25 replies to this topic

[rhodeder]

research paper here
How can a person overexpress this hormone in themself though?

[Sillewater]

I've been doing some research on this pathway with regards to phosphate and FGF32 (which is also related to phosphate and Vitamin D). Interesting stuff. For now I'm keeping my phosphate intake at the low end of normal.

[mwestbro]

Take statins.

1. Cardiovasc Res. 2004 Nov 1;64(2):331-6.

HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA
inactivation in IMCD3 cells.

Narumiya H, Sasaki S, Kuwahara N, Irie H, Kusaba T, Kameyama H, Tamagaki K, Hatta
T, Takeda K, Matsubara H.

Department of Hypertension and Nephrology, Kyoto Prefectural University School of
Medicine, 465 Kajii-cho Kawaramachi Hirokoji, Kyoto 602-8566, Japan.
naru1117@koto.kpu-m.ac.jp

OBJECTIVE: Klotho is thought to play a critical role in the development of
age-related disorders including arteriosclerosis. Statins may exert vascular
protective effects, independent of the lowering of plasma cholesterol levels. We
investigated the impact of statins on mRNA expression of the age-suppressor gene,
klotho in mIMCD3 cells.
METHODS AND RESULTS: Klotho mRNA levels were evaluated with real-time RT-PCR.
Atorvastatin and pitavastatin increased the expression of klotho mRNA in a
dose-dependent manner. This stimulatory effect was abolished by the addition of
mevalonate, GGPP and FPP, essential molecules for isoprenylation of the small
GTPase Rho. As was the case with the statin treatment, inhibition of Rho-kinase
by Y27632 up-regulated klotho mRNA. In contrast to the statin treatment,
stimulation with angiotensin II down-regulated klotho mRNA expression without
obvious morphological changes. Furthermore, pretreatment with atorvastatin
blunted the angiotensin II-induced response and ameliorated the decrease in
klotho mRNA expression towards basal levels. RhoA activity was further evaluated
by detection of its translocation. Angiotensin II activated RhoA, whereas statins
potently inactivated RhoA and blocked RhoA activation by angiotensin II.
CONCLUSION: Statins inactivate the RhoA pathway, resulting in over-expression of
klotho mRNA, which may contribute to the novel pleiotropic effects of statins
towards vascular protection.


PMID: 15485693 [PubMed - indexed for MEDLINE]

[rhodeder]

sounds like Rosuvastatin is the drug of choice to cause that to happen. The FDA voted to allow it to be available to a larger audience who dont have high cholesterol but want it to extend their lifespan. http://colinfarrelly...plications.html. The question is.... where can i buy a HMG-CoA reductase inhibitor without a prescription?

Take statins.

1. Cardiovasc Res. 2004 Nov 1;64(2):331-6.

HMG-CoA reductase inhibitors up-regulate anti-aging klotho mRNA via RhoA
inactivation in IMCD3 cells.

Narumiya H, Sasaki S, Kuwahara N, Irie H, Kusaba T, Kameyama H, Tamagaki K, Hatta
T, Takeda K, Matsubara H.

Department of Hypertension and Nephrology, Kyoto Prefectural University School of
Medicine, 465 Kajii-cho Kawaramachi Hirokoji, Kyoto 602-8566, Japan.
naru1117@koto.kpu-m.ac.jp

