Supplements Thoughts

[Ron Put]

I've been thinking about supplements. While I try to get most of my nutrients from foods (non-fortified), I also look at my daily pill assortment and think, "Wow! It's a lot of stuff!"

Here is what I take:

 

Curcumin (CurcuWIN 46x absorption): 2 caps

Lycopene: 15mg

Milk Thistle (30:1 extract): 2 cap

Glucosamine HCI: 1500mg

MSM: 1500mg

Vitamin B12: 1000mg

Vitamin D3: 2000

Vitamin K2 (MK-4)

Vitamin K2 (MK-7)

Alpha GPC: 150mg

Coenzyme Q-10: 200mg

Melatonin: 3mg

Resveratrol (Japanese Knotweed): 1450mg


I am thinking of stopping the vitamin K supplementation, since I seem to hit RDA every day now just from food.

I am also considering Biotin, since I seem to have trouble getting RDA according to Cronometer (but who knows how accurate it is, since for instance Almonds are not listed as containing any, but they do, as well as most nuts).

I am trying to decide on Calcium. I may follow Dean's example and add 250mg per day, since it's not easy to get RDA. BTW, baking soda seems to be especially rich in calcium, I wonder if it has any advantages over a pill?

Finally, I periodically go through a bottle of NMN, with maybe 2 month gaps between each bottle.

Anything wrong with the above?

Edited December 12, 2019 by Ron Put

[Dean Pomerleau]

Ron, 

Dietary vitamin K (as listed in the USDA nutrition database and tracked in e.g. Cronometer) is not the same as vitamin K2. I would suggest continuing with the K2, especially MK7 unless you get K2-MK7 from natto, the only significant dietary source as far as I know. I'm dubious about the value of everything else on your list except curcumin, lycopene, B12, and D3, besides giving you very expensive pee. But I've become a supplement skeptic in the last few years, so take that as you will. 

Regarding the baking soda for calcium. As I understand it, not all calcium is created equal when it comes to bioavailability. I'd personally rather take less of a more bioavailable form (e. g. calcium citrate malate) given the evidence suggesting adverse cardiovascular effects associated with high dosage of standard calcium supplements. 

I'm not sure about your diet, but as a vegan I also supplement with iron, zinc, iodine, strontium (for bone health), and one fatty fish meal's worth of algae-derived DHA per week. 

--Dean 

[Ron Put]

Thanks, Dean. Good point on the calcium. I will add it.

I do eat natto on periodically, when I buy a fresh batch. The stuff has a lot of protein though and I am already having trouble keeping mine low.

I eat 2-3 sheets of nori almost every day, good for iodine (100%+ of RDA), among other things.

I am a vegetarian (mostly vegan). For me, it seems easy to get enough iron, see the attached grab from Cronometer.

Strontium, hm? I never thought of it. It seems to be found in leafy vegetables, but perhaps not in sufficient amounts. Any drawbacks of taking it as a supplement?

I started taking glucosamine again recently, because of studies like this one: https://www.bmj.com/content/365/bmj.l1628

Similarly for melatonin: https://academic.oup.com/ehjcvp/article/2/4/258/2197075

And Q-10: http://www.clevelandheartlab.com/blog/horizons-coq10-what-are-the-heart-health-benefits/

I take MSM and milk thistle kind of as liver insurance, and MSM supposedly helps with skin elasticity. I may reconsider MSM, since it may increase methionine production. 

Edited December 12, 2019 by Ron Put

[Clinton]

Ron,

You and Dean have the micronutrients covered including D3, K2 and CoQ10.
Glucosamine is excellent as you’ve found - Vince Giuliano dedicated a glucosamine article on his blog covering its powerful in-vivo effects on decreasing all-cause mortality.

Lycopene is a carotenoid and is very beneficial, and I believe it’s valuable to get plenty of natural forms of vitamin A such as lutein, zeaxanthin, and beta-carotene (I consume carrots and spinach for this).

As far as polyphenols go, I would place a good green tea supplement at the top of the list.  One of the best is AOR Active Green Tea - I take this instead of drinking green tea since I want an effective dose and prefer to drink coffee.

Clinton

Edit:  I’ve recently been taking 250mg daily of Nicotinamide Riboside (instead of NMN).

 

Edited December 13, 2019 by Clinton

[Dean Pomerleau]

Ron,

Regarding iron. I wouldn't put too much stock in meeting the RDA via vegan sources, since absorption varies so much by food type, food pairing and individual variation. Fortunately iron levels are easy to test. If your serum iron, haemoglobin and ferritin levels are within the normal range based on your diet alone, I wouldn't be inclined to supplement. 

Regarding glucosamine - that study seems like a pretty impressive result with respect to lowering cardiovascular disease. It is an anti-inflammatory, so it might make sense that it would be beneficial, at least in the general population. But I wonder if it would have the same benefits in people such as ourselves with very low baseline inflammation and low risk of CVD to start with due to our impeccable diet and lifestyle. I worry it might it be like another anti-inflammatory, aspirin, which seems beneficial for "normal" people at significant risk of CVD, but on balance not good for people with low risk of CVD due to (in aspirin's case) its potential to increase intestinal bleeding.

But the known side effects of glucosamine seem pretty mild, so it is a bit tempting. Glucosamine is commonly taken by people with osteoarthritis (OA). The authors of the head scratcher of a study linking OA to improved cognition and longevity (discussed here and here) claimed to have ruled out the effects of OA-related supplements/medications to explain their seemingly paradoxical finding. But who knows, maybe a lot of the OA sufferers were taking glucosamine and it was beneficial. 

Regarding melatonin, the review article you linked to I found less impressive, particular for those of us whose sleep patterns are already good. 

Regarding CoQ10, I'm not convinced of the benefits for those of us with low risk of CVD, already low levels of inflammation, already good cholesterol levels and blood pressure.

