#8

I’m quite active on Wikipedia, but for whatever reason, I’m not convinced the Wiki model will work here (even though I advocated for it initially and also contributed to the Longevity Wiki). I think it’s because all our discussions here are about topics that are controversial or still at the stage of research and not confirmed. Anyway, I won’t edit :slight_smile:

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#9

Rapamycin is not listed: it doesn’t lower hsCRP? (@RapAdmin @John_Hemming any thoughts/experience on this?)

#10

I had my CRP really low before starting on rapamycin.

I think baseline CRP is a representation of the senescence burden. I dont’t think Rapamycin hits this directly. Hence over a period of time it may have some benefit, but not an obvious one.

The other issue is that people don’t often try to measure the baseline. They simply take a single value at one time.

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#11

I hate to even bring it up, but if in the case of CRP, there is the obvious distinction between just lowering the marker itself, hsCRP, without changing the underlying inflammation, and lowering hsCRP, by actually lowering the underlying inflammation the marker is measuring, how do we know which of the interventions listed in the wiki is which?

Unless we have some other way of measuring inflammation, we can’t be sure that an intervention isn’t simply gaming the hsCRP number.

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#12

If an intervention acted to inhibit IL-6 to stop the liver creating CRP your point would be correct. However, if the intervention reduces the underlying generation of IL-6 because inflammation is lower (which is what most interventions do) then it is a good outcome. I am pretty certain that is what is happening.

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#13

I know PQQ and Ashwagandha can possibly lower CRP as well

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#14

Has anyone here experienced hsCRP reduction with omega 3? The literature seems to conclude that omega 3 is useless when it comes to hsCRP:

#15

In reviewing an unrelated paper, I came across this. Is anyone deep on this mutation?

“. . . alleles in the HNF1A gene associated with lower CRP levels have been linked to an increased risk of cardiovascular disease, indicating that low CRP levels do not always correlate with reduced disease risk.”

I then took a quick look (no drilling down yet) using o1 and others to find:

Variants in the HNF1A (Hepatocyte Nuclear Factor 1 Alpha) gene, particularly those associated with lower C-reactive protein (CRP) levels, have paradoxically been linked to an increased risk of cardiovascular disease (CVD). The key variant in this context is:

  • rs1169288 (HNF1A-I27L, A allele)
  • rs1800574 (HNF1A-S487N, T allele)

Mechanism and Implications

  1. HNF1A and CRP Regulation
  • HNF1A is a transcription factor that regulates hepatic CRP expression. Loss-of-function variants in HNF1A lead to lower CRP production, independently of systemic inflammation levels.
  • This means that carriers of certain HNF1A variants may have genetically lower CRP, which can confound the use of CRP as a marker for systemic inflammation or cardiovascular risk.
  1. The Paradox: Lower CRP But Higher CVD Risk
  • In Mendelian randomization studies, individuals with these HNF1A variants have lower circulating CRP but a higher risk of cardiovascular disease.
  • The association between these variants and CVD risk suggests that CRP is not directly causal in ASCVD but rather a marker of inflammation and risk.
  • This supports the notion that CRP is reactive, rather than protective or directly harmful.
  1. Possible Biological Explanation for Increased CVD Risk
  • HNF1A has roles beyond CRP regulation, including glucose metabolism, lipid metabolism, and liver function.
  • HNF1A variants are associated with increased triglycerides, dyslipidemia, and type 2 diabetes (T2D)—all independent CVD risk factors.
  • The increased CVD risk in these individuals is likely mediated by metabolic dysfunction rather than inflammation per se.

Clinical Implications

  • CRP alone is not a perfect measure of cardiovascular risk—especially in individuals with HNF1A loss-of-function alleles.
  • Using CRP as a risk stratifier in patients with these variants could underestimate true cardiovascular risk.
  • The metabolic phenotype of these carriers suggests a need for aggressive lipid and glucose management, independent of CRP levels.

All interesting and deserving of follow up. My apologies if it is behind us. I did not see anything on HNF1As.

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#16

My hsCRP has gone from 0.9 to 0.26 in the past two years. I’m thinking the key things I’ve changed during that time is adding ezetimibe and Ashwagandha (if the first post in this thread is accurate).

