Dietary CD38 Inhibitors: Are They Correlated With Biological Age?
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- Опубліковано 30 лип 2021
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Apigenin, quercetin, luteolin data: USDA Database for the Flavonoid
Content of Selected Foods
www.ars.usda.gov/arsuserfiles...
Kuromanin data: phenol-explorer.eu/contents/po... - Наука та технологія
The amount of work you put into your analysis is impressive. I really like your food first approach.
Thanks rvdt4ever!
Amazing in-depth analysis!
I know I’m 2 years behind the pack, but got to say this is very well presented. Concise, informative and no messing about 👍
Thanks @Sydopath!
Great stuff!!!!
Thanks Lucky Hanger 13!
Interesting case study.
That is a lot of Parsley :-)
Very good work, thanks!
Could it be that you aren't seeing much of an impact because your NAD+ levels are not actually problematic? If what you're doing is maintaining a healthy NAD+ baseline, keeping it there with the help of cd38 inhibitors won't make you any younger. The effect is is perhaps saturated, but still helpful for pheno-age maintenance rather than pheno-age reduction.
Yes, that's true, good point. To see if it stays that way, I can do a yearly update for CD38 inhibitor intake vs biological age.
Fantastic video as always Michael. Do you think you could cover ideal RHR for longevity?
Thanks Matt. Have you seen this video?
ua-cam.com/video/XskTAUb6-ac/v-deo.html
Michael, maybe it's not a question of not emough Cd38 inhibitors, but that the sum of everything you do masks out the effect of the amount of CD38 inhibitors in your food. You probably have very good gut barrier function due to the way you eat and this could carry more weight. And your lowest daily consumption of ~160 mg is still fairly high compared to the vast majority of people. Maybe one experiment would be to remove the small group of foods that contribute the most in terms of CD38 inhibitors, basically drive down your total daily consumption to a small fraction of current values, say < 10 mg/d, without shifting anything else to any degree. The down side is that you would potentially subect your body to negative effects for many months.
Thanks Peter, that's a good point, and I considered it, too. While that would be a good way to test the hypothesis, I'm not going to take out parley and berries, mostly because of, as you mentioned, any potential negative effects without having them in my diet. Plus, while it would be easy for me to take out parsley, I'm addicted to berries, so taking them out wouldn't last long. Alternatively, one could argue that up to 387 mg/d is a lot, and we'd expect to see correlations with biological age, or more significant correlations with individual biomarkers at that dose.
Dr. Lustgarten,
I would be very curious to see you do a video on the recently published article about the secondary bile acid: isoalloLCA in centenarians. I'm sure you are aware of the article in Nature due to your work with the microbiome and longevity.
Hey Tyler Oakes, I don't know if I'll make a video about it (I've got a few videos on the list first), but it's an interesting find. Relatively higher cholesterol levels are associated with CVD risk, but for those who don't get CVD, higher total cholesterol is also associated with reduced all-cause mortality risk in 85 yr olds. That study ties in with that-higher cholesterol-->more cholesterol metabolizing bacteria-->increased conversion into secondary bile acids by those bacteria story in the Nature paper.
Thank you Micheal. Excellent content as always. Do you think dried parsley would be effective as well?
Yes, why not? I prefer whole foods in order to maximize nutrient density. I'd recommend blood testing, as I've done in the video, to see if it works for you (or not).
@@conqueragingordietrying1797 Excellent thank you. I would prefer whole foods as well, I just have a boatload of it in my pantry that needs to be utilized.
Great video, a few comments. When you're summing up all the intake of your CD38 inhibitors, aren't you assuming that they all have the same strength/dose? What if Luteolin is 100x more effective than kuromanin? What if Kuromanin is assosciated with decreased red blood cells, and Quercitin is associated with increased red blood cells? IMO the study should study each one individually, and take a safe but (increased) clinical dose to be sure that there is no correlation or what the correlation actually is. Also since this study was done over years, and you are human...Could you have increased the dose over time of one of the foods which made it seem like it's correlating with increased aging, when in fact you are just getting older? Last thing, what if it isn't actually the CD38 inhibitors that are showing these effects but some other chemical that just happens to be present in one or more of the foods you are taking? Another reason to take a clinical (isolated) dose rather than study the much more complex food which contains it.
Yes, that's a fair point. I have the individual data, too-in future videos, I'll present them separately and all together. I weight literally everything that I eat, so the diet data is close to accurate as you can get. Ha, in terms of me getting "older" check out my biological age videos, I'm doing pretty good at slowing that down. That's also a fair point about other aspects of the foods outweighing the benefits of the CD38 inhibitors. In theory, to properly test this, I'd keep my diet the same and use the CD38 inhibitors as supplements, but I'm not going to do that. Others can try it and report back if they like!
