Short report: The state of the mitochondria portion of the aging biotech field:

50 companies!
$1.4+B raised
700+ people
150+ clinical trials

many MoAs/targets:
mitophagy, transplant, fission, NAD+, UrolithinA, CD38, PINK1, PPARδ, DRP1, USP30, Complex 1, OMA1, & more

Read on: Why is this important?
Mitochondria are central to aging:
It's one of both the original 9 Hallmarks & 7 SENS areas.
It's one of the subareas most directly tied to other subareas.
It's one of the subareas with the most direct relevance to a wide variety of age-related diseases.

New PEARL rapamycin study vs CALERIE mild (12%) CR study 🧵:

CR & rapa both ↓mTOR. But frustrating the designs aren't more apples-apples. Many things improved by 1 not reported in other. (Also unfortunate for both we don't have more direct biomarkers of mTOR pathway activity.) We want to estimate long-term benefit. What do these 2 short (relative to lifespan) 1-2yr studies tell us?
What metrics can we directly compare?
See below...
(Links to all papers included below too.)

Direct-to-consumer aging clocks give very inconsistent answers. I tried TruDiagnostic, Elysium, GlycanAge, & reg blood draw for PhenoAge on same day in Feb & from same venous blood draw at LabCorp, except Elysium's uses saliva which I did right before going to LabCorp. Notes: 🧵 I chose these 4 clocks for the same-day comparison since they are most respected & used clocks avail to consumers currently. Specific reasons for each:

@TruDiagnostic: team (eg @RyanSmithEpiAge, @VarunDw, @EverythingEpi) comes & presents at aging confs regularly, its the basis for the leaderboard Bryan Johnson's team maintains, they licensed DunedinPACE, & they provided an intrinsic vs extrinsic split per the mix change of immune cell types issue @alantomusiak from Eric Verdin's lab identified recently as a problem with most clocks.

Elysium briefly had @DrMorganLevine as advisor & she supposedly helped develop the 100k+ cpg site Index test, which should be robust to the test-retest variability issue that her recent PC clock paper identified as a problem with most clocks. (TruDiagnostic's clock is also supposed to be robust wrt this issue.)

@GlycanAge: team (@GordanLauc, @entreprylexia) also comes & presents at aging confs & its based on a completely different signal.

PhenoAge (also from @DrMorganLevine) is a gen2 clock that's widely used even clinically by notable longevity expert doctors, & it was easy to add with just a basic blood draw.

Data from the new TargetD trial suggests that prior vitamin D trials were flawed:

Many people, even professionals, still think vitamin D was a false profit that was disproven by big RCTs. This view is very flawed, for several reasons. A brief history:news-medical.net/news/20231113/… For decades, thousands of studies have shown reliable correlation of low vitamin D levels & bad health outcomes. Scientifically, the proper way to test the hypothesis that this correlation is causal is RCTs that meaningfully alter the low vitamin D status & then measure outcomes.

Highly recommend the most recent good review of mechanisms of action of vitamin D affecting Covid risk pubmed.ncbi.nlm.nih.gov/35308241/
by notable Irish researchers who've published in the area throughout the pandemic.

Notable: Directly addresses satisfying Hill's Criteria for causation. Image is Fig 2: "Molecular pathways in the pathology of Covid-19 thought to be affected by vitamin D"

That's a lot of diff Covid related biology affected by vitamin D!

Great job @RoseAnnekenny1 & co

Some direct quotes f/ the main text of the paper are worth repeating here:

🧵

The most basic implication of the uncontroversial strong association between vitamin D levels & health outcomes:

Vitamin D level should be tested in clinical trials for many conditions, including Covid.

Why isn't this routine? Why isn't this discussed more?

Short 🧵 1/5 Vitamin D's causal influence on many health conditions is controversial, mostly for not enough big positive RCTs. But vitD's correlation w/ outcomes in many important conditions (CVD, cancer, diabetes, Covid, etc) is uncontroversial.