Regarding strontium, here is a discussion Michael and I had a few years back on the pros and cons. Michael doesn't (or didn't then) think the tenuous link between strontium and cardiovascular issues was worth worrying about. I'm not sure what he thinks now. In Europe, strontium is reserved as a treatment of osteoporosis in women patients at high risk of fracture without signs of cardiovascular disease. Here is a section from the full text of [1] on the pros and cons of strontium for bone health:

----------------------

Strontium ranelate

In the European Union, strontium ranelate is approved for
treatment of severe osteoporosis in women at high risk of
fracture who are not candidates for other osteoporosis therapies.[77] Strontium, which is absorbed onto the crystal surface
of bone, inhibits osteoclast activity and enhances osteoblast
activity, thereby decreasing bone resorption and increasing
bone formation, mass and strength.[77] Strontium ranelate
decreases risk of clinical vertebral fractures by 50% and all
osteoporotic fractures by 31%, but it has no effect on risk of
hip fracture.[78]

DRESS syndrome

Drug rash with eosinophilia and systemic symptoms (DRESS
syndrome) is a rare (1 per 49,959 patient-years) but life-threatening complication requiring permanent discontinuation of
strontium ranelate.[79] There have been eighty-six spontaneously reported postmarketing cases of DRESS and ten cases
of Stevens–Johnson syndrome and toxic epidermal necrolysis;
none were observed in the clinical trials.[80] Common DRESS
symptoms include skin rash, facial edema, enlarged lymph
nodes, fever, hypereosinophilia and multisystem (especially
hepatic) dysfunction.[79] DRESS typically occurs 2–6 weeks
after initiation and may persist after treatment discontinuation.[79] The mortality rate is about 8–10%.[79,81]

Venous thromboembolism and cardiovascular events

Strontium ranelate is associated with an increased risk of venous
thromboembolism (VTE) and myocardial infarction (MI). In a
pooled analysis of 7500 postmenopausal women treated with
strontium ranelate or placebo, incidence of VTE was 1.9%
versus 1.3% respectively (relative risk [RR] 1.5; 95% CI,
1.04–2.19), and incidence of MI was 1.7% versus 1.1% (RR
1.6, 95% CI, 1.07–2.38).[82] Strontium ranelate is contraindicated for persons with uncontrolled hypertension or a history of
or current VTE, ischemic heart disease, peripheral arterial disease or cerebrovascular disease; it should be reserved for patients
at high risk of fracture who are not candidates for other osteoporosis treatments.[77,82]

---------------

Here is a section from a very recent meta-analysis [2] of the effectiveness of various treatments to prevent osteoporotic fractures in men:

Strontium Ranelate and the Risk of Osteoporotic Fractures
Three studies (Ringe et al., 2010; Kaufman et al., 2013; Yan, 2014) reported strontium ranelate and the incidence of osteoporotic fractures. The overall effects of pooled analyses did not indicate any significant difference between groups concerning the risk of the vertebral fracture domain (RR, 0.79 [95% CI, 0.35–1.78]), nonvertebral fracture domain (RR, 0.52 [95% CI, 0.13–2.00]), or clinical fracture domain (RR, 0.71 [95% CI, 0.36–1.40]) (Figure S8).

Here is figure S8 from that meta-analysis:

As you can see, there is a definite trend towards reduced fracture risk from strontium in men. But as the authors indicate, the error bars are large and so even the pooled risk reduction is non-significant.

Given the above data, including identified risks and modest (at best) rewards (at least in men) and my general skepticism about supplements as of late, I think I may cut out my  strontium supplement out of an abundance of caution.

[Note to Saul: surprisingly, that same meta-analysis of osteoporosis treatment in men [2] also found that Forteo (aka teriparatide) was not associated with reduced fracture risk in men.]

Ron, thanks for prompting me to look at the most recent data on strontium.

As I said, glucosamine looks a bit tempting. Does anyone else here (besides Ron and Clinton) take it or have an opinion on it?

--Dean   

------------

[1] Expert Rev Clin Pharmacol. 2015;8(6):769-84. doi: 10.1586/17512433.2015.1099432. 

Epub 2015 Oct 20.

The safety and tolerability profile of therapies for the prevention and treatment
of osteoporosis in postmenopausal women.

Komm BS(1), Morgenstern D(1), A Yamamoto L(2), Jenkins SN(1).

Author information: 
(1)a Pfizer Inc , Collegeville , PA , USA.
(2)b Pfizer Japan Inc , Tokyo , Japan.

At a time when the prevalence of osteoporosis and related fractures is
increasing, initiation and continuation of pharmacologic therapies for prevention
and treatment of postmenopausal osteoporosis have declined. This decline has been
at least in part attributable to concerns about safety of these agents, such as
atypical fractures with bisphosphonates and breast cancer with estrogen/progestin
therapy, particularly when they are used long term by older women. However, in
many cases, absolute risk of serious adverse effects is small and should be
balanced against the larger potential for fracture reduction. Here, we review the
safety and tolerability of available therapies for postmenopausal osteoporosis.
Taking into consideration their relative efficacy, we also provide strategies for
optimization of the risk:benefit ratio.

DOI: 10.1586/17512433.2015.1099432 
PMID: 26482902  [Indexed for MEDLINE]
 

----------------

[2] Front Pharmacol. 2019 Aug 9;10:882. doi: 10.3389/fphar.2019.00882. eCollection

2019.

Does Routine Anti-Osteoporosis Medication Lower the Risk of Fractures in Male
Subjects? An Updated Systematic Review With Meta-Analysis of Clinical Trials.

Zeng LF(1)(2)(3), Pan BQ(4), Liang GH(1)(2), Luo MH(1), Cao Y(5), Guo D(1), Chen 
HY(1), Pan JK(1), Huang HT(3), Liu Q(6), Guan ZT(6), Han YH(3), Zhao D(3), Zhao
JL(3), Hou SR(3), Wu M(3), Lin JT(3), Li JH(3), Liang WX(1), Ou AH(1), Wang Q(1),
Yang WY(1), Liu J(1)(2)(3).