Great analysis! Is there a way to directly estimate CD38 levels from your data and correlate that with the inhibitor amounts? Some ideas to consider that you already know: CD38 is associated with white blood cells, suggesting that Inflammation might upregulate those cells and the receptor. Also there is an association with the thymus suggesting that thymus health is an important variable. And there are associations with calcium, suggesting D3 and K2 might play a roll. Increasing glucose levels in the blood obviously upregulates the worst aspects of all of these too. I enjoyed this work!
I can measure CD38 in blood cells, but that test isn't commercially available, as far as I know, and thanks Earwaxfire909!
So much work with no awesome result... Science is hard!
How about now also doing CD38 blood tests (with the CD38 inhibitors in diet and then later without them in the diet) to see whether or not CD38 levels are actually being effected?
If we were testing causation in the lab, that's exactly what we'd do. But taking out all these CD38 inhibitors likely affects my health in other ways, so I'm not keen on taking them out. Increasing my intake though, so see how high I can go may be the route i go. I'm up to 50g of fresh parsley in my smoothie today.
Great video and really interesting results. How about using dried parsley as your apigenin source, ive been able to add 10g/d easily to meal replacement shakes without any change in flavour and its much more apigenin dense. Watercress is also a great way of adding quercetin in a super low caloric way. Im also curious as to the strength of these CD38 inhibitors, i would guess that kuromanin may not be as significant as the others. Also, there seems to be quite a strong relationship between CD38 Inhibitors and testosterone levels that would be interesting for you to measure as well.
Dried parsley sounds like a great idea. How has your experience been with it?
The IC50 for inhibiting CD38 for those 4 flavinoids is as such, you could use the reciprocal (1/IC50) as a multiplier and get a standarized "CD38 inhibitor dose" that should correlate better with CD38 inhibition.
Quercetin: Approximately 16.4 μM
Luteolin: Approximately 8.2 μM
Apigenin: Approximately 15 μM
Kuromanin: Approximately 6.3 μM
Wow, I will have to increase my intake of these and grow some parsley.
I wonder if there is a way to assess any impact if digestive health on the ability to influence the dose dependent response of dietary consumption of apigenon and other longevity micronutrients/antioxidants/polyphenols etc.
The 2021 "Regulation of Neurotransmitters by the Gut Microbiota and Effects on Cognition in Neurological Disorders" reviewed associations in that regard.
Not sure, though, that poor bioavailability of polyphenols can be remedied by choosing one out of tens of thousands of specific gut microbiota species. There are too many additive / antagonistic / synergistic combinations to analyze even before twenty species, so researchers won't get sponsored for those studies.
Finding out what your gut microbiota specifically want and giving that to them could be a productive approach. Maybe that will improve polyphenol bioavailability as well?
Do you recommend doing blood tests fasted to get a consistent picture of blood markers? How would food in your stomach affect blood markers during blood test?
All my blood test data is fasted. Alternatively, one could eat different diets and see how it affects blood test data right after. I haven't done that yet...
Maybe you’ve covered this is in a different video but I’d be interested in seeing any correlations between your spermidine intake and biological age markers.
Thanks Amy, that's on my to-do list! Also fisetin, but it looks like fisetin is mostly found in strawberries, so comparing that would just be a marker of strawberry intake, whereas the CD38 inhibitor data comes from many foods.
do u by chance know if apigenin, quercetin, luteolin, and kuromanin per mg/amount are equally effective at inhibiting cd38? or do they have different power levels in that regard? :P
Off the top of my head, I believe that apigenin has the strongest effect.
Thanks for sharing. Would it be worth measuring and tracking CD38 directly. Also does science have an object measurement for lifespan?
Biological age is used as a proxy for that, but other than studies in mice, I don't think an objective measure of lifespan exists.
@@conqueragingordietrying1797 Steve Horvath has produced several iterations of relative age since last year's "Reversing age: dual species measurement of epigenetic age with a single clock." Human age maximum of 122.5 years was used there, but that may change.
Alcaline phosphatase is almost significant with a p of 0.08 and r of 0.47, so it seems it goes in the wrong direction since more AP is worse. But apigenin doesn't seem to be the culprit, since p=0.64 and r=-0.13.