See mdpi.com/2072-6643/14/3… for a review.
2/5

There are now (at min) 4 big systematic meta-analyses of vitamin D & Covid since Dec'21.
3 study D levels & 2 supplementation. Newest both.
Strong, consistent, & highly statistically significant results:
Low D raises & supplementation lowers all stages of Covid risk by ~1.5-3x
🧵 This 🧵 is an update & elaboration of a prior thread:

https://twitter.com/KarlPfleger/status/1486565564671692804

since 2 more MAs are now available & since they cover supplementation, not just D levels.
You might want to glance over that thread too.

In nutrition, when RCTs & observational studies disagree, there are good reasons to trust the observational studies even though tendency is to defer to RCTs, say Harvard researchers, inc Willett (one of the most cited researchers in all clinical med):academic.oup.com/advances/artic… Quote:
when RCTs contradict the findings of observational studies, there is a tendency for the academic community to believe that RCTs conclusively refute the hypotheses generated by such observational studies.
...

@CharlesMBrenner @aubreydegrey @LauraMinquini
Didn't see place yet for Qs for Thu live event. Here are my Qs + high level comment:

Was a mistake to simul-debate general Q of LEV feasibility by any means vs SENS prog specifically. Should be separate discussions in that order.🧵

https://twitter.com/LauraMinquini/status/1523619450926542848

Qs for anyone skeptical of general feasibility of Longevity Escape Velocity:

On car analogy:
Generally agreed an old car can be kept in youthful functioning order indefinitely. Humans more complex. ADG & CB agreed.
Living (& having DNA) vs not alive is another binary difference.

1st evidence I've seen of any booster benefit @ >6mo:
medrxiv.org/content/10.110…
In this case against severe Covid for age 60+yo in Israel.

But there are big caveats (besides just being a preprint), especially possible selection bias problems: see caveat #4 below.

Here's a list: 1. Unclear if generalizes to age<60.
Even if does & no issues w/ the data, Number Needed to Treat (NNT) goes up fast w/ lower age. 70s NNT 2x 80+. 60s 2.5x the 70s. So even if dose 3 efficacy % holds across ages, this doesn't justify need for boosters for young or middle age.

@sfdph,
Apr 6 CA DPH "Removed quarantine recommendations for asymptomatic exposed person (for the general public)" cdph.ca.gov/Programs/CID/D…
When will SF DPH adopt the new state policy instead of the up-to-date requirement at sfdph.org/dph/covid-19/i… which was last updated Apr 1?
Or ...when will the SF DPH definition of up-to-date itself be updated to require the most recent mRNA shot no more than 5-6mo prior, since all data show that booster benefit wanes after this amount of time?

What's the justification for not making one or the other of these changes?

New vitamin D prophylactic RCT for Covid infection:
1st placebo controlled & 1st blinded such RCT.
& multicenter (4 hospitals) so ticks all good RCT boxes.
sciencedirect.com/science/articl…
4000IU/d
Huge effect size: RR 0.23; 95% CI 0.09–0.55
77% reduction (95% confidence of 45% lower)
🧵 This trial was pre-registered: clinicaltrials.gov/ct2/show/NCT04…
4 hospitals involved & authors (checked last 2) appear to be legitimate academic authors w/ multiple papers to their names.
Authors don't seem to have any conflicts of interest.
So no huge red flags to suggest outright fraud.

The biggest weakness I see in the CORONAVIT trial preprint is the lack of mention of dates of events considered. It takes months for 25(OH)D to rise increased intake. 0 to 3200 will take ~1-2months. See
academic.oup.com/ajcn/article/7… (fig 1)

If analysis for the 3200 vs no-offer wasn't limited to dates for which 3200 arm could be expected to have increased their levels, any effect may have been largely diluted. Vaccinations could exacerbate this by leaving fewer months before vax reduced all infections. I hope this issue can be addressed before publication.

