Sirtuins, Klotho and Ray Peat

Mauritio

It seems that Peat didn't really like sirtuins. He mentions them negatively several times.

Here's a quote from an interview where he talks about sirtuins:

After reading that quote I decided to check if it's true that sirtuins decrease Klotho and p53 and looked through some studies:

"We found that decreased Klotho levels were linked with Sirt1 deficiency, whereas sKL treatment restored Sirt1 expression in aged hearts and mitigated the DNA damage response pathway activation. "
https://pubmed.ncbi.nlm.nih.gov/38976132/
"Recombinant Klotho (rKlotho) protein and the SIRT1 agonist SRT1720 could significantly attenuate MIR injury in diabetes by activating Klotho/SIRT1 signaling pathway to reduce oxidative stress and restore autophagy levels."
https://pubmed.ncbi.nlm.nih.gov/38904464/
I found a great review that looked at the connection between Klotho and sirtuins.
Here's some good quotes:

"In this study, increasing expression of Klotho increased the expression of SIRT1 and exerted its effects by modulating the Wnt/β-catenin signaling pathway (Chen et al., 2021)"

"SIRT1 has been proposed as a key regulator in modulating the Wnt/β-catenin signaling pathway (Bartoli-Leonard et al., 2018). Therefore, it appears that Klotho exerts its beneficial effects on atherosclerotic plaques through SIRT1."

".. they showed in another part of their study that there is a positive correlation between the expression of Klotho and SIRT1 in normal tissues of the brain, heart, and blood vessels, and the epithelium of the digestive system. They suggested that the Klotho-SIRT1 regulatory pathway is widespread in human tissues; and may have an essential biological regulatory function."

"The administration of Klotho protein in these animals inhibited the decrease of SIRT6 protein expression and improved the function and structure of the heart. Interestingly, the knockdown of SIRT6 blocked the ameliorating effect of Klotho on the heart."

"For the first time, Gao et al. showed that the level of expression and activity of SIRT1 is reduced in the aorta of Klotho gene knockout mice."

"On the other hand, overexpression of SIRT1 in Klotho knockout mice reduced aortic stiffness and hypertension."

"Klotho regulates the activity of SIRT1 to some extent by impacting its protein expression. Based on the findings of this study, SIRT1 administration did not impact the expression level of Klotho in tissues, suggesting that Klotho is an upstream regulator of SIRT1 (Gao et al., 2016)."

But there is evidence for some correlational negative effects. From the same review :

"However, not all studies reported a positive association of sirtuin with Klotho. In people with kidney failure, the serum level of SIRT1 was increased, while the amount of α-Klotho was lower than that of the control group. The increase of SIRT1 and the decrease of α-Klotho concentration were associated with the severity of renal dysfunction. Decreased α-Klotho levels were associated with cardiac hypertrophy in hemodialysis patients."

So there was a correlation between SIRT1 and some pathologies, but correlation doesn't equal causality, so I tend to agree with the authors that "suggested that the increase in sirtuin level is a secondary response to oxidative stress, and the effect of oxidative stress is dominant over the effect of Klotho (Zbroch et al., 2020)."

That response seems similar to the increase in FGF21 in response to certain stressor discussed here

And coincidentally SIRT1 increases FGF21 and vice versa.

"On the other hand, FGF21 increases the expression of SIRT and its activity..."

"Another study has shown that the situin1 signaling pathway increases the expression of FGF 21 (Furukawa et al., 2021)."

So to me it seems quite clear that sirtuins don't block klotho, but that they possibly even increase Klotho and even more so that klotho increases sirtuins.
This is the same mistake many people made when quickly dismissing FGF21 as a stress hormone, which i discussed at length here.

But what about p53, the anti tumour protein ?
It seems like sirtuins and Klotho both suppress it:

"Other factors blocked by SIRT1, including p53, PAI-1, and p66Shc, participate in the protection against endothelial senescence [68,69,70]."

"Klotho and SIRT1 prevent the aging of endothelial cells by inhibiting p53 (Hwang et al., 2022)."

If you follow the Klotho and the sirtuins pathway you can see that they both inhibit it

Besides that, I'm not sure if p53 is something you want to increase, but that's a different question.

"Klotho deficiency enhances the expression of p53 and p21, leading to an increase in the number of senescent cells, which can be reduced by suppressing p53 or p21 [61]."
https://www.sciencedirect.com/science/article/pii/S2352906725000326

So if Peat says sirtuins are bad because they block p53, then Klotho is bad too. So that's not really a valid criticism, since he's big proponent of Klotho .

Another interesting fact is that many peaty substances increase sirtuins:

Caffeine increases SIRT3
https://pmc.ncbi.nlm.nih.gov/articles/PMC7493682/
Taurine increases SIRT1
https://pubmed.ncbi.nlm.nih.gov/38549461/
And niacinamide, often mentioned as a SIRT inhibitor, might actually increase sirtuins.
Because B3 increases NAD+, which increases SIRT1. So for a short while niacinamide inhibits SIRT, but since it gets converted and metabolized it to NAD+ , you might actually get a net increase in SIRT activity.
https://pubmed.ncbi.nlm.nih.gov/28417163/

This is impressively corroborated by this in vivo study:

"...NAD, the NAD/NADH ratio, Sirt1, 2, 3, and 6 mRNA expressions, and Sirt1 activity all increased in livers of NAM 100-treated rats."
https://pubmed.ncbi.nlm.nih.gov/24314867/

4.SIRT3 reduced the conversion of SFAs to MUFAs
https://pubmed.ncbi.nlm.nih.gov/31160717/

Im courios what you guys think of that ?
@DavidPS I've seen you post about sirtuins from time to time.
@cs3000

DavidPS

@Mauritio said in Sirtuins, Klotho and Ray Peat:

Im courios what you guys think of that ?
@DavidPS I've seen you post about sirtuins from time to time.

I try not to overthink the effects of sirtuins. My posts about sirtuins have mostly been to support the effects of healthy foods. Here are my posts from the RPF.

https://lowtoxinforum.com/search/2681847/?q=sirtuins&c[users]=David+PS&o=relevance

Dr. Peat's quote about sirtuins needs to read in context. It may have been written many years ago. In addition, it does not distinguish which of the numbered sirtuins applies.

If Peat says sirtuins are bad because they block p53, the context matters here aw well.

Peatbot: P53 is a well-known tumor suppressor protein that plays a critical role in regulating the cell cycle and preventing cancer. It is often referred to as the "guardian of the genome" because of its role in maintaining genomic stability by preventing mutations. When p53 is functioning properly, it can help protect against cancer by repairing DNA or initiating apoptosis (programmed cell death) if the DNA damage is irreparable. However, mutations in the p53 gene can lead to a loss of its tumor-suppressing functions, which can contribute to the development of cancer.