Author information: 
(1)The 2nd Affiliated Hospital of Guangzhou University of Chinese Medicine
(Guangdong Provincial Hospital of Chinese Medicine), Guangzhou, China.
(2)Bone and Joint Research Team of Degeneration and Injury, Guangdong Provincial 
Academy of Chinese Medical Sciences, Guangzhou, China.
(3)The Second Clinical College of Guangzhou University of Chinese Medicine,
Guangzhou, China.
(4)Department of Traditional Chinese Medicine, Guangdong Women and Children
Hospital, Guangzhou, China.
(5)Department of Clinical Research/National Clinical Trials Institute, Sun
Yat-sen University Cancer Center, Guangzhou, China.
(6)World Federation of Chinese Medicine Societies, Beijing, China.

Background: Several epidemiological articles have reported the correlations
between anti-osteoporosis medication and the risks of fractures in male and
female subjects, but the specific efficacy of anti-osteoporosis medication for
male subjects remains largely unexplored. Objective: The aim of this study was to
evaluate the correlation between anti-osteoporosis medication and the risk of
fracture in relation to low bone mass [including outcomes of osteoporosis,
fracture, and bone mineral density (BMD) loss] in male subjects analyzed in
studies within the updated literature. Methods: Randomized controlled trials
(RCTs) that analyzed the effectiveness of a treating prescription for male
subjects with osteoporosis (or low BMD) and that focused on the outcomes of
fracture were included. Relevant studies from Embase, Web of Science, PubMed, and
Chinese database of CNKI were retrieved from inception to January 30th, 2019. Two
staff members carried out the eligibility assessment and data extraction. The
discrepancies were settled by consultation with another researcher. We calculated
the pooled relative risks (RRs) based on 95% confidence intervals (CIs). Results:
Twenty-seven documents (28 studies) with 5,678 subjects were identified. For the 
category of bisphosphonates, significant results were observed in pooled analyses
for decreased risk of the vertebral fracture domain (RR, 0.44 [95% CI,
0.31-0.62]), nonvertebral fracture domain (RR, 0.63 [95% CI, 0.46-0.87]), and
clinical fracture domain (RR, 0.59 [95% CI, 0.48-0.72]) compared with those of
controls. Participants with bisphosphonates had a 56% (95% CI = 38-69%) lower
risk of vertebral fractures, 37% (95% CI = 13-54%) lower risk of nonvertebral
fractures, and 41% (95% CI = 28-52%) lower risk of clinical fractures.
Furthermore, meta-analyses also demonstrated a decreased risk of the vertebral
fracture domain via treatment with risedronate (RR, 0.45 [95% CI, 0.28-0.72]) and
alendronate (RR, 0.41 [95% CI, 0.23-0.74]), but not with calcitriol, calcitonin, 
denosumab, ibandronate, monofluorophosphate, strontium ranelate, teriparatide, or
zoledronic acid, compared with that of controls. Conclusions: This systematic
review confirms that bisphosphonates were connected with a decreased risk of
vertebral fractures, nonvertebral fractures, and clinical fractures for male
subjects with osteoporosis. Future research is needed to further elucidate the
role of nonbisphosphonates in treating fractures of osteoporosis subjects.

DOI: 10.3389/fphar.2019.00882 
PMCID: PMC6695469
PMID: 31447677 
 

[TomBAvoider]

As I said, glucosamine looks a bit tempting. Does anyone else here (besides Ron and Clinton) take it or have an opinion on it?

I take glucosamine. But let's face it - as I said in a post about metformin: we simply do not know, period. There are so many interactions with other drugs, your diet, lifestyle, genes, individual physiology, age, gut microbiota and so forth, that it's almost impossible to make additive recommendations about an individual supplement such as glucosamine (as opposed to subtractive, such as "don't smoke" and "don't shoot yourself in the head"). The fact that glucosamine seems to work for people in aggregate is a statistically derived effect which may mean absolutely nothing by the time you are looking at a particular individual - and Dean is absolutely correct in pointing out that folks participating on these boards are a whole other kettle of fish compared the cohort from which that statistcal glucosamine effect was gleaned.

I am acutely aware that taking glucosamine, is a gamble on my part, as it is with pretty much all my interventions - and worse, a gamble the result of which I cannot ever know, it being a n-1 experiment without a corresponding control - it is essentially unknowable (at least at this stage of medical science, and I suspect probably for the next 100 years to come too). 

You asked about "opinions" - well, that's mine; it looks interesting, and I'm rolling the dice on it /shrug/, but don't ask me to "prove" anything, as that's impossible at this point in time and any speculation is going to be for entertainment purposes only. YMMV.

[Clinton]

Michael Rae takes 1500mg of glucosamine daily as well if you look at his daily supplement regimen.

 Tom, I agree with your comments on the epidemiological studies on glucosamine and trying extrapolating those effects to an individual; however those studies aren’t the only reason why I maintain consuming glucosamine.

Glucosamine seems to be a powerful up regulator of AMPK, and based on the 28% increased lifespan in rodents by ‘mimicking a low carb diet’, it seems to act like an actual CR mimetic in this regard (as opposed to other ‘CR mimetics’ that don’t appear to do much in healthy humans).

Finally, if you believe rapamycin and metformin combo seems to be a powerful anti-aging combo (which I believe but am not on at the moment), glucosamine is one of the closest (natural) mimetics to metformin, as EGCg (catechin of green tea) is to rapamycin (ref: ‘Towards Natural Mimetics of Metformin and Rapamycin’ Aliper, Jellen, Cortese and others.  Www.aging-us.com. Aging 2017 vol 9 No 11).

Clinton 

 

 

Edited December 13, 2019 by Clinton

[TomBAvoider]

I fully understand the reasons why one could decide to take glucosamine - after all, I too take it. However, I'm not as optimistic as you are regarding how valid our justifications are. Sure glucosamine up-regulates AMPK, but that's classic biomechanistic reasoning, which is extremely poor grounds for any prescriptive actions - the only valid measure is long term health/longevity outcomes. The history of supplements and drugs is littered with promising sounding biomechanical justifications and poor outcomes.

