Vitamin D is not a Magic Bullet,
but Vitamin D Deficiency is a Poison Arrow�
Feb 2022
Karl Pfleger
Stanford AI PhD & former Google Data Scientist.
Now Philanthropist & Investor focused on Biology of Aging/Longevity.
Note: No conflicts of interest related to vitamin D.
[Note: Not an MD. This is a science presentation with implications for public health policy,
but this is not prescriptive medical advice.]
Outline
Q&A
Vitamin D basics
(Part 1.)
Vitamin D deficiency (VDD):
by far the most common deficiency of an essential molecule
Global deficiency ~= 50% (<20ng/ml, the nearly universal government rec min serum level)
~ ¾ globally “insufficient” (<30ng/ml, the min rec of the Endocrine Society)
Food is not an adequate source.
Most comes from the sun (UVB). [So it’s not technically a vitamin.]
Outside the tropics hardly any can be made from sun in winter.
Supplements needed for:
Even nearer the equator than most of US & Europe, many deficient:
Dark skinned minorities particularly at risk &
VDD is partially responsible for racial health disparities
Of the several causes of racial health disparities, VDD is by far the most easily correctable cause.
Ames, Grant, & Willett “Does the High Prevalence of Vitamin D Deficiency in African Americans Contribute to Health Disparities?” Nutrients (2021).
(Divide by 2.5 to obtain ng/mL)
So 96%, 87%, & 65% have low vitamin D.
Willett is the 2nd most cited author in all of clinical medicine per Wikipedia.
Vitamin D is essential to many aspects of health, especially immune health
Vitamin D family of molecules (inc. metabolites) regulate the expression of thousands of genes, including many for innate immunity & many for adaptive immunity.
Examples:
Vitamin D kills viruses by inducing antimicrobial peptides (eg cathelicidin).
Inhibits inflammatory cytokines (regulates CD4+ T-cell responses eg inhibiting Th1).
Maintains cell tight junctions.
Deficiency linked to most chronic diseases of aging.
Deficiency linked to auto-immune diseases.
Vitamin D acts as a hormone & exhibits not only endocrine signaling but also paracrine & autocrine.
Some vitamin D history
2006
2017
2020
Cod liver oil (rich in D) prevented respiratory infections
Vitamin D effects on influenza seasonality
1930
SARS-CoV-2….
Meta-Analysis: Vit D supplementation helps prevent acute respiratory tract infections
2010
2014
immune health timeline:
RDA set to 600 IU/day (only bone health considered)
Error in RDA math published
IoM acknowledges error, declines to raise RDA
RDA timeline:
Seasonal variation of 25(OH)D levels –�Vitamin D deficiency is common in winter
Cannell JJ, Vieth R, Umhau JC,et al. Epidemiol Infect. 2006
Vitamin D Controversy
(Part 2.)
Vitamin D has been a huge controversy in health & medicine for decades
History:
Current status:
The latter side is (too slowly) gaining ground:
Why have Vitamin D Studies yielded mixed results?
Trial methodology used for novel drugs inappropriate:
Re-analysis of many studies in proper ways did show benefits, eg cancer, T2D.
For more details see:
No government group held accountable for eradicating deficiency
No consensus on intake->response
RDA calculation mistake is still not widely enough known.
Intake->response literature clear that RDA not high enough, but this also not widely appreciated, even by experts.
No definitive paper & wide disagreement amongst experts, seemingly just due to lack of knowledge of what literature does exist.
RCTs not needed for intake -> response characterization.
Bizarre bias against testing to ensure sufficiency.
Vitamin D mistakenly thought to be more dangerous than it is (it’s very safe)
Vitamin D and Aging
(Part 3.)