@@quantifiedmax With so few datapoints I was wondering indeed if the method averall is reliable and wouldn't give a lot of false signals. As you say using the CI could perhaps help to be more confident, or also maybe using a p even lower than 0.05 as a criterion, say 0.02 or something, or perhaps some combination of the 2.
Alternatively, when accounting for multiple comparisons (q-values), likely only the glucose correlation would be statistically significant.
Did you test each sub-CD38 inhibitors individually with your biological age results? For example Apigenin consumption alone vs biological age results?
I did-when compared with 20 biomarkers (including Phenotypic Age), apigenin was only significantly correlated with 1 biomarker (Lp(a)), quercetin was significantly correlated with 8 biomarkers (glucose, creatinine, lymphocyte %, homocysteine, neutrophils going in the right direction; RBCs, alkaline phosphatase, AST going in the wrong direction), kuromanin with 3 biomarkers (glucose in the right direction; platelets, RBCs in the wrong direction), and luteolin with 7 biomarkers (glucose, lymphocytes, lymphocyte %, homocysteine, neutrophils in the right direction; RBCs, alkaline phosphatase in the wrong direction).
Thanks for showing that eating a handful of blackberries (most of the CD inhibitor assembly seems to be kuromanin from blackberries) does not have a striking effect on biological aging.
Life does not need to be that simple. I would also suggest not to see biological age as a static entity (not increasing as time goes by), but rather seek correlations with years gained or lost (chronological age - biological age). Furthermore, there is not much spread between the different values you obtained for biological age, and there is not baseline value (like without taking any CD inhibitors). The lack of spread makes it a bit difficult to show statistical evidence. It may even seem also like the values for biological age themselves, are not statistically different from each other.
Otherwise, I much appreciate your publications. The fact of measuring biological age with simple blood tests was I real eyeopener when I discovered it. For years, I thought only in normal or abnormal blood tests results, but it is much more complicated than that.
Hey Guido, my goal was not to debunk the idea that CD38 inhibitor intake doesn't affect biological age, but nonetheless, based on my data, that may not be the case. I'll continue tracking diet and bloods, so with more blood tests, we'll see if this is a real effect or not.
It will be impossible to have literally 0 mg/d of those inhibitors, as I'd have to eat a carnivore diet and no plants, which I won't do. I disagree about the spread of the data-there's a 2-fold range for my CD38 inhibitor intake, and the data shows no significant correlations for biological age within that range. I can go higher, though.
Sorry of I missed it, but have you looked at research or your own data in relation to gut microbiome and longevity?
I've quantified gut microbiome composition 4x, and each time I have a lot of Faecalibacterium, which are known SCFA producers.
Freeze dried oregano is said to have far more apigenin per gram of material and to be far more bioavailable when it comes to apigenin which is absorbed of the total. I eat it with some refined coconut oil. Seems to be a far greater dosage of bioavailable apigenin.
Did you measure your epigenetic age?
Isn't oregano oil toxic?
I suggest to do this analysis not on absolute levels of blood-markers and phenotypic age, but on the CHANGE of these markers during the period you consume a certain amount of apigenine. So e.g. how much does your phenotypic age Change, depending on amount of apigenine consumption, and is There a significant correlation.
That approach will yield the same data as looking at correlations.
Thx Michael. Will these results cause you to now alter your current cd38 inhibitor dietary strategy and regime ? If so which inhibitors given weak biological p value outcomes.
I've been increasing my apigenin content through more parsley over time, and I'm working to wards 50g/d of fresh parsley atm. It may be tough to go above my current intake, especially considering that the majority of CD38 inhibitors are coming from the berries, and while I could eat more of that, it will displace other nutrition. So other than supplementation, I think this is close to my maximalCD inhibitor intake, at least for now.
@@conqueragingordietrying1797 As usual great video with interesting information. What is your average daily intake of berries in grams? And do you typically eat fresh or frozen, organic, non-organic?
Thanks Amy. For the dietary period that corresponds to my latest blood test (7/21/21), I averaged 788g of berries/day, which is up when compared to my average berry intake since I started tracking that info in 2018 (667g/d). I get frozen, organic mixed berries from Costco, as they're cheaper (~$3.50/lb) when compared with fresh (about $6lb or more in Boston)
@@conqueragingordietrying1797 Thanks for the Costco tip! I hadn't looked in their frozen section because I usually run a series of errands during the same trip, but today I did.
@@conqueragingordietrying1797 I had to buy a bigger fridge recently to store the bags and bags of frozen berries😂. Here in Spain, depending on the season, frozen berry prices can be as low as 25% of fresh berries.
