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 cell.com/fulltext/S0092… ... let that result sink in a minute /3
The 2nd way to measure aging in yeast is to see how many times a single mother cell can produce daughters. This is called replicative aging. Realize that half of the cells in a dividing culture have never been mother cells (they budded off mothers and are brand new daughters) /4
The other half of the culture have been mothers some number of times. 25% of the culture has been a mother once, 12.5% has been a mother twice, 6.25% has been a mother three times. Get it? /5
There are elaborate tricks to purify old mothers--they'd be mother cells that have 10 or more bud scars. If you look for these cells in a growing culture, you will NOT FIND THEM! /6
Amazingly, a yeast mother can produce daughters about 20 times & if you calorie restrict it, it can do this around 40 times. We know this ONLY BECAUSE we install a graduate student at a microscope for a week, who removes the daughter cells every 90 minutes or so & counts /7
the number of replicative cycles of physically separated mothers. it's true that more SIR2 extends the mother's replicative lifespan (just as lack of SIR2 extends chronological lifespan). also true that yeast needs SIR2 to extend replicative lifespan on calorie restriction /8
but the idea that based on this result, one would expect SIR2 to have been conserved as a longevity gene is silly on its face. there is no selective advantage for this phenotype & there are no observable old mothers in a growing culture /9
Based on the yeast results, if you were making an evolutionary prediction--a gene was conserved to confer a longevity survival advantage--you'd be influenced by the chronological aging experiments: sir2 deletion survives better to form a colony from an old culture /10
In contrast, the replicative longevity phenotype of SIR2 is totally dispensable: >97% of the cells in a culture have been mothers 4 times or less! 20-time mothers have no selective pressure on them. Thus, when ppl did worm & fly experiments in particular strain backgrounds /11
they should have been surprised that there were any effects of SIR2 overexpression & looked at other strains themselves. They would have saved TENS OF BILLIONS OF $ of future investment in sirtuins if they looked critically at their own results /12
Instead of questioning the relevance of a yeast assay for whether incredibly rare 20-time mothers can form a daughter a 21st time & recalling the long-lived phenotype of sir2 yeast in the chronological assay, they were confirmation biased /13
High impact journals published the results claiming that SIR2 genes are anti-aging in animals to great fanfare and the sirtuin cult was formed in earnest. Later, when these results were debunked, others have come along to express a sirtuin in one tissue or another /14
in experiments that are intended to rehabilitate the confirmation biased results. We're told you do get the result if SIR2 is overexpressed in the fat body, etc, etc. Sorry, that's not what the prediction was. The prediction--based on a totally dispensable phenotype of /15
old yeast mothers was that overexpression of SIRT1 homologs should extend lifespan. Not just in some worm or fly strains, in all of them. And not if you only turn it up in one tissue but the idea is that this is a fundamental longevity gene that you want to rev up in ppl /16
I'm explaining all this bc @BelenkyLab & I showed that NR extends yeast lifespan in the old mother yeast assay. I also consulted for Sirtris & know the data as well as anyone. Sirtuins are moderately interesting enzymes & they use NAD /17
They are LESS REGULATED than almost any NAD-dependent enzyme that I can think of: certainly less regulated than members of the PARP superfamily, SARM1, the intracellular form of CD38 or any redox enzyme /18
They have not been shown to mediate the beneficial effects of NAD repletion, though that is what many groups have tried to show. Sirtuins are said to be longevity genes but after 20+ years, it's a fact that the only good data are in yeast! /19
In the chronological aging assay, SIR2 is an antilongevity gene & in the old mother assay, SIR2 is a longevity gene that doesn't confer a survival advantage that would qualify it as a longevity gene. Now, back to figuring out why our metabolism declines at 60 ☮️😏✌️

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More from @CharlesMBrenner

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 nytimes.com/2012/05/08/bus…
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 molecularbrain.biomedcentral.com/articles/10.11…
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 molecularbrain.biomedcentral.com/articles/10.11…
Read 5 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

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