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#17

Yes. Mine has declined similarly but over a 3-4 year period. However, I have made so many changes that it is no longer possible to assign attributions. I also think doing so doesn’t make sense at some point. It seems likely that many interventions will lower baseline inflammation, and by a significant amount but each succeeding addition lowers it less in absolute terms even though the percent change may be similar. Austin’s law of diminishing fleas or something like that I think.

The population data suggests it is worth following up on if ASCVD is a concern on one’s overall profile.

The frequency of HNF1A variants associated with lower CRP and increased cardiovascular disease (CVD) risk varies by population and specific allele.

1. rs1169288 (HNF1A-I27L, A allele)

  • Global Frequency: ~25-35%
  • European ancestry: ~27-30%
  • East Asian ancestry: ~30-40%
  • African ancestry: ~15-20%

This variant has been linked to lower CRP, increased triglycerides, and a higher risk of type 2 diabetes and ASCVD.

2. rs1800574 (HNF1A-S487N, T allele)

  • Global Frequency: ~5-10%
  • European ancestry: ~7-10%
  • East Asian ancestry: ~5-7%
  • African ancestry: <5%

This variant has a weaker effect on CRP but is still linked to metabolic dysregulation and cardiovascular risk.

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#18

I have a CAC of 950. hsCRP three months ago was .2 at Quest. (So they might have rounded down from .24.) What does this tell me about my CVD ‘risk’?

#19

If the above genetic variant issue is correct, it would depend on whether you are generically in the group of people who test low on CRP but actually have elevated risk. So far as I know, however, all of the knowable ASCVD risk is still subsumed by two markets: Lp(a) and Apo(b). This is likely a “to be continued” issue.

Assessing TNF-α & IL-10 will indicate the broader NF-κB pathway activity. This should give you good indication of the balance between pro- and anti-inflammatory cytokines and provide a crosscheck on your low CRP level.

#20

I haven’t looked at these SNP’s but most complex traits are highly polygenic, with lots of SNP’s, so you have to sum up the effects of all the genes you have that are relevant (+ or -) for a total score or effect:

See this thread:

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What is your geneticgenie methylation profile?
#21

That’s great. And both were inline with other surrounding datapoint (and not just that you eg had an infection close to the first test but not second test)?

What else could it have been - did you change visceral fat / overall fat levels? I recall you also changed/increases some of your excessive regime?

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#22

Yes - normal health in both cases. I have ramped up my exercise program to about 1 hour +, 4 or 5 times a week. I’ve done this for the past 3 or 4 months - so that might have had an effect.

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#23

My CRP fell from 1.6 to 0.25 over a 9-month period. I believe the main contributors were starting ashwagandha 900 mg, quercetin 500 mg, and astaxanthin 24 mg. All of these have some studies reporting CRP lowering benefits.

My CRP actually rose a bit over my first 8 months of rapamycin. So, there hasn’t been any clear sign it is helping in that regard for me, but I am still taking it.

#24

Ezetimibe did nothing to me and research shows it does nothing for hsCRP (the first post was incorrect and I fixed it). So ashwagandha might be the cause. How much do you take? Any thoughts on ashwagandha @John_Hemming?

#25

I personally have tried aswaghandha twice. The first time was well before I really understood what was going on and I did not conclude it helped. The second time it made me ill (one of only two substances to do that the other being PQQ which was probably an interreaction with alcohol).

There is an Indian MD who campaigns against it because it can cause liver disease (which is true).

I don’t understand how it does any good if it does. It may do some good, but as a general principle I recommend against using it. I do maintain an open mind and if there was good evidence to take it then I would consider it.

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#26

Same for me. My hsCRP was going down slowly but went below 1 with rosuvastatin 20mg.
Ezetimibe and Empagliflozin did not improve that further but Tirzepatide did and at 0.29 it was improved by a factor of more than 10 compared to the bad state I started.
Obviously Covid increased it but it’s still below 1.

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#27

I take 2 capsules (1,000mg total) every day of this product: https://www.costco.com/youtheory-ashwagandha-1000-mg%2C-180-vegetarian-capsules.product.4000181013.html

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