AMPK is not like an on-off switch - there are at least 3 major pathways to upregulating AMPK, and they are not all equivalent. And merely upregulating AMPK does not tell you much about ultimate outcomes. Note, f.ex. that metformin is a famous AMPK upregulator, as is exercise. So people naturally thought that metformin and exercise would be additive. The opposite is true. Metformin - an AMPK upregulator - blunted the effect of the other AMPK upregulator, exercise. So how do you know that glucosamine, an AMPK upregulator is not working at cross purposes to exercise or any other element of your supplement, diet, exercise or lifestyle regimen - after all, metformin an AMPK regulator does that too!

For that matter, did you know that statins also upregulate AMPK? See this study of atorvastatin (which I take!):

https://www.ncbi.nlm.nih.gov/pubmed/17116771

Statins activate AMP-activated protein kinase in vitro and in vivo.

Abstract

BACKGROUND:

Statins exert pleiotropic effects on the cardiovascular system, in part through an increase in nitric oxide (NO) bioavailability. AMP-activated protein kinase (AMPK) plays a central role in controlling energy and metabolism homeostasis in various organs. We therefore studied whether statins can activate AMPK, and if so, whether the activated AMPK regulates nitric oxide (NO) production and angiogenesis mediated by endothelial NO synthase, a substrate of AMPK in vascular endothelial cells.

METHODS AND RESULTS:

Western blotting of protein extracts from human umbilical vein endothelial cells treated with atorvastatin revealed increased phosphorylation of AMPK at Thr-172 in a time- and dose-dependent manner. The AMPK activity, assessed by SAMS assay, was also increased accordingly. The phosphorylation of acetyl-CoA carboxylase at Ser-79 and of endothelial NO synthase at Ser-1177, 2 putative downstream targets of AMPK, was inhibited by an adenovirus that expressed a dominant-negative mutant of AMPK (Ad-AMPK-DN) and compound C, an AMPK antagonist. The positive effects of atorvastatin, including NO production, cGMP accumulation, and in vitro angiogenesis in Matrigel, were all blocked by Ad-AMPK-DN. Mice given atorvastatin through gastric gavage showed increased AMPK, acetyl-CoA carboxylase, and endothelial NO synthase phosphorylation in mouse aorta and myocardium.

CONCLUSIONS:

Statins can rapidly activate AMPK via increased Thr-172 phosphorylation in vitro and in vivo. Such phosphorylation results in endothelial NO synthase activation, which provides a novel explanation for the pleiotropic effects of statins that benefit the cardiovascular system.

Now, statins famously are muscle-unfriendly - again, you'd think that since exercise upregulates AMPK, you'd have statins being additive to exercise, but no. And yet statins can certainly be very good for your vascular system through - as the study indicates - your endothelial cells.

The point being is that just because a given supplement does something that's considered "good" biomechanically, like "upregulates AMPK" doesn't mean much without seeing the full spectrum of interactions. Statins may still be an overall good for someone like me, who has uncontrollably high LDL cholesterol that is not amenable to diet/exercise interventions - but statins may be a big negative for someone who has naturally low LDL. Your individual physiology, your genetic/epigenetic profile, your dietary, exercise and other supplementary regimes all determine whether adding supplement "X" in a specific protocol will transpire to be a net positive.

Here is a fascinating talk given by a scientist who studied the effect of exercise - especially glucose transport - and zeroed in on AMPK, metformin, aicar ("exercise in a pill") - this was before the effect of metformin on exercise was illuminated, so it's an amazing experiment in time showing how our understanding has evolved:

 

If you want to jump straight to AMPK, you can start from minute 18:50.

 

 

Edited December 13, 2019 by TomBAvoider

[Clinton]

Good points, thanks Tom.

 

[Ron Put]

All good and informative points. Thanks.

As to Dean's comment about iron intake, my numbers are within the "normal" range, if on the low end:

Ferritin: 30 ng/mL (22-415)
HGB: 14.7 g.dL (14.0-18.0)
Iron: 127 ug/dL (35-168)

I guess absorption really matters, since according to Cronometer I am averaging 300% of dietary Iron RDA, yet my results are relatively low.

[TomBAvoider]

Association of habitual glucosamine use with risk of cardiovascular disease: prospective study in UK Biobank.
Ma H, Li X, Sun D, Zhou T, Ley SH, Gustat J, Heianza Y, Qi L.
BMJ. 2019 May 14;365:l1628. doi: 10.1136/bmj.l1628.
PMID: 31088786
Abstract
OBJECTIVE:
To prospectively assess the association of habitual glucosamine use with risk of cardiovascular disease (CVD) events.
DESIGN:
Prospective cohort study.
SETTING:
UK Biobank.
PARTICIPANTS:
466 039 participants without CVD at baseline who completed a questionnaire on supplement use, which included glucosamine. These participants were enrolled from 2006 to 2010 and were followed up to 2016.
MAIN OUTCOME MEASURES:
Incident CVD events, including CVD death, coronary heart disease, and stroke.
RESULTS:
During a median follow-up of seven years, there were 10 204 incident CVD events, 3060 CVD deaths, 5745 coronary heart disease events, and 3263 stroke events. After adjustment for age, sex, body mass index, race, lifestyle factors, dietary intakes, drug use, and other supplement use, glucosamine use was associated with a significantly lower risk of total CVD events (hazard ratio 0.85, 95% confidence interval 0.80 to 0.90), CVD death (0.78, 0.70 to 0.87), coronary heart disease (0.82, 0.76 to 0.88), and stroke (0.91, 0.83 to 1.00).
CONCLUSION:
Habitual use of glucosamine supplement to relieve osteoarthritis pain might also be related to lower risks of CVD events.

[Saul]

But another large study showed an inverse association between osteoarthritis and CVD, and also lifespan and healthspan more generally.