OBJECTIVE: Klotho is thought to play a critical role in the development of
age-related disorders including arteriosclerosis. Statins may exert vascular
protective effects, independent of the lowering of plasma cholesterol levels. We
investigated the impact of statins on mRNA expression of the age-suppressor gene,
klotho in mIMCD3 cells.
METHODS AND RESULTS: Klotho mRNA levels were evaluated with real-time RT-PCR.
Atorvastatin and pitavastatin increased the expression of klotho mRNA in a
dose-dependent manner. This stimulatory effect was abolished by the addition of
mevalonate, GGPP and FPP, essential molecules for isoprenylation of the small
GTPase Rho. As was the case with the statin treatment, inhibition of Rho-kinase
by Y27632 up-regulated klotho mRNA. In contrast to the statin treatment,
stimulation with angiotensin II down-regulated klotho mRNA expression without
obvious morphological changes. Furthermore, pretreatment with atorvastatin
blunted the angiotensin II-induced response and ameliorated the decrease in
klotho mRNA expression towards basal levels. RhoA activity was further evaluated
by detection of its translocation. Angiotensin II activated RhoA, whereas statins
potently inactivated RhoA and blocked RhoA activation by angiotensin II.
CONCLUSION: Statins inactivate the RhoA pathway, resulting in over-expression of
klotho mRNA, which may contribute to the novel pleiotropic effects of statins
towards vascular protection.


PMID: 15485693 [PubMed - indexed for MEDLINE]

[rwac]

sounds like Rosuvastatin is the drug of choice to cause that to happen. The FDA voted to allow it to be available to a larger audience who dont have high cholesterol but want it to extend their lifespan. http://colinfarrelly...plications.html. The question is.... where can i buy a HMG-CoA reductase inhibitor without a prescription?

I'd be wary of statins. It's got a bunch of side effects, and i'm not sure it's great for life extension.

Edited by rwac, 15 April 2011 - 01:32 AM.

[rhodeder]

*bump* where can i buy a HMG-CoA reductase inhibitor without a prescription?

[rwac]

Tocotrienols inhibit HMG-CoA. No clue about the statins.

http://www.ncbi.nlm....pubmed/12656204
http://www.ncbi.nlm....pubmed/11882333

Edited by rwac, 19 April 2011 - 07:30 PM.

[rhodeder]

That's a pretty nice find. I'm going to have to buy some. http://www.amazon.co...s/dp/B0013OXLHQ

[rwac]

That's a pretty nice find. I'm going to have to buy some. http://www.amazon.co...s/dp/B0013OXLHQ

I suggest getting something without tocopherols. Tocopherols promote HMG-CoA Reductase.

[rhodeder]

I bought some to start taking daily. I'll update you in 30 years to let you know how well daily supplementation has slowed my aging.

[Sillewater]

Aging (Albany NY). 2010 Oct;2(10):632-3.
Linking Klotho, Nrf2, MAP kinases and aging.
Balasubramanian P, Longo VD.

How bout just acting on Nrf2. Could also benefit skin (http://www.longecity...post__p__462341)

[Donnie]

Aging (Albany NY). 2010 Oct;2(10):632-3.
Linking Klotho, Nrf2, MAP kinases and aging.
Balasubramanian P, Longo VD.

How bout just acting on Nrf2. Could also benefit skin (http://www.longecity...post__p__462341)

A ketogenic diet may activate Nrf2.

Acute oxidative stress and systemic Nrf2 activation by the ketogenic diet.
Milder JB, Liang LP, Patel M.

Graduate Program in Neuroscience, University of Colorado Anschutz Medical Campus, Aurora, CO 80045, USA.


Abstract
The mechanisms underlying the efficacy of the ketogenic diet (KD) remain unknown. Recently, we showed that the KD increased glutathione (GSH) biosynthesis. Since the NF E2-related factor 2 (Nrf2) transcription factor is a primary responder to cellular stress and can upregulate GSH biosynthesis, we asked whether the KD activates the Nrf2 pathway. Here we report that rats consuming a KD show acute production of H(2)O(2) from hippocampal mitochondria, which decreases below control levels by 3 weeks, suggestive of an adaptive response. 4-Hydroxy-2-nonenal (4-HNE), an electrophilic lipid peroxidation end product known to activate the Nrf2 detoxification pathway, was also acutely increased by the KD. Nrf2 nuclear accumulation was evident in both the hippocampus and liver, and the Nrf2 target, NAD(P)H:quinone oxidoreductase (NQO1), exhibited increased activity in both the hippocampus and liver after 3 weeks. We also found chronic depletion of liver tissue GSH, while liver mitochondrial antioxidant capacity was preserved. These data suggest that the KD initially produces mild oxidative and electrophilic stress, which may systemically activate the Nrf2 pathway via redox signaling, leading to chronic cellular adaptation, induction of protective proteins, and improvement of the mitochondrial redox state.