Are all those inhibitors equally potent? Maybe weight them by potency x mg?
In vitro studies have identified the potency of those CD38 inhibitors, but whether they're that potent in me is a different story. There's no way to know, other than direct quantification of NAD+ with and without all of the CD38 inhibitors.
- these CD38 inhibitors have very different ic50 values... probably you have to weight them according to their power...
- given the role of cd38 in the modulation of immune system, part. related to unspecific immune response, your results regarding the makeup of the blood profile red+white make sense, indeed very much so.
It is however very interesting so see the the association with reduced glucose... which in itself is a major long term risk factor. - Hence I would like to ask, how is kuromanin related to the Hba1c? especially, if you correct that influence fr the fiber intake that influences it as well...
Thank you
Online postings about how much apigenin (or anything else) is in your food is generic. Depends how your food is grown etc
From the methodological perspective - does it make sense to sum all the flavonoids groups into one number? Wouldn't be multiple regression approach be more appropriate? I agree that in general, a correction for multiple testing should be applied. On the other hand, this is very much an exploratory phase, from the research standpoint. Hence, it might be valuable to be less strict in terms of statistical significance - in order to formulate a testable hypothesis that can be tested with more data in the future. This is not a peer-reviewed paper after all.
Hey ayasugihada, I summed the CD38 inhibitors because they likely don't work in isolation, and collectively, I'd expect their sum to have the most impact on CD38 and NAD. Yes, future videos will include q-values to correct for multiple comparisons.
The point of these data isn't to publish them in a journal (at least not yet), it's for others to follow my journey towards optimal health and lifespan, and based on my biomarker data, so far so good. Also, others can use a similar approach to identify the factors that best optimize their health, rather relying on the hope that epi studies will translate at the individual level.
@@conqueragingordietrying1797 I understand what you mean, but this would require all inhibitors to have the same or at least highly similar effect on the measured markers of biological age. But consider for example Luteolin having ten times the effect per mg compared to Kuromanin. Moreover, there could even be interactions, which cannot be captured by correlating one inhibitor after another. Hope I made it a bit clearer. Love your work. Cheers!
Thanks @@ayasugihada, and that's a fair point. For my next video on this (after a few more blood tests), I'll include the analysis separately for each inhibitor, correlations between the inhibitors, q-values, and the sum of them all. Thanks for your insight, its comments like yours that help the content evolve!
@@conqueragingordietrying1797 Glad to help! I think multiple regression is the most meaningful way to approach the problem... On the condition that the data reasonably fulfill the statistical requirements.
There is a lot of work going into your video, thanks, but I can`t understand
why you don`t use supplements (apigenin, NAC , glycine, etc.) or metformin
to influence the biomarkers. Why are you leaving out all hormones? What
is your intention with this video?
I supplement with VitD in the winter, and methlyB12 for homocysteine. In terms of the rest, my hypothesis is that you can't out-supplement a bad diet or sedentary lifestyle, so those are the factors that I focus on most. I've had progress with that approach, see my previous video:
ua-cam.com/video/hvKogCUOqyA/v-deo.html
That said, I'm not anti-supplement, but they should be secondary to the factors that will impact our health and longevity the most, diet and exercise.
Seems like there would have to be a step increase in CD38 inhibitors in order to tell a difference. Everyone eats foods with CD38 inhibitors and yet it increases with age in everyone. So, it seems to me that a strong change would be needed in order to tell the difference.
I'm not sure that people eating foods with CD38 inhibitors are high in the general population. Most people don't eat a lot of fruit or veg, which is where most CD38 inhibitors are found.
Why don’t you pop 1000mg nicotinic acid (Niacin). 30% turns into NAD. It’s cheap. Only downside flushing
I’ve taken high-dose niacin in the past, and it was bad for my liver enzyme levels.
@@conqueragingordietrying1797 Thanks. I was doing 1500 dropped to 1000 AST/ALT normal. Hate taking it cuz even the mild flush is inconvenience
Have you thought about analyzing the lymphocyte to monocyte ratio and if this changed?
I haven't done that yet, but I'll put it on the list! I just checked, and my LMR average over 29 blood tests since 2015 is 6.8.
BTW, since you are doing multiple testing, you should correct the cut-off for your p-values. At least do the Bonferroni correction and divide by 10 and respectively by 20. After that correction, nothing is statistically significant. en.wikipedia.org/wiki/Bonferroni_correction
I prefer q-values over Bonferroni, but you're right, and in future videos I'll include multiple-testing corrections.
