Charles Brenner, PhD Profile picture
Discovered nicotinamide riboside as an NAD precursor vitamin Dept Chair @CityofHope Chief Sci Advisor @ChromaDex IG and CH @charlesmbrenner Tweets mine alone
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11 Oct
organisms’ lifespans are determined by their genes & environment. we can modify our environment (diet, exercise, sleep, etc). we can modify gene activities w drugs/vitamins or possibly w CRISPR but we 1st have to understand the process of aging itself to know what to target. /1
the gene set any organism has was selected for in evolution. parents who produce lots of reproductively successful offspring pass on their genes. the selections for these genes took place over evolutionary time in conditions that were different from current conditions. /2
most animals achieve reproductive capability early & don’t live much longer than they can reproduce. why? bc the brain, liver, musculature, etc are there to present males to females & help us care for young til they are reproductively capable.

this is the way biology works. /3
Read 13 tweets
4 Oct
Living things maintain their order by taking in fuel to run chemical reactions. the fuels are protein, fat & carbohydrate. in common parlance, we burn these fuels to generate ATP that runs chemical reactions, to make everything in our bodies, repair everything, move & think. /1
Fully oxidized, the carbon in the fuels is exhaled as CO2. /2

The energy in the fuels consists of high energy electrons, whose energy is derived from the sun (that lesson for another day). /3
The difference between living things & locomotive machines that imparts the ability to build ourselves is that we have NAD coenzymes that capture the energy associated with fuel oxidation in a nearly lossless manner. /4
Read 8 tweets
29 Aug
Defining age reversal via a score on an aging clock rather than a functional measurement would constitute the single biggest scam in the entire tawdry history of anti-aging scams. let me explain /1
There's a buyer for the promise of anti-aging of course. this person wants to maintain functions for a longer period of time. maybe they run 7 min miles with their grandson, maybe they play competitive chess, maybe they skateboard and need to be able to recover from scrapes /2
Those are functional metrics: running, playing chess, wound repair. in all of animal history, every animal has declined in its motility, mental ability and repair capacity after it reaches some level of maturity. people want to prolong their mastery or better: reverse aging /3
Read 12 tweets
22 Aug
Valproate is a potentially dangerous drug used for ppl with seizures. Abbott was penalized $1.6 billion for off-label marketing this drug in nursing homes as a sedative /1…
The data in the paper David cites do not show that valproate restores swimming ability of fish--fig. 1D shows that most low dose valproate-treated fish swim WORSE than control. High dose was clearly much worse /2…
The SIRT1 western blots in Fig. 4 are some of the worst I've ever seen published. With respect to swimming, rather than look at dozens of fish as they did in Fig. 1 (already a fishy result), they decided to look at only 3 fish with valproate + EX527 /3…
Read 5 tweets
19 Aug
I'll defend model organisms. However, the proposal that something is conserved for longevity needs to be specifically examined. It's time to explain something about yeast that ppl haven't thought about enough and yes, this concerns SIR2 /1
there are two assays one can use to analyze lifespan in yeast. The 1st one is called chronological lifespan. It's simple. Grow a culture of yeast and see how long the cells are viable to form a colony. Chronological lifespan is measured in days or weeks /2
it might surprise you that sir2 DELETION lives longer in this assay. the work was done by Valter Longo and was published in Cell… ... let that result sink in a minute /3
Read 20 tweets
13 Aug
scicomms is very important. if we are making progress on matters related to human health, we should do our best to explain the developments to the general public. however, it must be remembered that the entirety of human history has been marked by false & exploitative claims /1
with respect to longevity. plants & their extracts have always been claimed to have essentially magical properties of age reversal. extraordinary claims require extraordinary proof. journals have repeatedly failed us & have legitimized overblown claims, exciting- /2
sounding mechanisms & nonreproducible results that were heavily biased by models, expectations & the subsequent exploitation of the resulting stories. the longevity field has assuredly been fouled by this stuff. publication & defense of bad science undermines real progress. /3
Read 9 tweets
13 Aug
The Gross Clinic by Thomas Eakins is one of the most important paintings from the 19th century & the history of medicine. It depicts Samuel Gross, teaching surgery to Jefferson Medical College students prior to the use of white coats /1
The black suits were what the students and Gross wore outside on the dirty streets of Philadelphia. Gross gesticulates with a bloody scalpel. The patient’s mother cannot bear to watch /2
This painting was owned by Jefferson and on display in Jefferson Alumni Hall when I was an assistant prof—it was subsequently sold & is on display at the Philadelphia Museum of Art. It is breathtaking.
Read 4 tweets
9 Jul