© 2010 Elsevier Inc. All rights reserved.
PMID: 20594978 [PubMed - in process]

Interestingly, I believe someone mentioned in the KD thread that they're skin texture improved. Could be more than just the low carb intake.

Edited by Donnie, 03 May 2011 - 05:57 PM.

[Sillewater]

Interestingly, I believe someone mentioned in the KD thread that they're skin texture improved. Could be more than just the low carb intake.

My skin definitely improved on a very low carb diet, improved a lot, when I went back to near vegetarian diet it got worse.

[amark]

NAC increases  glutathione in the liver. Is that relevant to this conversation.? Thanks

[Phoenicis]

No one should run off taking these with seeking independent medical advice, I'm not qualified to give any. HDACi inhibitors like tributrin or Na Butyrate should be studied more since they behave very similar to trichostatin A 

 

The anti-aging gene KLOTHO is a novel target for epigenetic silencing in human cervical carcinoma

 

Background

Klotho was originally characterized as an anti-aging gene that predisposed Klotho-deficient mice to a premature aging-like syndrome. Recently, KLOTHO was reported to function as a secreted Wnt antagonist and as a tumor suppressor. Epigenetic gene silencing of secreted Wnt antagonists is considered a common event in a wide range of human malignancies. Abnormal activation of the canonical Wnt pathway due to epigenetic deregulation of Wnt antagonists is thought to play a crucial role in cervical tumorigenesis. In this study, we examined epigenetic silencing of KLOTHO in human cervical carcinoma.

Results

Loss of KLOTHO mRNA was observed in several cervical cancer cell lines and in invasive carcinoma samples, but not during the early, preinvasive phase of primary cervical tumorigenesis. KLOTHO mRNA was restored after treatment with either the DNA demethylating agent 2'-deoxy-5-azacytidine or histone deacetylase inhibitor trichostatin A. Methylation-specific PCR and bisulfite genomic sequencing analysis of the promoter region of KLOTHO revealed CpG hypermethylation in non-KLOTHO-expressing cervical cancer cell lines and in 41% (9/22) of invasive carcinoma cases. Histone deacetylation was also found to be the major epigenetic silencing mechanism for KLOTHOin the SiHa cell line. Ectopic expression of the secreted form of KLOTHO restored anti-Wnt signaling and anti-clonogenic activity in the CaSki cell line including decreased active β-catenin levels, suppression of T-cell factor/β-catenin target genes, such as c-MYC and CCND1, and inhibition of colony growth.

Conclusions

Epigenetic silencing of KLOTHO may occur during the late phase of cervical tumorigenesis, and consequent functional loss of KLOTHO as the secreted Wnt antagonist may contribute to aberrant activation of the canonical Wnt pathway in cervical carcinoma.

[airplanepeanuts]

Klotho is linked to higher intelligence:

 

http://onlinelibrary...0.1002/acn3.161

 

On the other hand statins seem to be detrimental to intelligence (not in all studies):

 

http://www.ncbi.nlm....pubmed/20413854

 

This is despite the Klotho raising effect of statins. So maybe this effect is offset by other detrimental effects of statins.

[YOLF]

Tocotrienols are a favorite of mine, esp the delta fraction from annatto as it contains no tocopherols.

 

Metformin and Acarbose raise FGF21 and something tells me that's good for Klotho, though I'm not remembering why. Both are pretty available at online pharmacies w/o a script.

[brosci]

Tocotrienols are a favorite of mine, esp the delta fraction from annatto as it contains no tocopherols.

