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LPS Increases During Aging: Besides Calorie Restriction, What Else Can Reduce It?


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LPS increases during aging, which may explain the age-related increase for CD38 and decreased NAD+. LPS is decreased on a calorie restricted diet, but what else can reduce it? In this video, I present evidence for intestinal alkaline phosphatase's (IAP) role on LPS, and posit that interventions that increase IAP may be an important approach for increasing NAD+.

 

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This is why I have doubts about the validity of the markers of biological age in a previous video of yours which included things such as alk phos assigning weights to their values with respect to an optimum.  But alk phos is a composite of multiple isoenzymes including IAP which as you point out here might be better to have higher in advanced age while one or more of the other flavors such as from bone or liver might be indicative of trouble when high.

Lipoproteins such as LDL also play a role in neutralizing LPS.  High LDL in response to high LPS burden might be a good thing despite a high LPS burden being harmful.  I see something similar with WBCs where low counts are associated with better health not because WBCs are harmful but because they can be a marker of disease resulting in increased need.  Pesticide induced anemia could lower disturbingly high WBCs without actually reducing ones biological age.

Edited by Todd Allen
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"But alk phos is a composite of multiple isoenzymes including IAP which as you point out here might be better to have higher in advanced age while one or more of the other flavors such as from bone or liver might be indicative of trouble when high."

-That's not accurate. Intestinal alkaline phosphatase (IAP) is only found in the gut, whereas serum alkaline phosphatase is found in the blood. Yes, they're isozymes, but they're found in different locations. Levine's biological age test measures serum levels, which are correlated with IAP-lower IAP in the gut is correlated with higher serum AP. Ideally, as I mentioned in the video, having higher IAP in the gut, and correspondingly, lower serum AP is ideal.

In terms of LDL, yes, that's true, and when considering that gut barrier function declines during aging, whereas LPS and LDL both increase, it makes sense that having higher cholesterol likely aids the immune system (and AP) in LPS detoxification.

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6 minutes ago, Mike Lustgarten said:

That's not accurate. Intestinal alkaline phosphatase (IAP) is only found in the gut, whereas serum alkaline phosphatase is found in the blood. Yes, they're isozymes, but they're found in different locations. Levine's biological age test measures serum levels, which are correlated with IAP-lower IAP in the gut is correlated with higher serum AP. Ideally, as I mentioned in the video, having higher IAP in the gut, and correspondingly, lower serum AP is ideal.

A serum alk phos isoenzyme test includes IAP which has a significant non-zero reference range.

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1 minute ago, Mike Lustgarten said:

Also, if IAP is elevated in the blood, that further suggests gut barrier dysfunction (i.e. it leaks from the lumen to the blood).

It could.  Or it might be transiently high due to a high fat meal.  And it could be low in the blood because it is too low in the bowels.  Don't you see the inadequacy of lumping a bunch of unrelated things together each of which could be high or low for both good and bad reasons?

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High fat meals-->increased LPS in the blood (https://academic.oup.com/ajcn/article/86/5/1286/4651083). They're not unrelated, and higher AP, whether it's from serum, intestine, bone, or their sum in the blood is not a good thing, unless you have evidence that contradicts that statement. My initial statement was that high levels of IAP in the intestine (measured in stool samples, for ex., see https://www.thelancet.com/article/S2352-3964(15)30211-5/fulltext) is good, and relatively lower AP in the blood is optimal.

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3 hours ago, Mike Lustgarten said:

They're not unrelated, and higher AP, whether it's from serum, intestine, bone, or their sum in the blood is not a good thing

There are also many identified harmful causal factors for low levels of the various isoforms.  Having one isoform drop too low lowers the computed biological age of someone with another isoform that is too high.  It makes as much sense as a fat person being comforted by sarcopenia or osteopenia because their only measure of health comes from a scale.

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I think you're misunderstanding me, Todd. High levels of IAP are good for longevity, do you dispute that? Also, relatively lower levels (~50) of serum AP are associated with a reduced all-cause mortality risk. There are papers that support each of these ideas. Do you dispute that?

