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Charles Brenner, PhD Profile picture
@CharlesMBrenner
Jul 29, 2020 • 10 tweets • 2 min read • Read on X
NAADP is one of the most peculiar & powerful NAD metabolites: a calcium mobilizing 2nd messenger that is important for cell migration in response to IL8. For yrs, it was known to be produced by CD38 but how? We now know dx.doi.org/10.1096/fj.202…
It had been proposed that CD38 reacts on the outside of cells with nicotinic acid (NA) & NADP in an exchange reaction that would form the NAADP plus NAM but there are problems with this idea
1st, there isn't sufficient NA to do this rx. 2nd, forming NAADP outside of cells doesn't solve the problem of calcium mobilization from acidic intracellular stores. 3rd, there has to be a specific signal to form NAADP. NAADP is too powerful to be made willy nilly
Tae-Sik Nam, Dae-Ryoung Park, Uh-Hyun Kim & I figured out how & where NAADP is formed by CD38. It's truly amazing. Also, great thanks to So-Young Rah, Tae-Gyu Woo & Hun Taeg Chung in the Kim group at Chonbuk National University
IL8 starts a signaling cascade that assembles vacuolar ATPase on endolysosomes & stimulates EPAC-RAP1-PP2A-dependent dephosphorylation of Cx43. Cx43 is an NADP transporter that is active when dephosphorylated. CD38 is already on endolysosome membranes w active site in the lumen
Guess what else is in the lumen: the enzymes to make our old friend NAAD (NAPRT & NMNAT3). Really interesting because no one knew how NAD metabolites are made in organelles & NMNAT3 has been misclassified as a mito enzyme (mouse KO doesn't support mito localization)
So this means that there's NAAD being made in endolysosomes & that there are CD38 active sites in endolysosomes. IL8 leads to signal-dependent acidification & transport of NADP. Then CD38 exchanges the NAM piece of NADP off & uses the NA from NAAD to form NAADP. Astonishing!
If you are an NAD or calcium signaling person, you are experiencing maximal geeky pleasure. If you are a lay person, you may wonder, why is this interesting? This is, to my mind, the most tightly regulated set of NAD reactions that have ever been described
The discovery explains how cells convey calcium signals through the NAD system & have implications in development & metastasis. We don't usually know where basic research will lead
Back in the day, I was minding my own biz working on glutamine-dependent NAD synthetase when I realized that there might be another way to make NAD (the NR pathway). Watch for the Kim group & ours to make further discoveries on signal-dependent NAADP formation. Thanks for reading

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More from @CharlesMBrenner

Charles Brenner, PhD Profile picture
Jul 12, 2023
today @davidasinclair is telling the world that he has achieved age reversal with chemical cocktails

he submitted the paper on June 30 & it was accepted on July 4 by a journal of which he is coeditor-in-chief

paper was sent to me 3 days ago by a reporter for comment
reporter was told it is a "groundbreaking study" & "the first chemical approach to reprogram cells to a younger state"
reason WSJ didn't cover that paper is that ppl have been reporting chemical compounds that drive conversion of cells to induced pluripotency for the last 10-15 years

all of the compounds in today's paper were previously reported by others, mostly in 2013
Read 10 tweets
Charles Brenner, PhD Profile picture
May 11, 2023
a lesson about selected traits & how to tell if someone is BSing about aging

look in the animal word, especially wild animals:

animals are clever, terrific at finding food, protecting themselves & their babies

they use strength, appearance & guile to mate

1000s of genes
are required for these abilities & they are selected:

animals w good brains & musculature have babies w good brains & musculature

animals that can't see or smell predators don't survive & therefore contribute little to the gene pool

that's how selection works

dobzhansky said
"nothing in biology makes sense except in light of evolution"

this is your strongest protector against BS

now let's switch to yeast

if you want to look at aging there are two ways to study it:

you can either keep cells in a very old test tube & see how long they survive
Read 10 tweets
Charles Brenner, PhD Profile picture
Jan 12, 2023
there's a peer review failure today doi.org/10.1016/j.cell… in which an individual with 59 collaborators claims to have tested the information theory of aging

he did not test the information theory of aging
the claim is that he induced dsDNA breaks that are easily repaired, don't cause a DNA damage response or mutagenesis or cell death--only an epigenetic change

he knows this is not true because his co-first author & he published this paper in dec '21

ncbi.nlm.nih.gov/pubmed/34932948
the exact treatment causes a p53-dependent damage response, differentiation & cell elimination

far from a purely epigenetic mechanism, he's aged the cells bc he damaged their DNA & a bunch of cells differentiated & died in the process
Read 4 tweets
Charles Brenner, PhD Profile picture
Dec 11, 2022
hi all

there are a few issues being addressed here. let’s start w safety

human placebo controlled trials have never shown adverse events attributable to Niagen. note that LDL-C is raised in humans w Basis & pterostilbene alone
the class of compounds to which NR belongs is vitamin B3

there are decades of human data on these molecules showing human safety. niacin is unique in causing flushing but nicotinamide was tested in large Australian skin cancer and was shown to be cancer-preventative in ppl
there’s a hierarchy of evidence w human RCTs (and meta-analysis of RCTs) on the top. human case reports & good quality rodent studies are lower. cell studies are lower. poorly conducted rodent and/or poorly conducted cell studies are garbage in/garbage out
Read 13 tweets
Charles Brenner, PhD Profile picture
Nov 17, 2022
with ppl's heightened awareness of NAD, it's important to reset expectations on aging and what the use cases are for compounds like NR

aging is not optional

if you are reading this, you are aging

you can age poorly or you can age better but you are going to age
human aging is remarkably different from yeast, worm, fly & mouse aging

it is not true that dominant longevity genes found in yeast promote longevity in ppl

while it is true that there are worm & mouse mutants that are extremely long lived, they are sterile dwarves
CRISPR doesn't enable human lifespan extension bc there's no known gene you'd want more copies of to extend your life

there are no activators of longevity genes--the resveratrol story said so but it's known to be incorrect

it's just a story
Read 8 tweets
Charles Brenner, PhD Profile picture
Sep 19, 2022
🧵

the ancient writer Herodotus is considered the father of history

in his writings are legendary waters that allow its inhabitants to stay forever young

the story was bullshit of course
explorers used such stories to go on adventures and conquests

around 120 yrs ago, Diamond Lil MacConnell created a Florida theme park out of a well on her property but the waters have no magical property
today we can ask whether all the longevity talk is still a grift or is there a substantive advance behind some folks’ optimism about lifespan?

the most vocal optimists are all selling something: books, podcasts, seminars, drugs, etc
Read 16 tweets

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