So the apparent positive health benefits of glucosamine might actually just be because a significant fraction of osteoarthritics might be taking glucosamine.

"Correlation is not causation."

  -- Saul

[Ron Put]

Hah! But it's also possible that OA sufferers are more likely to take glucosamine.... :)

Based on the discussion here and elsewhere, I've added a combined Calcium, Magnesium and Zinc supplement by Solimo (Amazon brand): https://www.amazon.com/gp/product/B079C799K4/ref=ppx_yo_dt_b_asin_title_o03_s00?ie=UTF8&psc=1

I take 1 caplet per day, which supplies:

Calcium: 333mg

Magnesium: 133mg

Zinc: 5mg

(The serving size is 3 caplets per day).

[Sibiriak]

From Al's Papers' Citations:

Associations of regular glucosamine use with all-cause and cause-specific mortality: a large prospective cohort study.

Li ZH, Gao X, Chung VC, Zhong WF, Fu Q, Lv YB, Wang ZH, Shen D, Zhang XR, Zhang PD, Li FR, Huang QM, Chen Q, Song WQ, Wu XB, Shi XM, Kraus VB, Yang X, Mao C.

Ann Rheum Dis. 2020 Apr 6. pii: annrheumdis-2020-217176. doi: 10.1136/annrheumdis-2020-217176. [Epub ahead of print]
PMID: 32253185 

https://ard.bmj.com/content/annrheumdis/early/2020/04/05/annrheumdis-2020-217176.full.pdf
 

Quote

Abstract

OBJECTIVES:
To evaluate the associations of regular glucosamine use with all-cause and cause-specific mortality in a large prospective cohort.

METHODS:
This population-based prospective cohort study included 495 077 women and men (mean (SD) age, 56.6 (8.1) years) from the UK Biobank study. Participants were recruited from 2006 to 2010 and were followed up through 2018. We evaluated all-cause mortality and mortality due to cardiovascular disease (CVD), cancer, respiratory and digestive disease. HRs and 95% CIs for all-cause and cause-specific mortality were calculated using Cox proportional hazards models with adjustment for potential confounding variables.

RESULTS:
At baseline, 19.1% of the participants reported regular use of glucosamine supplements. During a median follow-up of 8.9 years (IQR 8.3-9.7 years), 19 882 all-cause deaths were recorded, including 3802 CVD deaths, 8090 cancer deaths, 3380 respiratory disease deaths and 1061 digestive disease deaths. In multivariable adjusted analyses, the HRs associated with glucosamine use were 0.85 (95% CI 0.82 to 0.89) for all-cause mortality, 0.82 (95% CI 0.74 to 0.90) for CVD mortality, 0.94 (95% CI 0.88 to 0.99) for cancer mortality, 0.73 (95% CI 0.66 to 0.81) for respiratory mortality and 0.74 (95% CI 0.62 to 0.90) for digestive mortality. The inverse associations of glucosamine use with all-cause mortality seemed to be somewhat stronger among current than non-current smokers (p for interaction=0.00080).

CONCLUSIONS:
Regular glucosamine supplementation was associated with lower mortality due to all causes, cancer, CVD, respiratory and digestive diseases.

 

Quote

[...]Our current study, with nearly two additional years of follow-up, has provided further evidence supporting the association between glucosamine use and a lower risk of CVD mortality. Besides, our study has shown a reduction of cancer-specific mortality in association with glucosamine use agrees with the VITAL study, which found an inverse association between glucosamine use and the risk of colorectal12 and lung cancer.29 

With regard to respiratory-specific mortality, only one study supports our finding that the use of glucosamine is associated with a reduced risk of death from respiratory disease.18 From a mechanistic perspective, our observation is supported by the fact that anti-inflammatory drugs have been proposed as an approach to hinder the progress of chronic obstructive pulmonary disease.30

To our knowledge, the association between glucosamine use and digestive disease mortality has not been reported previously. Although low dose aspirin reduces the risk of CVD events, it may increase the risk of upper gastrointestinal complications, particularly when it is administered in conjunction with NSAIDs or even acetaminophen.31 32  Unlike aspirin or NSAIDs, glucosamine is considered relatively safe.33  Future studies are needed to investigate the associations of glucosamine use with digestive diseases and mortality.

Glucosamine and chondroitin supplements are often taken together in a single daily supplements,1 and it is therefore possible that our observed associations are driven by either of these supplements. To address this issue, we performed sensitivity analyses examining the associations of glucosamine use alone (excluding participants who took chondroitin) with all-cause and cause-specific mortality. We found that the estimates did not change substantially. Therefore, it is likely that glucosamine use may reduce the risk of mortality, regardless of the co-administration of chondroitin.

 

Quote

Several potential mechanisms could explain the inverse association between glucosamine use and mortality. First, nuclear factor-κB (NF-κB) has been implicated in several diseases, such as inflammation-related CVD and cancers.34 Glucosamine use may affect inflammation by inhibiting the transcription factor NF-κB from translocating to the nucleus,6 35 reducing inflammation and thus lowering related mortality. Indeed, several previous studies have demonstrated that such anti-inflammatory properties of glucosamine might promote healthy outcomes.6–8

For example, glucosamine use was found to be associated with a significant reduction of concentrations of C reactive protein.8 Reduction of this important marker for systemic inflamma-tion36 could be related to subsequent lowering of morbidity and mortality risk.37 38 Moreover, orally administered glucosamine reduced the markers of inflammation in peripheral blood, as well as atherosclerotic-induced femoral lesions, in a combined rabbit model of chronic arthritis and atherosclerosis.39 Glucosamine also prevented the development of inflammation-associated aortic lesions.39

Aside from reducing inflammation, an animal study reported that glucosamine use could trigger a mimic response of a low carbohydrate diet, via reducing glycolysis and increasing amino acid catabolism in mice.26 This could explain the linkage between glucosamine use and its protective effect, as population-based studies found that low carbohydrate diets are indeed related to a reduced risk of mortality.27 40 In addition, several trials reported that a low carbohydrate diet could promote beneficial health outcomes.41 42

Mechanisms other than anti-inflammation, reducing glycolysis and increasing amino acid catabolism might also be involved in mediating our observed outcomes. Future studies are needed to explore the diverse pharmacological roles of glucosamine on different health outcomes.