Low D correlates with higher all cause mortality and with most chronic diseases of aging
all cause mortality:
chronic diseases of aging:
CVD, hypertension, cancer, diabetes, Alzheimer’s
(see "A Narrative Review of the Evidence for Variations in Serum 25-Hydroxyvitamin D Concentration Thresholds for Optimal Health" 2022)
all cause mortality vs vitamin D status
Vitamin D extends C.elegans lifespan
Published in 2016 by Gordon Lithgow’s lab at the Buck Institute
Vitamin D reversed Horvath clock age in (deficient) humans
Fahy et al (2019, TRIIM trial) showed 1.5 year age reversal in n=10 all-male humans using 1year of treatment with a cocktail of drugs & supplements, with no control group. This made big waves in the longevity community.
Chen et al (2018) showed 1.6-1.8 year age reversal in n=27 D deficient, African Americans of both sexes using 16 weeks of vitamin D (2000-4000IU/d), in an RCT (total n=51). This went unnoticed.
Using early generation aging clocks like this is questionable (eg see Levine), but both results may be real nonetheless.
Vitamin D affects numerous known aging markers/pathways/hallmarks
Aging & insufficient vitamin D both affect, in the same direction:
Vitamin D also affects TGF-β (several papers)
Mechanism identified by which vitamin D helps clear Aβ (2012)
Note: Most (if not all) of these are targets of various aging/longevity biotech companies.
Vitamin D and Covid-19
(Part 4.)
Group correlations:
Covid risk groups match VDD risk groups
Covid-19 vs…
latitude
vitamin D deficiency by country
elderly in care homes (96% vitamin D insufficient in 1 US study)
race
obesity
comorbidities
etc. (dozens of published studies)
This was just hypothesis generating, but the data came early.
Individual patient data:
Dozens of MAs, millions of patients
See https://twitter.com/KarlPfleger/status/1486565564671692804
for links to recent meta-analyses of dozens of observational studies:
VDD -> OR of infection 1.83, of ICU 2.16
VDD -> OR of infection 1.46, severe disease 1.90.
Roughly a doubling in odds of ICU for those with Vitamin D Deficiency, across millions of patients & ~50%+ greater odds of infection.
Biological mechanisms:
D helps for Covid19 more than other infections
Reduces risk of SARS-CoV-2 docking at ACE2 receptors.
Stimulates antimicrobial proteins eg cathelicidin
Some D metabolites directly inhibit SARS-CoV-2 replication.
Modulation of Th1 shutdown helps prevent cytokine storm.
Not an exhaustive list.
Dozens of papers at this point.
An early paper by a top vitamin D researcher received ~1000 citations w/in 1st year & now has ~1500.
Causal evidence
Age, obesity, & comorbidities as risk factors unquestioned.
Seatbelts, smoking warnings. Lots of public health w/out RCTs.
Lots of Support of D for Covid
Full list: https://vitamindforall.org/rollcall.html
Summary & Take-Homes
(Part 5, last part.)
Lack of D is a disease more than D is a therapeutic
Vitamin D is not a magic bullet (that fixes everything).
But insufficient vitamin D is a sort of evil magic bullet, or poison arrow: something that makes lots of things worse (just like obesity, aging, chronic sleep deprivation, chronic dehydration, smoking, etc. all do also):
D is analogous to water & sleep in this sense, and that should have implications for how interventions to supply it are evaluated.
Low D’s prevalence affects much of medicine
Take-home: Effect sizes seen in studies of other interventions may be lower or absent when limited to subjects with sufficient vitamin D.
Testing & serum targets
Testing is the surest way to ensure staying in the optimal range. Testing is cheap & easy (eg $50).
Sun has benefits besides D (eg nitric oxide, melatonin, circadian) & D production from Sun is self limiting. But hard for many to get enough from sun alone, so mix of sun + supplements (or UV lamps) often recommended, varying by season.
all cause mortality (hazard ratio)
but some debate & some contradictory evidence in this range
some physicians, experts, & papers suggest 40-60ng/ml
20ng/ml (clinical deficiency threshold)
30ng/ml (sufficiency & Endocrine Soc rec min)
no good data suggests better to be in this range
lots of data for many conditions (inc. Covid) suggests being to the right of these thresholds
Q&A
Resources for more reading/listening (clickable f/ slides):