#89

Testing is not necessarily beneficial. “Overtesting” can cause harm and is well-documented even if the intention was prevention.

1 Like
#90

Why did some people evolve very dark shades of skin near the equator that literally results in stopping too much of all that purported highly “beneficial” “1000 gene” activation?

#91

There is, of course, a problem with UV in that it can cause skin cancer. I would assume that if you take someone with a dark skin living a normal life near the equator they would generate a similar sort of annual 25OHD cycle to someone with a light skin living away from the equator.

What I have not tried to read up on is what other creatures make use of vitamin D.

You can look at it another way and ask the question “Why do we have a vitamin D dependent part of the metabolism.”

1 Like
#92

Abstract

Background: At sufficient sun exposure, humans can synthesize vitamin D3 endogenously in their skin, but today’s lifestyle makes the secosteroid a true vitamin that needs to be taken up by diet or supplementation with pills. The vitamin D3 metabolite 1α,25-dihydroxyvitamin D3 acts as a nuclear hormone activating the transcription factor vitamin D receptor (VDR).

Methods: This review discusses the biological effects of micronutrient vitamin D ranging from calcium homeostasis and bone formation to the modulation of innate and adaptive immunity.

Results: Since normal human diet is [in]sufficient in vitamin D, the need for efficient vitamin D3 synthesis in the skin acts as an evolutionary driver for its lightening during the migration out of Africa towards North. Via activating the VDR, vitamin D has direct effects on the epigenome and the expression of more than 1000 genes in most human tissues and cell types.

Conclusions: The pleiotropic action of vitamin D in health and disease prevention is explained through complex gene regulatory events of the transcription factor VDR.

#93

That paper was subject to a paywall, but this one isn’t

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6470874/

Whilst I am on this issue I would make the point that Gene Expression uses energy. Off the top of my head I think it is one molecule of ATP for each amino acid placed in a protein, but I have not tried to get to the bottom of this question.

This is a relevant paper
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4417112/

I would think that ATP is required both to create the mRNA and also to create the protein from the mRNA.

Hence it may be two molecules of ATP for each amino acid.

Still this is a key thing in terms of the metabolic need for energy. As Gene Expression goes down the energy demands go down.

#94

Yep, clearly, there are tradeoffs and Vitamin D doesn’t have overwhelming benefits when compared to the risks of skin cancer. So one should quickly discard it as some miracle vitamin.

We don’t even know with any precise certainty what extent is “optimal” - the genetic variation controlling vitamin D levels is large. If it was so clearly beneficial, why is there no pressure on genes to keep Vitamin D levels extra high?

#95

I don’t think Vitamin D is a “miracle” vitamin.

The reason there is no pressure on genes to keep Vitamin D levels high is that historically food levels were variable and a creature which survived through the winter would be able to procreate whereas one which goes with a massive metabolic demand throughout the year would die.

This is a conflict between longevity and survival. Adaptable creatures may not survive as long as pro-longevity creatures, but they will cope with variations in food supply. Some experiments were done on this I think with C. Elegans.

#96

C. elegans isn’t a “bad” organism to study but it doesn’t necessarily translate to humans for a lot of things.

As far as I can tell, there isn’t a strong pressure for longevity, but there is plenty geared towards survival. Simple heritability calculations show that ~15% of the variation in lifespan among humans could potentially be genomic related and even then that many are far more likely to be mortality risks from a specific form of illness which counts in the survival bucket rather than “aging”

Ultimately, there is no large pressure to keep Vitamin D levels up. We can’t conclude what is a precise level from any of this and empirically, there is likely harm if levels are too high.

#97

I think it’s not that vitamin D in sufficient or high levels is beneficial, but being deficient is highly detrimental. And high levels of vitamin D may also be detrimental. It’s probably a U shaped curve.

1 Like
#98

I did a video about Vitamin D a couple of years ago.

In that video I explain that you can take too much Vitamin D. I, however, am not sure there is any harm from having twice the higher normal threshold and there may be a benefit. However, as for now I am focussed on getting gene expression maximised for the longer genes.

Once I have finished that experimentation I would like to do a few weeks running higher levels of vitamin D.