Edited April 9, 2020 by Sibiriak

[Mike41]

Considering covid 19s main cause of dearth is inflammation of the respiratory system and that glucosamine is associated with anti inflammatory properties as well as lower death rates from respiratory illness It may be reasonable to take glucosamine as a supplement at this point in time based on the below citation posted by Sibiriak

On 4/9/2020 at 8:37 AM, Sibiriak said:

From Al's Papers' Citations:

Associations of regular glucosamine use with all-cause and cause-specific mortality: a large prospective cohort study.

Li ZH, Gao X, Chung VC, Zhong WF, Fu Q, Lv YB, Wang ZH, Shen D, Zhang XR, Zhang PD, Li FR, Huang QM, Chen Q, Song WQ, Wu XB, Shi XM, Kraus VB, Yang X, Mao C.

Ann Rheum Dis. 2020 Apr 6. pii: annrheumdis-2020-217176. doi: 10.1136/annrheumdis-2020-217176. [Epub ahead of print]
PMID: 32253185 

https://ard.bmj.com/content/annrheumdis/early/2020/04/05/annrheumdis-2020-217176.full.pdf
 

 

 

 

Edited April 10, 2020 by Mike41

[Ron Put]

I started taking glucosamine after seeing several such studies (I linked one in my second post above, which shows lower mortality from CVD).

I still take it, since I see no harm at this point. I doubt it'll have much of an impact on any corona virus or influenza infections, but who knows?

Rhonda Patrick suggests that Vitamin C might help in various cases:

 

