUPPLEMENTS (in thread) to support LongeCity (this will replace the google ad above).

#50 medievil

  • Guest Irresponsible Drug Addict
  • 3,747 posts
  • 20
  • Location:Belguim

Posted 17 September 2014 - 08:21 PM

Icariin is a PDE5 inhibitor and PDE5 plays a role in vision. Testosterone production may be stimulated at high doses >1g. I don't think long-term consumption is advised, or would you take Sildenafil on a daily basis?

Tadalafili is known to be safe taken on a daily basis for people with erectile dysfunctioning.





Also tagged with one or more of these keywords: new research

0 user(s) are reading this topic

0 members, 0 guests, 0 anonymous users