 

Metformin and Acarbose raise FGF21 and something tells me that's good for Klotho, though I'm not remembering why. Both are pretty available at online pharmacies w/o a script.

I'm curious how the strength of Tocotrienols and other natural options might compare with something like a statin pharmaceutical.

 

This article mentions a few other interesting natural candidates:

The Role of Nutraceutical Supplements in the Treatment of Dyslipidemia: http://onlinelibrary...11.00576.x/full

 

If one was to haphazardly / randomly cycle tocotrienols + pantethine, might there be some risk of rebound effects?

 

Stopping Statins May Cause Rebound That Triples Risk Of Death: https://www.scienced...20306074451.htm

[YOLF]

Tocotrienols and pantethine? Can you explain what would happen there?

 

Subjectively, the effect of tocotrienols is very strong. When I injured my knees, I was taking glucosamine, chondroitin, msm, and glycine at high levels, sometimes 2-8g each, plus a small amount of lysine, proline, and vitamin C, and a few grams of krill oil a day, the tocotrienols were the most effective at shoring up tissue and relieving pain (though I don't think there's a paper on it), raising Klotho with IGF1 caused more pain, though it's a sublingual preparation with some other things in it including L Arginine, Epimedium, Tribulus, and Eucomyia Longfolia. I later switched to Ester C to go with the lysine and proline and that seemed to improve things more too (cya). Now I just use more glycine in place of the lysine and proline as they can cause side effects or potentially strain kidney function. Not sure if/how T effects klotho, it probably doesn't or men would have more, but it seems to compliment it well as I'm thinking arginine restriction does. 

 

So yeah, as far as structural fidelity is concerned klotho/tocotrienols are king and my mood tends to be better. May improve allergies. I've switched to a palm oil extract as opposed to the annatto bean extract and my skin seems a little more itchy lately.. but I really can't say I was paying that much attention, it could be something else. I am supposed to limit my tocopherol intake according to my genome though.

[brosci]

Tocotrienols and pantethine? Can you explain what would happen there?

 

Subjectively, the effect of tocotrienols is very strong. When I injured my knees, I was taking glucosamine, chondroitin, msm, and glycine at high levels, sometimes 2-8g each, plus a small amount of lysine, proline, and vitamin C, and a few grams of krill oil a day, the tocotrienols were the most effective at shoring up tissue and relieving pain (though I don't think there's a paper on it), raising Klotho with IGF1 caused more pain, though it's a sublingual preparation with some other things in it including L Arginine, Epimedium, Tribulus, and Eucomyia Longfolia. I later switched to Ester C to go with the lysine and proline and that seemed to improve things more too (cya). Now I just use more glycine in place of the lysine and proline as they can cause side effects or potentially strain kidney function. Not sure if/how T effects klotho, it probably doesn't or men would have more, but it seems to compliment it well as I'm thinking arginine restriction does. 

 

So yeah, as far as structural fidelity is concerned klotho/tocotrienols are king and my mood tends to be better. May improve allergies. I've switched to a palm oil extract as opposed to the annatto bean extract and my skin seems a little more itchy lately.. but I really can't say I was paying that much attention, it could be something else. I am supposed to limit my tocopherol intake according to my genome though.

These reduce HMG-CoA Reductase.

 

The gamma/delta from of tocotrienols inhibits cholesterol synthesis by suppression of HMG-CoA reductase activity by two post-transcriptional actions.  These include increased controlled degradation of the reductase protein and decreased efficiency of translation of HMG-CoA reductase mRNA. The tocotrienols block the adaptive response of upregulation of HMG-CoA reductase secondary to competitive inhibition by the statins.

 

Pantethine inhibits cholesterol synthesis and acclerates fatty acid metabolism in the mitochondria by inhibiting hepatic acetyl-CoA carboxylase; increases CoA in the cytoplasm, which stimulates the oxidation of acetate at the expense of fatty acid and cholesterol synthesis; and increases Krebs cycle activity. In addition, cholesterol esterase activity increases and HMG-CoA reductase activity decreases. There is 50% inhibition of fatty acid synthesis and 80% inhibition of cholesterol synthesis.