Treatment with intravenous vitamin C reduced death rates in patients with sepsis and severe acute respiratory failure. Sepsis is a potentially life-threatening condition caused by the body’s innate immune response to acute infection. Under some circumstances, aspects of this response that are typically associated with defense against infection can induce extensive cell and tissue damage, leading to multiple organ failure, the hallmark of sepsis. Acute respiratory distress syndrome (ARDS) is a common sepsis-associated organ injury that can lead to respiratory failure and death. A 2019 phase 2 trial found that intravenous vitamin C reduced death rates among patients with sepsis and ARDS.    The randomized, double-blind, placebo-controlled, multicenter trial took place in seven medical intensive care units in the United States over a period of three years. The study participants included 167 male and female patients (average age, 55 years) with sepsis and ARDS. Every six hours for four days, the patients received either intravenous vitamin C (50 milligrams per kilogram of body weight) or a placebo.    The authors of the study noted a substantial difference in the death rates among the two groups. Whereas approximately 30 percent of patients who received intravenous vitamin C died, more than 46 percent of patients who received the placebo died. Patients who received vitamin C also had fewer ventilated days, spent less time in intensive care (seven days versus ten), and their hospital stays were approximately one week shorter than those who received the placebo.    These findings suggest that intravenous vitamin C administration might be beneficial in critically ill patients who have sepsis and respiratory failure.  Link to the full study.   Large doses of vitamin C up to 8 grams per day might reduce the duration of the common cold. The bulk of scientific research on the effectiveness of vitamin C in fighting infection has centered on reducing the symptoms and duration of the common cold, with mixed results. Most of these studies have used doses of approximately 1 gram per day, however. Findings from a 2017 study suggest that much larger doses might be more effective at reducing a cold’s duration.    Although most adults typically have only one or two colds per year, cold symptoms are the reason for many lost days of work or school. Some evidence suggests that the financial costs associated with having a cold are similar to those associated with having high blood pressure or a stroke.    The author of the study reviewed the findings of two randomized trials focused on the effectiveness of vitamin C in reducing cold symptom duration. One of the trials had four treatment groups: one group that took a placebo, two groups that took 3 grams per day, and one group that took 6 grams per day. The 6-gram dose reduced cold symptom duration by about 17 percent – roughly twice as much as that observed with only 3 grams. The placebo had no effect on symptom duration. The other trial had three treatment groups: one that took 4 grams per day, one that took 8 grams per day, and one that took a placebo. Taking 8 grams per day reduced symptom duration by 21 percent, compared to the placebo group.    These findings suggest that large doses of oral vitamin C might reduce the duration of symptoms associated with the common cold, but self-dosing should commence as soon as cold symptoms appear for the greatest benefit.  Link to the full study.   Vitamin C might reduce the duration of mechanical ventilation in critically ill patients. Mechanical ventilation – a therapeutic measure used to assist or replace spontaneous breathing – is an important strategy used to treat people experiencing respiratory failure. A recent meta-analysis found that vitamin C treatment shortened the duration of mechanical ventilation among patients in intensive care.    The investigators looked at the findings from eight trials involving 685 patients. They found that vitamin C shortened the duration of mechanical ventilation an average of 14 percent. But the investigators noted major differences in the effect of vitamin C between the trials, with the greatest benefit, observed among patients who were on mechanical ventilation for the longest duration – the patients who were most critical. In five trials involving more than 470 patients requiring ventilation for more than 10 hours, providing 1 to 6 grams of vitamin C per day shortened ventilation time an average of 25 percent.    These findings indicate that vitamin C shortens the duration of mechanical ventilation, especially among critically ill patients.  Link to study abstract. Vitamin C reduces C-reactive protein among some groups of people.   Inflammation is a biological phenomenon triggered by the immune system in response to a physical injury or infection. Vitamin C’s immune-boosting and antioxidant properties can mediate the body’s inflammatory response, reducing the symptoms or risk of various diseases. Evidence suggests that vitamin C can lower C-reactive protein (CRP), a marker of inflammation.    C-reactive protein is a protein that increases in the blood with inflammation and infection as well as following a heart attack, surgery, or trauma. It is one of several proteins that are often referred to as acute phase reactants. Blood levels of CRP greater than 1 milligram per liter are indicative of elevated cardiovascular disease risk.    The randomized study involved nearly 400 healthy adults (average age, 44 years) who took 1 gram of vitamin C, 800 international units of vitamin E, or a placebo every day for two months. The findings revealed that vitamin E had no effect on lowering CRP; however, vitamin C supplementation decreased CRP 16.7 percent compared to pre-treatment measurements, but only in participants who had baseline CRP levels above 1 milligram per liter. This reduction in CRP was comparable to those achieved with statins (cholesterol-lowering drugs).    Interestingly, the study identified a strong link between obesity and elevated CRP levels. Whereas 25 percent of normal-weight people had elevated CRP levels of CRP, 50 percent of overweight participants and 75 percent of obese participants had elevated levels.    These findings suggest that vitamin C might decrease inflammation to a similar magnitude as some statins in people at a higher risk of cardiovascular disease based on CRP levels.  Link to study abstract.   Vitamin C increased the bioavailability of the catechins present in green tea. Catechins are bioactive compounds present in green tea. Some catechins, such as epigallocatechin gallate (EGCG), are potent scavengers of reactive oxygen species with demonstrated antioxidant, anti-inflammatory, and anticarcinogenic properties in both clinical and in vitro studies. Evidence suggests that vitamin C might increase the bioavailability of the catechins present in green tea.    Consumers of green tea commonly add milk, lemon, or other substances to their tea. To assess the impact that these additives have on catechin bioavailability, the authors of the study added varying quantities of citric acid, BHT and EDTA (common preservatives), ascorbic acid (vitamin C), milk (cow’s, soy, and rice), and citrus juice (orange, grapefruit, lemon, or lime) to prepared tea. Then they subjected the tea formulations to simulated digestive processes and measured the amount of catechins they recovered.    They found that overall, green tea catechin recovery was poor, with more than 80 percent loss of catechins during digestion. Adding milk to tea increased catechin recovery considerably, but the greatest improvements were observed with the addition of vitamin C or citrus juices, the latter of which increased recovery to 98 percent.    Citrus juices contain bioactive compounds that might influence catechin recovery, but they are also rich in vitamin C. These findings suggest that consumption of green tea with vitamin C, especially in conjunction with other bioactive compounds in citrus juices, increases the recovery of the beneficial components present in the tea.  Link to study abstract.   Evidence suggests vitamin C substantially reduces bronchoconstriction caused by exercise. Exercise-induced bronchoconstriction – a narrowing of the airways in response to exercise – occurs in up to 10 percent of the general population and up to 50 percent of some competitive athletes. Findings from a meta-analysis suggest that vitamin C might reduce the incidence of exercise-induced bronchoconstriction.    Previous research demonstrated that vitamin C can triple respiratory tissue levels within an hour or two of a single oral dose of 1 or 2 grams. This local increase in vitamin C concentration appears to protect against acute increases in airway oxidative stress. In addition, vitamin C inhibits the production of prostaglandins and leukotrienes, biological compounds that participate in the pathogenesis of exercise-induced bronchoconstriction. In addition, vitamin C halved the incidence of the common cold among people experiencing heavy short-term physical stress – an indication that vitamin C might also have other effects on people experiencing heavy physical exertion.    The authors of the current study conducted analyses of nine studies that investigated varied aspects of the effects of vitamin C on exercise-induced bronchoconstriction. Three placebo-controlled studies analyzed the relative exercise-induced decline in forced expiratory volume, or FEV1, (a measure of respiratory capacity) with or without vitamin C. These trials found that doses ranging between 0.5 and 2 grams of vitamin C reduced FEV1 decline by half. Similarly, five studies investigated the effects of vitamin C supplementation on respiratory symptoms after short-term heavy physical work and found that incidence was halved. One study investigated the duration of respiratory symptoms in young male swimmers and also found that incidence was halved.    The authors noted that a variety of factors might influence whether and to what degree vitamin C affects respiratory function during exercise, including the type of activity and the conditions under which it is performed, among others.  Link to the full study.   Large doses of vitamin C might mitigate the body's stress response, thereby improving immunity. The human body responds to mental stress by releasing hormones called corticosteroids, triggering the body’s fight or flight response. Chronic activation of these hormones can impair immune function, increasing susceptibility to infection and disease. Findings from an early study in mice demonstrate that vitamin C mitigates the body’s stress response, thereby improving immunity.    The authors of the study immobilized mice for an hour every day for three weeks to induce stress. They also fed the mice 200 milligrams of vitamin C daily – roughly equivalent to several grams per day in humans. A control group of mice also received vitamin C but they were not subjected to stress.    The stressed mice that received large doses of vitamin C in their diets exhibited fewer signs of stress as evidenced by lower levels of corticosteroid hormones as well as other physical manifestations, such as weight loss. The mice also exhibited higher levels of IgG, the most abundant antibody in circulation, responsible for binding a broad selection of pathogens such as viruses, bacteria, and fungi, to prevent infection. Interestingly, the non-stressed mice that received large doses of vitamin C exhibited even greater increases in IgG, suggesting that stress cancels out some of the beneficial effects of the vitamin.    These findings suggest that high dose vitamin C might improve immune function, especially during times of mental and physical stress.  Press release.   Vitamin C deficiency impairs fatty acid oxidation ("fat-burning") during exercise. Vitamin C is essential for the synthesis of carnitine, a compound required for fatty acid oxidation – the utilization of fatty acids as energy – commonly referred to as “fat burning.” Carnitine deficiency is associated with fatigue and poor exercise tolerance. Findings from a new study suggest that high doses of vitamin C improves fatty acid oxidation.    The two-part clinical study involved 22 men and women between the ages of 18 and 38 years. Fifteen of the participants had marginal vitamin C blood levels (less than 34 micromoles per liter) and seven had adequate vitamin C blood levels (greater than 34 micromoles per liter).    In the first part of the study, all of the participants completed a 60-minute treadmill walk at 50 percent of their VO2 max. Fat utilization during the treadmill walk was 25 percent lower among participants with marginal vitamin C status, suggesting that vitamin C status affects fuel utilization during exercise.    In the second part of the study, the participants' vitamin C levels were depleted over a period of four weeks. Then they took either 500 milligrams of vitamin C or a placebo every day for four additional weeks. At the end of the eight-week period, the average blood vitamin C levels in the supplemented group were 41.7 micromoles per liter, but average levels among the depleted group were 9.7 micromoles per liter. Fatty acid utilization in the supplemented group was approximately four times greater than the vitamin C depleted group. Poor fatty acid oxidation during exercise was related to higher levels of fatigue.    These findings suggest that low vitamin C status is associated with poor fatty acid oxidation during exercise and may explain why some people are unsuccessful when trying to lose weight.  Link to the full study.