One of the urban myths of NAD metabolism is the idea that NAD+ is good, while NADH is bad. NAD+:NADH are a redox couple that differ by a hydride group (a proton with 2 electrons) /1
NAD+ picks up the hydride when small molecules are oxidized, forming NADH. NADH donates the electrons to generate ATP and/or heat at the inner mitochondrial membrane. NADH is also the source of electrons in ketone body formation and gluconeogenesis /2
Thus, ketogenesis and gluconeogenesis are run in a reducing environment while fuel oxidation to produce ATP and/or heat requires oxygen as the ultimate electron acceptor to maintain a high NAD+/NADH ratio /3
Read 5 tweets
4 Jul
I'd like to counter some weird obfuscation that appeared today /1
I'm a metabolism scientist @cityofhope. Prior to that I was @uiowa and @dartmouth /2
in 2004, Pawel Bieganowski and I were 1st to describe the NR kinase pathway to NAD+, which--along with 3 related coenzymes--is the central catalyst of metabolism in all forms of life /3
Read 48 tweets
27 Sep 20
our lab's foundational discovery is that the 4 NAD coenzymes, Crown Jewels of metabolism, are not locked in a vault inside a castle & patrolled by guards. instead, they are exposed to the elements of metabolic stress. many conditions of metabolic stress disturb NAD systems. /1
alcohol, overnutrition, deafening sound, DNA damage, ROS, heart failure, neurodegeneration, inflammation & infection ALL disturb NAD systems in one or more tissues. aging reportedly disturbs NAD, though the evidence is weaker than in all other conditions. /2
when NAD comes under attack, repair processes are compromised, ATP generation is impaired & anabolic processes are disturbed. attributing all of NAD metabolism to SIRTs is just dumb & should have been checked by good reviewers >10,000 publications ago. /3
Read 8 tweets
29 Jul 20
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…
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
Read 10 tweets
25 May 20
every week, i get an email from a desperate parent whose kid has a potentially incurable cancer, asking if they should take #NR, often in a cocktail with resveratrol & other stuff /1
experiences like these make me shudder at the 💩 being peddled in the name of "anti-aging." no phd scientist should tell any such parent that their kid's rare malignancy is curable with their favorite elixir /2
i remind ppl that NR is active in many rodent models of human diseases & conditions of metabolic stress in which the NAD system is under attack (heart failure, fatty liver, neurodegeneration, central brain injury, etc) /3
Read 10 tweets
21 May 20
Many thoughts: 1. Know that blood is rarely the target tissue we are trying to address. These mito disease pts have a muscle disorder but are walking around with low blood NAD. Blood NAD easy to measure and can be increased by NR, NA or NAM
2. Main diffs between activity of these B3s is genes to convert to NAD, NADPH etc. NA pathway not expressed in several key tissues like neuron. NR pathway typically upregulated when NAD under attack, eg heart failure, nerve damage & coronavirus infection
3. Yes we recently unblinded study with postpartum rats with 9 different types of food that indicates that trp, NA, NAM, NR & NMN are not equivalent for pup survival & development into adulthood. Still analyzing massive amounts of data but we will release when we can
Read 4 tweets
15 May 20
NR clinical trials have been done based on hope rather than mechanistic design. Trials of fatty liver, body composition & anti-inflammation require smart patient selection criteria, sufficient duration & should be combined with exercise. Please read this…
Note that the 12 week trial in which NR seemed to move the needle on fatty liver in men is here…
The 3 week trial showing anti-inflammatory activity is here…
Read 4 tweets
20 Apr 20
Ppl have asked me how do mitochondria fit into the CoV infection-NAD story. The 1st connection is that when cells detect dsRNA, MDA5 protein interacts with MAVS, which is in the mito membrane. This is required for interferon expression, which turns on the PARP induction program/1
Note that IFN is secreted, which means PARPs are induced in neighboring cells that haven't seen virus yet. This will disturb cytoplasmic NAD, which controls mito NAD, where most of the ATP is made /2
Virus needs ATP, GTP to make more virus but host cells need ATP, GTP, NAD, etc for their defense against virus. Good way of thinking about this is that the antiviral PARPs are the soldiers on a battlefield--these enzymes need NAD to stop the virus /3
Read 4 tweets
19 Apr 20
@HeerCollin @FehrLab @MichaelNADbio & I just published…. This is our 1st of several works on #SARSCoV2. We show that the virus upsets the NAD system in powerful & potentially actionable ways /1
Some years ago when @FehrLab was with Stanley Perlman @uiowa, they discovered that coronaviruses encode a gene that takes ADPribose off of proteins & use this gene to be highly infective. They also showed that the virus turns on expression of several PARP genes /2
With my former student, Sam Trammell, we obtained data showing that coronaviruses upset cellular NAD. This is important because our cells need NAD coenzymes to run everything including our defense against viruses--the virus also hijacks our metabolism to make more virus /3
Read 15 tweets
1 Apr 20
A lioness of the Iowa City community emailed this morning to what would have been her seder invitation list:

"With Passover just around the corner, I turned to one of my most trusted doctors, Dr. Seuss. The good doctor (of blessed memory) gave me these words to share /1
on social distancing during Passover.

'I do not want you in my house.
I do not want you or your spouse.
I do not wish to eat with you
At Seder one or Seder two!

Don't get me wrong,
I think you're nice.
Doctor Fauci
Gave out this advice, /2
"Ten Plagues are enough,
You don't need one more.
Turn away Elijah, the prophet,
If he shows up at your front door."

This year's only guests:
Father, mother, son, neighbor.
NEXT YEAR in Jerusalem,
We will say to each other. /3
Read 5 tweets
26 Mar 20
So important to support grad students now. Many are wondering whether their rotations will be extended & when they are expected to match with labs. PIs should be in touch with their students & students should realize this is a real world test of lab life under stress conditions/1
As I said in yesterday's fac mtg, if a student rotated in 2 equally exciting labs, 1 which requires lab visits to mate crocodiles & 1 which can function with ppl @ home, their current experience is telling them which lab to join in 2020 /3
While we should accommodate students who need more time, we should also realize that some labs are extraordinarily productive now & that work brings the satisfaction that students are seeking by deciding to pursue PhD /4
Read 4 tweets
25 Mar 20
We were about to change topics @IowaBiochem class from lipids to N metabolism when we were rudely interrupted by #COVID19 -- I think we need to provide a service to explain what soap is and how it inactivates viruses. We'll also explain what detergents are including bile acids /1
Students will recall that the bulk of animal & plant fats are triglycerides (3 fatty acids esterified to glycerol) & that when TAGs are digested by us, lipases hydrolyse the FAs from glycerol so that they can be beta oxidized /2
Most animal fat has long chain saturated FAs--saturated FA can pack closely & are thus solid at room temp. Different plants make different lengths of FAs based on the plant's FA synthase (how many 2C units it adds before the FA is hydrolyzed off) and its desaturases /3
Read 11 tweets
15 Mar 20
Viruses can be described as ingenious but they gain nothing from killing the host. SARS-CoV-2, the causative agent for #COVID19 has a tiny RNA genome less than 30k bases long—it’s goal is replication. It evolves to cause resp symptoms to be spread to more ppl /1
Though lethal in perhaps 3% of infections, this is essentially accidental & not something it evolves toward. It requires ATP & many other factors from living ppl to replicate & requires ppl to contaminate other ppl /2
We can arrest transmission with #soap & #PhysicalDistancing (#SocialDistancing not the right term bc we can be social remotely) /3
Read 5 tweets
11 Mar 20
Why do I point out that the foundational SIR2 and sirtuin data are deeply flawed? Because more than a decade of papers on yeast, flies & worms shaped expectations of what sirtuins would do in vertebrates (extend lifespan) /1
It is true that sirtuins use NAD+ to modify protein function by removing acyl groups from protein lysines. It is not true that they are essential for the longevity benefit of calorie restriction. It is not true that they are the primary mediators of NAD /2
It is distinctly wrong that they are critical regulators of DNA repair. It is not true that they are essential for mitochondrial biogenesis or mitochondrial function. All of these ideas were suggested, however, by papers in model organisms that turn out to be wrong /3
Read 10 tweets