Endotoxin (LPS) suppresses "anti-aging protein" Klotho

[Limon9]

Molecular cloning of rat klotho cDNA: markedly decreased expression of klotho by acute inflammatory stress​

Biochem Biophys Res Commun. 1998 Oct 29;251(3):920-5. Ohyama Y et al.

"We have recently identified a novel gene, termed klotho, that is involved in the suppression of several aging phenotypes (1). A defect in klotho gene expression in mice leads to multiple disorders including arteriosclerosis, osteoporosis, pulmonary emphysema and skin atrophy in addition to short life-span and infertility. This observation suggests that Klotho may play a part in the signaling pathway that regulates aging and the development of age-related diseases."

"In the present study, we isolated rat klotho cDNA and examined its tissue distribution in rats. The chromosomal localization of rat klotho was also determined by fluorescence in situ hybridization (FISH). In order to explore functions of Klotho, we investigated effects of acute stress on klotho expression."

"Northern blot analysis using the rat klotho cDNA probe identified a single transcript of 5.2 kb in size expressed predominantly in the kidney (Fig. 2A), while RT-PCR detected low levels of expression also in the brain, lung, intestine, and ovaries (Fig. 2B). To determine whether klotho expression undergoes developmental regulation, RNAs were isolated from kidneys of prenatal and neonatal rats at different ages. Expression in the kidney was faintly detected at 18 days of prenatal life (E 18) and 1 day of age, and markedly augmented after 4 days of age (Fig. 2C)."

"Northern blot analysis showed that klotho expression was not affected either by acute hypertension induced by L-NAME, an inhibitor of NO synthesis (Fig. 3A), or by hypovolemic stress produced by withdrawal of blood (Fig. 3B). On the other hand, klotho expression was markedly decreased in LPS-injected rats (Fig. 3C). Dose dependent decrease of klotho mRNA by LPS was observed, and the decreased expression could not be prevented by simultaneous injection of L-NAME."

"The present study also shows that klotho expression is markedly decreased in LPS-injected rats, suggesting that expression of klotho is affected by acute inflammatory stress. Nonetheless, we could not demonstrate that expression of klotho is down-regulated by the combination of LPS and TNF-a and IL-1b in 293 cells or in RPTEC. The decreased expression of klotho may be produced by other factors involved in acute inflammatory responses. Further studies are needed to elucidate the mechanisms by which the klotho expression is regulated in acute inflammation."

The Metabolic, Neuroprotective Cardioprotective And Antitumor Effects Of The Klotho Protein
Androgens Boost, Estrogen Inhibits, Anti-aging Gene Klotho

 

[Mauritio]

Interesting.
Thanks for sharing.
Another reason go keep endotoxin at bay.

 

[Limon9]

Interesting.
Thanks for sharing.
Another reason go keep endotoxin at bay.

Yup. I think the Klotho protein is an unrecognized target of many popular pharma drugs, and it might explain some of their beneficial effects.

Rapamycin: Inhibition of the Mammalian Target of Rapamycin May Augment the Increase in Soluble Klotho Levels in Renal Transplantation Recipients
Simvastatin: Simvastatin enhances the hippocampal klotho in a rat model of streptozotocin-induced cognitive decline
Angiotensin II blockers: Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat "Aging-Related Disorders"
Angiotensin II blockers (again): Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria
... again : Elevated circulating alpha-klotho by angiotensin II receptor blocker losartan is associated with reduction of albuminuria in type 2 diabetic patients
Metformin: Basic Research in Diabetic Nephropathy Health Care: A study of the Renoprotective Mechanism of Metformin

Angiotensin II is considered a major endogenous antagonist of Klotho, and we know that policosanols are a natural replacement for statins and blood-pressure medication, reducing cholesterol and BP/aldosterone values. With its effects on calcification and vitamin D levels, it's pretty obvious that the regular bulk form has the same effect as the fancy ****, as you discussed here.

 

[Jamsey]

Yup. I think the Klotho protein is an unrecognized target of many popular pharma drugs, and it might explain some of their beneficial effects.

Rapamycin: Inhibition of the Mammalian Target of Rapamycin May Augment the Increase in Soluble Klotho Levels in Renal Transplantation Recipients
Simvastatin: Simvastatin enhances the hippocampal klotho in a rat model of streptozotocin-induced cognitive decline
Angiotensin II blockers: Expression of Longevity Genes Induced by a Low-Dose Fluvastatin and Valsartan Combination with the Potential to Prevent/Treat "Aging-Related Disorders"
Angiotensin II blockers (again): Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria
... again : Elevated circulating alpha-klotho by angiotensin II receptor blocker losartan is associated with reduction of albuminuria in type 2 diabetic patients
Metformin: Basic Research in Diabetic Nephropathy Health Care: A study of the Renoprotective Mechanism of Metformin

Angiotensin II is considered a major endogenous antagonist of Klotho, and we know that policosanols are a natural replacement for statins and blood-pressure medication, reducing cholesterol and BP/aldosterone values. With its effects on calcification and vitamin D levels, it's pretty obvious that the regular bulk form has the same effect as the fancy ****, as you discussed here.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/S0014-5793(03)00894-9

“iron chelation suppressed the angiotensin II-induced down-regulation of this gene, suggesting that alteration in iron metabolismma has a role in the angiotensin II-induced downregulation of renal klotho expression. Furthermore, a free radical scavenger also suppressed the angiotensin II-induced down-regulation of klotho, supporting the involvement of an increased production of reactive oxygen species in this process.”