If you have data for age-related changes or all-cause mortality data for the various blood AP isoforms, I'd like to see that.

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20 hours ago, Mike Lustgarten said:

I think you're misunderstanding me, Todd. High levels of IAP are good for longevity

Yes and this good thing increasing IAP in the intestines will increase slightly serum alkaline phosphatase, moving it in the same direction as a bad thing, intestinal cellular damage resulting in increased rate of IAP leakage.  Alkaline phosphatase includes enzyme from liver, bones and other tissues and there are good and bad things that lower each isoform and good and bad things that raise each isoform.  It is wrong to state that an alk phos of 40 is some amount more desirable/younger then of 45.   Only for a population in a statistical sense are there optimal values.  On an individual basis context matters.  Most if not all of the biomarkers used in the biological age formula suffer from similar problems.  Tests are included in standardized panels because they are easy/cheap to do not because they are the best or even good.

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"Yes and this good thing increasing IAP in the intestines will increase slightly serum alkaline phosphatase".

-If you have published evidence for this, I'd like to see it. In fact, the opposite is true. For ex., less IAP in the intestine-->more circulating LPS (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7213802/). LPS causes increases for serum alkaline phosphatase (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3622013/).

I never said that an alkaline phosphatase of 40 is better than 45. Values ~50 are optimal based on all-cause mortality data in > 9 million subjects: https://michaellustgarten.com/2019/10/07/alkaline-phosphatase/. Serum alkaline phosphatase levels also increase during aging, which is why I said that generally lower is better (with 50 as a cutoff).

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Do you have published evidence that someone with an alkaline phosphatase of 25 can double it by drinking? Ha, because again, it looks like the opposite is true: alcohol consumers have significantly lower ALP (https://pubmed.ncbi.nlm.nih.gov/27334005/). So she's have to give up the alcohol, which would potentially raise her ALP, and I'd bet that lots of other variables would improve, too.

Levine's Phenotypic age calculator was derived on ~10,000 subjects in NHANES III, this isn't an arbitrary measure based on nothing.

Edited by Mike Lustgarten
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1 hour ago, Mike Lustgarten said:

Do you have published evidence for someone with an alkaline phosphatase of 25 can double it by drinking? Also, you assume that she'd optimize her biological age by improving alkaline phosphatase without altering the other variables.

We can look at text books for alk phos and find a large number of things which are bad that lower it and a large number of things which are bad that raise it.  We don't need research to show exact amounts by which these things do so to recognize that a given value or change in values is meaningless without the context of the causes for that resulting value.  And yes there is a possibility that another biomarker might change in a way that compensates for this ones failure.  But they might also exaggerate the problem as the other biomarkers also have problems.  For example, the anorexic woman has very little muscle mass so her creatinine was also too low but the drinking aggravates her early stage kidney disease optimizing her creatinine in addition to her alk phos.

Edited by Todd Allen
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5 hours ago, Mike Lustgarten said:

Do you have published evidence that someone with an alkaline phosphatase of 25 can double it by drinking? Ha, because again, it looks like the opposite is true:

001612: Alkaline Phosphatase Isoenzymes | Labcorp

Liver is the isoenzyme most frequently elevated when total ALP levels are elevated. Liver ALP increases in the blood early in liver disease before most other liver function tests show abnormalities. The wide group of conditions leading to increased liver ALP include acute hepatitis, cirrhosis, fatty liver,
 
Those can each be caused by excess alcohol consumption.  And a 25 point increase in ALP is tiny so it would only take the earliest stage of disease to produce it.  But let's assume from your
 reference that moderate consumption lowers ALP.  In that case we can correct an elevated ALP by moderate drinking which still is unlikely to actually be reducing biological age.
 
Edited by Todd Allen
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That's not a direct, published reference. Alternatively, alcohol consumption didn't affect alkaline phosphatase in this study (https://pubmed.ncbi.nlm.nih.gov/2884551/).

If you think it's so easy to "hack" biological age, whether it's alkaline phosphatase or other variables, do the experiment, see for yourself. Otherwise it's mere speculation.