[TomBAvoider]

A lot of info on vit. C to take in, Ron. Some of the recommendations, of multiple grams of vit. C are surprising insofar as I've read that supposedly you achieve tissue saturation at around 500mg, and the rest is flushed out, but according to some of the above you cited it appears:
 

"Previous research demonstrated that vitamin C can triple respiratory tissue levels within an hour or two of a single oral dose of 1 or 2 grams."  

But taking vit. C acutely for limited periods of time is one thing. I've also read that taking vit. C in supradoses long term is counterindicated, and it can be couterproductive when it comes to exercise. 

[Ron Put]

On 4/10/2020 at 11:31 PM, TomBAvoider said:

A lot of info on vit. C to take in, Ron. ...

Yeah, apologies for it. It was a copy/paste from the periodic Rhonda Patrick emails I get and I was in a hurry to leave, so I over-pasted :)

I personally don't take C and haven't for years -- if I recall, in large doses it promotes adverse cellular changes. Although Pauling used to take massive amounts and lived until 93. But then, Calment smoked occasionally.... Perhaps Pauling could have lived to 113 had he taken less C :)

But still, short-term high doses of C might be useful to alleviate respiratory issues, so yes, I agree.

[Ron Put]

I've stopped taking calcium, as my levels are fine, if low, which appears to be optimum based on what I read.

But I've been rethinking my supplementation with Vitamin D, too. My curiosity was peaked by several studies, but mostly based on my genome data related to longevity:

"Levels of 25-hydroxyvitamin D in familial longevity: the Leiden Longevity Study. Concluded that familial longevity was associated with a lower vitamin D levels and a lower frequency of the allelic variation in the CYP2R1 gene. Genome-wide association study of circulating vitamin D levels. This SNP is part of CYP2R1, which encodes a key C-25 hydroxylase that converts vitamin D3 to an active vitamin D receptor ligand. This SNP, along with rs2282679, rs3829251, and rs6599638 accounted for 2.8% of the variance in circulating vitamin D levels."

See also: "Low vitamin D levels linked to longevity, surprising study shows."

With supplementation, my serum levels hover around 45-46 ng/mL currently, but there is some evidence that supplementation may be irrelevant, and at times detrimental.

What are others here doing about Vitamin D levels and supplementation?

Edited April 10, 2021 by Ron Put

[Todd Allen]

4 hours ago, Ron Put said:

See also: "Low vitamin D levels linked to longevity, surprising study shows."

From that paper:

Quote

"We also found that the offspring had a lower frequency of common genetic variants in the CYP2R1 gene; a common genetic variant of this gene predisposes people to high vitamin D levels.

Having a higher level due to a genetic variant may be quite different.  Do you have one of these variants?

[Ron Put]

18 hours ago, Todd Allen said:

Having a higher level due to a genetic variant may be quite different.  Do you have one of these variants?

At rs2060793 I am A;A, which Prometease flags as positive, with a frequency of 15.9%,  but the magnitude is 2, so yes, I am generally predisposed to lower levels of vitamin D (based on the other parts of CYP2R1 too).

Without supplementation, I was at about 22 ng/mL. While my doctor had suggested supplementation, I am wondering if it's a good choice now.

[Ron Put]

This is another interesting study relating to vitamin-D that seems to suggest that supplementation or even sunlight exposure have a limited effect on bioavailability:

Study Reveals Connection Between Gut Bacteria and Vitamin D Levels

Vitamin D can take several different forms, but standard blood tests detect only one, an inactive precursor that can be stored by the body. To use vitamin D, the body must metabolize the precursor into an active form.
“We were surprised to find that microbiome diversity — the variety of bacteria types in a person’s gut — was closely associated with active vitamin D, but not the precursor form,” said senior author Deborah Kado, MD, director of the Osteoporosis Clinic at UC San Diego Health. “Greater gut microbiome diversity is thought to be associated with better health in general.” ...

“Our study suggests that might be because these studies measured only the precursor form of vitamin D, rather than active hormone,” said Kado, who is also professor at UC San Diego School of Medicine and Herbert Wertheim School of Public Health. “Measures of vitamin D formation and breakdown may be better indicators of underlying health issues, and who might best respond to vitamin D supplementation.”...

“It seems like it doesn’t matter how much vitamin D you get through sunlight or supplementation, nor how much your body can store,” Kado said. “It matters how well your body is able to metabolize that into active vitamin D, and maybe that’s what clinical trials need to measure in order to get a more accurate picture of the vitamin’s role in health.” ...

 

[Ron Put]

And more on Vitamin D supplementation, and supplementation in general (to an extent):

Vitamin D Supplements Are Not Effective, And Could Be Dangerous, Studies Find
 

This article is from 2016, so older than the microbiome study I posted above. But the microbiome study has really made me think about regular D supplementation, and supplementation in general (other than B-12 and possibly K-2).

Do members here check their D levels and if so, take supplements? 

I am pausing my supplementation with vitamin D for now.