 

From the article, a full stack could include something like Tocotrienols, Pantethine, Red yeast rice, Sesame Lignans, Green tea extract, Citrus bergamot, Garlic extract, Curcumin, Gamma-linolenic acid, Plant sterols, and Fish oil.  There are several others as well, like vitamin C, or lovastatin (like you would get from eating oyster mushrooms.)

 

If these inhibit HMG-CoA Reductase, I'm curious what happens when you run out of these or switch to a different supplement -- does HMG-CoA Reductase not swing in the other direction once it's no longer being actively reduced?

[HaplogroupW]

Tocotrienols inhibit HMG-CoA. No clue about the statins.

http://www.ncbi.nlm....pubmed/12656204
http://www.ncbi.nlm....pubmed/11882333

 

Unrefined red palm oil is ~800 ppm vit E, with 70% of that being tocotrienols:

 

• alpha tocopherol: 187 ppm
• alpha tocotrienol: 208 ppm
• gamma tocotrienol: 376 ppm
• delta tocotrienol: 98 ppm

according to table 4 here:

http://journals.sage...482650002100213

 

Although there are supplements now that claim no tocopherols, only tocotrienols.

 

They guys claim to be two years from clinical trials:

https://www.klotho.com/

 

 

Edited by HaplogroupW, 05 October 2017 - 04:25 AM.

[slotrite]

Ursolic acid and aronia are both conducive to high levels of klotho.

 

[Daniel Cooper]

 

 

 

They guys claim to be two years from clinical trials:

https://www.klotho.com/

 

 

I looked at their website and they appear to be a little thin on details.  I take it they are developing a synthesized klotho or klotho analog protein?  Orally deliverable would be nice.  Do we know any more about what they're doing?  

 

I noticed they called themselves a virtual company with no employees.  How does that work?

 

Hope they are successful.  Exogenous klotho might be just the ticket.

[YOLF]

 

Tocotrienols inhibit HMG-CoA. No clue about the statins.

http://www.ncbi.nlm....pubmed/12656204
http://www.ncbi.nlm....pubmed/11882333

 

Unrefined red palm oil is ~800 ppm vit E, with 70% of that being tocotrienols:

 

• alpha tocopherol: 187 ppm
• alpha tocotrienol: 208 ppm
• gamma tocotrienol: 376 ppm
• delta tocotrienol: 98 ppm

according to table 4 here:

http://journals.sage...482650002100213

 

Although there are supplements now that claim no tocopherols, only tocotrienols.

 

They guys claim to be two years from clinical trials:

https://www.klotho.com/

 

Annatto or Achiote is also a source of Delta and Gamma tocotrienols and lacks tocopherols. That's probably the supplement extract you're looking at that claims zero tocopherols.

[YOLF]

 

 

 

 

They guys claim to be two years from clinical trials:

https://www.klotho.com/

 

 

I looked at their website and they appear to be a little thin on details.  I take it they are developing a synthesized klotho or klotho analog protein?  Orally deliverable would be nice.  Do we know any more about what they're doing?  

 

I noticed they called themselves a virtual company with no employees.  How does that work?

 

Hope they are successful.  Exogenous klotho might be just the ticket.

 

Well as far as I know there are two klotho compounds, the peptide and the enzyme. I'm guessing they're studying the PEP1192 peptide and it looks like they are aiming for a pharmaceutical product rather than a supplement, but I imagine the stuff would be safe enough to fast track to an OTC medicine.

 

I'm betting they are just outsourcing their research to various labs.

[slotrite]

https://www.ncbi.nlm...pubmed/27470332

Ursolic acid and aronia are both conducive to high levels of klotho.

https://www.ncbi.nlm...okeberry klotho