 

[Jamsey]

Iron: an underrated factor in aging | Aging

Aging | doi:10.18632/aging.203612. Dennis Mangan

www.aging-us.com

“In turn, mTOR also exerts control over iron metabolism, and the inhibition of mTOR activity by rapamycin leads to inhibition of iron accumulation via the iron-regulating hormone hepcidin [10]. Transplant patients taking sirolimus (rapamycin) often develop a microcytic anemia, which has been linked to sirolimus-induced iron deficiency [11].”

https://mdpi-res.com/d_attachment/jcm/jcm-11-05251/article_deploy/jcm-11-05251-v2.pdf?version=1662431428

“Statin therapy decreases the circulating concentrations of ferritin, which might be beneficial for the prevention and/or progression of ASCVD.”

https://mrvsa.com/upload/Effects%20of%20metformin%20treatment%20on%20Iron,%20Zinc%20and%20Copper%20status%20concentration%20in%20the%20serum%20of%20female%20rats%20with%20induced%20polycystic%20ovary%20syndrome.pdf

“The PCO group2 treated with metformin showed a significant (p≤0.05) decrease in serum Fe concentration as compared with those in animals from group NC-I and PCO-I.”

 

[Limon9]

Iron: an underrated factor in aging | Aging

Aging | doi:10.18632/aging.203612. Dennis Mangan

www.aging-us.com

“In turn, mTOR also exerts control over iron metabolism, and the inhibition of mTOR activity by rapamycin leads to inhibition of iron accumulation via the iron-regulating hormone hepcidin [10]. Transplant patients taking sirolimus (rapamycin) often develop a microcytic anemia, which has been linked to sirolimus-induced iron deficiency [11].”

https://mdpi-res.com/d_attachment/jcm/jcm-11-05251/article_deploy/jcm-11-05251-v2.pdf?version=1662431428

“Statin therapy decreases the circulating concentrations of ferritin, which might be beneficial for the prevention and/or progression of ASCVD.”

https://mrvsa.com/upload/Effects%20of%20metformin%20treatment%20on%20Iron,%20Zinc%20and%20Copper%20status%20concentration%20in%20the%20serum%20of%20female%20rats%20with%20induced%20polycystic%20ovary%20syndrome.pdf

“The PCO group2 treated with metformin showed a significant (p≤0.05) decrease in serum Fe concentration as compared with those in animals from group NC-I and PCO-I.”

This is really good. Torres P et al make mention of the angiotensin/iron interaction. There's an ecological rationality in the protective effect of the fabled old(/Bulgarian) vitamin E, a notable source of Klotho-inducing policosanols, against iron damage.

 

[Jamsey]

This is really good. Torres P et al make mention of the angiotensin/iron interaction. There's an ecological rationality in the protective effect of the fabled old(/Bulgarian) vitamin E, a notable source of Klotho-inducing policosanols, against iron damage.

Yeah, my thoughts about klotho comes to down to basically Klotho regulates phosphate excretion and it’s absence or down regulation increases phosphate retention. Anything that increases oxidative stress(main culprits are iron and polyunsaturates participating in Fenton reactions) seems to downregulate klotho and increase phosphate retention, leading to excess parathyroid hormone release to raise blood calcium and counterbalance increased blood phosphate. Conversely, compounds like vitamin e, which stabilize polyunsaturates, and policosanols, which theoretically replace polyunsaturates, should lower oxidative stress and increase klotho expression, increasing phosphate excretion and lowering parathyroid.
I’ve also posted these before but angiotensin not only promotes iron accumulation,

Angiotensin II promotes iron accumulation and depresses PGI2 and NO synthesis in endothelial cells: effects of losartan and propranolol analogs

Angiotensin may promote endothelial dysfunction through iron accumulation. To research this, bovine endothelial cells (ECs) were incubated with iron (30 μmol·L[−1] ) with or without angiotensin II (100 nmol·L[−1] ...

www.ncbi.nlm.nih.gov

but also promotes labile(free) iron increase (iron liberation from stabilizing proteins).

JNK/p66Shc/ITCH Signaling Pathway Mediates Angiotensin II-induced Ferritin Degradation and Labile Iron Pool Increase

Angiotensin II (Ang II) induces deleterious changes in cellular iron metabolism and increases the generation of reactive oxygen species. This leads to an impairment of neuronal and vascular function. However, the mechanism underpinning Ang II-induced changes in iron metabolism is not known. We...

www.mdpi.com

Both processes increase oxidative stress