With biologically important molecules such as 1α,25-dihydroxyvitamin D3 we need to look at how they are active. 1α,25-dihydroxyvitamin D3 attaches to the transcription factor Vitamin D receptor. It, therefore, directly affects gene expression.

It may be that there a benefit for a period in which such genes are not expressed in the same way as the daily circadian cycle ideally has periods of maintenance/repair and periods of growth. However, we need to think about the mechanisms. The important thing to recognise about D3 is that it is stored as 25OHD and then used on demand as 1α,25-dihydroxyvitamin D3. Hence a big stash can be created during the summer and used during winter. As levels of 25OHD go down less is used.

I would be surprised if there are metabolic problems until 25OHD goes really high, but I have not tried to study the level at which hypervitaminosis D kicks in.

1 Like
#99

The guidelines of 600-800 IU per day recommendation under a minimal sunlight assumption already take into account provably “detrimental” levels. There are some studies that show <10 or <20 has higher mortality. But there are also several studies that show lower levels were not associated with increased all-cause mortality. (PMID 23139250, 23128285, 20631024) Depending on the study, you might get a U-shaped or reversed J-shaped curve.

#101

There are trials that show intermittent monthly mega dosing of Vitamin D or mega dosing of Vitamin D with calcifediol (Dedrogyl) to get to >30 increased the risk of falls - suggesting intermittent high doses should be avoided. (PMID 26747333)

1 Like
#103

I would be interested to see a link about mega dosing of Calcifediol/25OHD. The abstract you refer to used D3 and 25OHD. It was also one looking at a particular subset of people and is not that relevant. Furthermore it is paywalled. The doses averaged out over a day were also on the small side.

I think it is a mistake to intermittent megadose with Cholecalciferol/D3 because I find it mildly toxic (it messes up my sleep) prior to being processed into 25OHD. Personally I think it is better to dose gradually where possible.

2 Likes
#104

Please read through the entire paper:

" Interventions: Three study groups with monthly treatments, including a low-dose control group receiving 24,000 IU of vitamin D3 (24,000 IU group), a group receiving 60,000 IU of vitamin D3 (60,000 IU group), and a group receiving 24,000 IU of vitamin D3 plus 300 μg of calcifediol (24,000 IU plus calcifediol group)."

2 Likes
#105

Very interesting. Monthly massive doses should have worked. I’m surprised by the result.

It would be nice if they commented on overall health too. 58% were deficient (<20) and you would think fixing that would help considerably.

I know that Chris Masterjohn says that massive doses of fat soluble vitamins cause an increase in the biochemical machinery that cleans up an overstock of fat soluble vitamins. So a large dose could cause deficiency of E,A or K2 since that machinery does not distinguish between them. Just comes in to mop up the mess. Otherwise I don’t know what mechanism to blame this on.

1 Like
#106

Yes, the only reason to use gfj is to make your rapamycin dosing less costly.

Bryan Johnson made $800 million when they sold Braintree to paypal, so he’s probably not too concerned about the cost of rapamycin.

2 Likes
#107

I accept that link goes through to a non paywalled report.

1 microgram of vitamin D is 40 IU, hence 300 micrograms should be 12,000 (making the assumption that it converts 1 for 1 which I don’t think is the case I think it is better than that in effect)

Lets assume a month is 30 days so 24000 iu is 800 per day (the german recommendation), 60,000 IU is 2000 per day (which is less that the endocrine recommendation) and 36,000 (24+12) is 1200 IU per day still not massive.

Firstly monthly bolus doses are a bad idea as vitamin D really needs a steady state to be measured. It functions through enabling the VDR.

Secondly this is looking at a particular group of people (those who have already fallen) in a particular age range.

Where the report is good is that it looks at the serum level and outcomes based upon that so we don’t have the usual problem of comparing dosage to outcomes.

However, I have been through the supplementary tables to try to understand the detailed figures and not got to that point.

If you take etable 2 it gives figures for changes in the SPPB core, but does not indicate what the scores actually were. Similarly when you look at “numbers of fallers” it has figures 3.59, 1.73 and 5.52, but does not explain how that was calculated.

It would be good for this to see the actual figures on numbers of fallers in each group and follow that through.

2 Likes