One thing I've always wondered - there are datasets that are commonly used and have been subject to thousands of tests, e.g, national statistics on rainfall, automobile accidents, etc. - does that mean after a certain point, none of these analyses are valid since the aren't corrected for multiple tests? What difference does it make if the the analyses are done by one researcher vs. thousands of individuals?
@@rhyothemisprinceps1617 I wouldn't say that they're not valid, but instead it's data that may be true for most of the population. However, one has to do their own testing to see if it's true for them, and what works in a big population-based study may or may not work at the individual level. For example, there are studies that show protein intake to be almost perfectly correlated (r=0.99) with BUN, and for me, that's true, but I have clients that don't have a significant correlation for their protein intake with BUN.
@@conqueragingordietrying1797 I was just referring to the rationale for the Bonferoni Method/correction. Personalized medicine seems the way to go, if one has the wherewithal. Speaking of wherewithal, hope your Patreon goes well, can't contribute myself, but I did link to your book on a forum - hope you got some sales. Perhaps this is crass, but you could try to monetize the opportunity to vote on what intervention you will try next.
@@rhyothemisprinceps1617 Ah, gotcha. No worries on Patreon, and thanks for sharing the book! It's not crass to ask for a vote, which seems fair, but I follow the correlations in my data, and make dietary changes accordingly, so voting on an intervention wouldn't be the best option.
Wondering if the biological age is not affected until the fasting blood sugar is even lower.
I might be able to reduce glucose, trying an experiment for the next test...
How can you eat so much parsley? The problem is the foods required, like oregano and parsley, nobody eats these, I sure don't, disgusting foods lol. I actually tried this early on with dried parsley, whole parsley, the oregano, etc. I'll just take the extracts, which just seems more practical. Though if in the end it's not doing anything for aging, ugh, wasted time.
Ha, I mix it in a smoothie with raw beets, vanilla bean, some Whey protein, and berries or bananas. It's not bad like that, but I understand the want/need to get it with extracts. Nonetheless, one can do a similar experiment-track how much you take, and use blood testing to see if it works, or not.
I really can’t taste the parsley I add to my smoothies. Are there any health benefits to do with the vanilla?
@@MrGatward Nope, it's there for taste. Note that I'm cutting down on it, from 2g to 1g for my next blood test. It's correlated with a bunch of biomarkers going in the wrong direction, and whether it's causing those changes, we'll see.
tabouli can be good
I mix a tablespoon of each of dried parsley, oergano and dill weed into my yogurt. I buy the herbs by the pound. After a few minutes of mixing, the herbs soften and I realy do not notice them. The dill weed is high in quercitin
What are the risks with artificially reduced CD38 in the body?
I'm trying to keep CD38 low via whole foods (parsley), not artificially. That's the lowest-risk strategy, imo.
@@conqueragingordietrying1797 Is it necessary to take methyl donors while taking CD38 inhibitors? Side Q: what do you think about nattokinase for vascular plaque elimination?
How can we be sure about the accuracy of the phenotypic age which these tests claim to assert? Assuming for the sake of argument that you are actually 45 years old, and that these tests assert that you have a phenotypic age of 35 years old. Well, when a person who is actually 35 years old is tested, surely they will have a phenotypic age which is either above or below their actual age. So in order to calibrate these tests and establish a baseline, they would have to find a large sample of people in each age group whose actual age matches their phenotypic age...
As I presented in my last video, that has been done, and in large studies (> 10,000 people):
ua-cam.com/video/hvKogCUOqyA/v-deo.html
You don't say what your actual age is, but I'm guessing you are in your mid 30s. CD38 inhibitors are meant to protect NAD+ levels which decline with age, and CD38 presence is increased due to inflammation from senescent cells, also which increase with age. A person in their 30s is not likely to see much improvement from CD38 inhibitors simply because they probably don't have enough cellular damage and inflammation yet, whereas an older person who is in a farther state of decline would see a difference. The recommended dosage of apigenin for older people is generally 250 t0 500 mg when taken alongside an NAD+ precursor. Another strategy would be to use a senolytic. but the rate of improvement scales with age and younger people simply don't need it.
Ha, Ronald Koch chronologically I'm 50!
@@conqueragingordietrying1797 So your biological age is mid 30s according to your results, and you were expecting more from apigenin? I'm 63 and am just about to begin an NMN, TMG, Apigenin stack and I'm expecting more significant results. I've been dealing with metabolic syndrome for 20 years.
Well, hell, I could have told you THAT. Why waste your time in the matter? There are much more important studies to conduct.
Ha...Beyond belief, there is evidence in the data.