Edited by Mike Lustgarten
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2 hours ago, Mike Lustgarten said:

That's not a direct, published reference. Alternatively, alcohol consumption didn't affect alkaline phosphatase in this study (https://pubmed.ncbi.nlm.nih.gov/2884551/).

If you think it's so easy to "hack" biological age, whether it's alkaline phosphatase or other variables, do the experiment, see for yourself. Otherwise it's mere speculation.

You can find the same info in Harrison's Principles.  Numerous liver conditions can cause 2X the UL for ALP and alcohol is a potential cause of those conditions.  I'm not interested in hacking this.  I'm trying to help you see the Levine biological age formula is disconnected from reality and should not be used the way you are using it.  Another example, ALP is highest in our youth it does not linearly increase with age.  A given value tells you nothing about your age.

Edited by Todd Allen
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"I'm trying to help you see the Levine biological age formula is disconnected from reality and should not be used the way you are using it."

-This is your opinion, and it is not based in any facts, only speculation.

"Another example, ALP is highest in our youth it does not linearly increase with age."

I've yet to see evidence that ALP is highest in youth. For example, ALP levels are higher in those older than 50, when compared with younger ages: https://www-tandfonline-com.ezproxy.library.tufts.edu/doi/pdf/10.1080/00365510410002742?needAccess=true. ALP increased during aging in NHANES III (Table 1, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5260794/) one of the datasets that Levine used to derive the Phenotypic age test.

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3 minutes ago, Mike Lustgarten said:

This is your opinion, and it is not based in any facts, only speculation.

I've yet to see evidence that ALP is highest in youth.

Mike, open your eyes and use them to read medical text books.  You didn't even know that intestinal alkaline phosphatase is present in serum tests of alkaline phosphatase.

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I don't think that you realize that medical textbooks are written based on the published literature. I've supported my claims with an abundance of published literature, whereas you've offered opinions.

"You didn't even know that intestinal alkaline phosphatase is present in serum tests of alkaline phosphatase."

-This is a preposterous statement. Above, I said, "It looks like there are 2 different CPT codes for serum AP: AP by itself (84075), and the sum of all AP isoforms (84080). I'm not sure which is commonly measured on a CBC."

-You're going to tell me that you know which AP test is measured on the CBC? You're assuming that it's the sum of all isoforms, which would include IAP as a small component in the serum measure, but it could easily only be serum AP by itself (not IAP, bone AP, etc). 

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On 2/10/2021 at 9:16 AM, Mike Lustgarten said:

"But alk phos is a composite of multiple isoenzymes including IAP which as you point out here might be better to have higher in advanced age while one or more of the other flavors such as from bone or liver might be indicative of trouble when high."

-That's not accurate. Intestinal alkaline phosphatase (IAP) is only found in the gut, whereas serum alkaline phosphatase is found in the blood.

 

8 minutes ago, Mike Lustgarten said:

"You didn't even know that intestinal alkaline phosphatase is present in serum tests of alkaline phosphatase."

-This is a preposterous statement.

 

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Just now, Todd Allen said:

The video is about IAP, not serum AP's effect on lifespan. That you believe I didn't know that IAP can be measured in blood is absurd. What I don't know is which AP test is performed as a part of the CBC-AP by itself or as a composite of all the AP isoforms. Lef.org's CBC test (which is where I get the majority of my blood tests) only mentions AP, not which CPT code that they use. Nonetheless, the video doesn't discuss serum levels of AP, so this is a moot point. The video also explains how to increase intestinal levels of AP, not serum AP.

 

 

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39 minutes ago, Mike Lustgarten said:

You're going to tell me that you know which AP test is measured on the CBC? You're assuming that it's the sum of all isoforms, which would include IAP as a small component in the serum measure, but it could easily only be serum AP by itself (not IAP, bone AP, etc).

ALP is typically in a metabolic panel and not a CBC.  When part of these panels it will be the basic test 84075.   84080  adds an additional step of electrophoresis to stratify the isoforms.  IAP is present in each.  That you refer to serum AP as it were some type of AP and having informed us it is found in the blood as if the definition of serum was not the liquid part of the blood makes a terrible impression...

 

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