At this point, it is beyond question that Vitamin D Deficiency (VDD) is a significant risk factor for Covid just like age, obesity, comorbidities. Many dozens of studies show this & correlation-doesn't-imply-causation isn't a valid objection to classification as a risk factor. 🧵 The data showing age, above-normal-weight, & comorbidities are significant risk factors is also based entirely on correlation. No RCTs establish these as risk factors but no one questions that they are. VDD should be thought of as another comorbidity, just like diabetes.

Insufficient vitamin D speeds aging. It increases mitochondria damage, inflammation, & loss of proteostasis. Vitamin D regulates thousands of genes & many pathways, affecting eg: klotho, NF-κB, Nrf2, SIRT3, TNFα, & more. Known in 2019 & before: mdpi.com/2079-7737/8/2/…
(1/7) Known since 2016: D extends lifespan of C.elegans (that have no bones) by 33%+, at least partially via proteostasis: ncbi.nlm.nih.gov/pmc/articles/P…
(2/7)

Best up-to-date summary material on vitamin D & Covid-19, a categorized list as of mid-March 2021:
@manoliskellis @MartinHewison @RoseAnnekenny1 @wbgrant2 @DrRichCarmona @Covid19Critical @gruffdavies @VatsalThakkarMD @RogerSeheult @foundmyfitness
1/9 Best systematic review of observational data:
Mar’21 Adv in Nutrition meta-analysis by Kazemi et al:
academic.oup.com/advances/advan…
“conclusion [..] a significant relation between 25(OH)D and SARS-CoV-2 infection, COVID-19 composite severity, and mortality.”
2/9

People continue to want to argue whether the scientific evidence that low vitamin D raises COVID-19 risk exceeds their preferred standard for scientific certainty, but this question is backwards when set in the context of widespread D deficiency/insufficiency. (1/7) Most governments set serum D level minimum targets of 20ng/ml (50nmol/L) & many professional societies (eg Endocrine Society) suggest 30ng/ml as the min target. 33-50% of people worldwide (& in many individual countries including US) fall below 20ng/ml. More below 30ng/ml. (2/7)

(1/4) Finally, the study I've been calling for since May: analysis of data from records of many people w/ both D & CV19 tests, in this case from Quest. n=191,779. Result is clear: lower COVID-19 infection risk as D levels rise, all the way to 55ng/ml. journals.plos.org/plosone/articl… (2/4) Main figure speaks for itself. The relationship was still significant in a multivariate model accounting for all demographic factors. The relationship persisted across latitudes, races/ethnicities, both sexes, and age ranges.

1/8 VitD & COVID19: Is the tide starting to turn? (As it did for masks.) Hopeful signs lately. Linda Benskin's great review researchgate.net/publication/34…
is I'm told peer reviewed & accepted. Publisher should be proud. Been in review a while so some stuff out-of-date: 2/8 It shouldn't include now-withdrawn Indonesian study (& Glicio's). June 16 cut-off misses important Israel study & others, but gets criticism of bad studies right, notes the mistake in setting RDA & has great comprehensive review of mechanism papers & group association papers.

1/4 Now added to my review & 1pager: Holick study n=235: 6.3% w/ D>40ng/ml died vs 9.7% D=30-40 vs 20% D<30. And severity correlation to low D still statistically significant after correcting for other risk factors. papers.ssrn.com/sol3/papers.cf… 2/4 That makes 4 studies correlating low D to different measures of C19 severity: n=782 hospitalization vs. not, n=134 ICU/ITU vs not, n=186 lung CT severity, & n=235 death & CDC severity criteria. Taken together, this evidence suggests that low D worsen C19 at multiple stages.

1/9 Big recent updates to #VitaminD #COVID19 evidence & thus now also to my review agingbiotech.info/vitamindcovid19: 3 highly cited preprints are out but even better studies replace them, including finally a large study of records from a big org. Main take-homes remain the same. Details: 2/9 2 preprints including very cited n=780 Indonesian study now withdrawn from SSRN. Another (Alipio's) suspected of being fraud. Details in section 9 of the review. All 3 removed from my 1pager summary agingbiotech.info/vitamindcovid1…. I now apply a new standard for preprints with data: