Chemically induced reprogramming to reverse cellular aging

I have posted this here because I think people will be interested and it was only published a short while ago. I don’t, however, think this is either reversal of aging or a practical solution to the diseases of aging. It is interesting and I think the strength of the Yamanaka Factors lies in SOX2 kicking off autophagy.


Would someone capable sleuth please try to decode the likely candidates of these 6 chemicals cocktails in this David Sinclair-led paper that generated much excitement? Chemically induced reprogramming to reverse cellular aging | Aging

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As far as I know, repsox doesn’t have many pharmacological data available. It seems to be mostly an in vitro thing. There are drugs that made it to phase II that may substitute, or not. The good thing is that this group claims success with only 2 compouds – most need at least 3 – and that the other is an approved drug.

It would sure be nice if someone did the work to find a partial reprogramming cocktail suitable for mammals. It seems like a fine needle to thread, though.


series of tweets by David Sinclair here:


And a series by Brenner with critics


The molecules VC6TF (Cocktail 1: C1) and C6NYSA (Cocktail 4: C4) were used as basal reprogramming cocktails and supplemented with other boosters known to increase iPSC efficiency, including sodium butyrate, basic fibroblast growth factor (bFGF), and alpha ketoglutarate (α-KG) (Figure 3A, 3B, Supplementary Tables 1 and 2) [54].

Valproic acid is a well-known broad-spectrum histone deacetylase inhibitor that leads to a rapid and dramatic spread of histone acetylation marks across the genome [73]. The fact that valproic acid is a critical component of many of the successful cocktails indicates that the spread of euchromatin may be an important component of partial epigenetic reprogramming [73]. Sodium butyrate is another histone deacetylase inhibitor that was effective in both human and mouse cocktails. It has been reported to improve the expression of genes associated with reprogramming, supporting the model that the regulation of histone acetylation marks is crucial for rejuvenation via reprogramming [54]. The final chemical in our most efficacious C1 cocktail, forskolin, is an activator of adenylyl cyclase that has been shown to drive reprogramming and trans differentiation, depending upon the combination of other compounds present [74, 75]. While the mechanism of action of forskolin in the context of rejuvenation remains to be identified, increasing cellular levels of cAMP and the triggering of signal cascades that are critical for adaptations in cell identity may be key.

So that is five - 1) sodium butyrate, 2) basic fibroblast growth factor, 3) alpha ketoglutarate, 4) valproic acid, 5) forskolin.


The sixth is below:

CHIR99021 is a GSK3α/β inhibitor, an effective inducer of CiPSCs and promoter of certain stem cell characteristics [66, 67]. E-616452, also known as RepSox, is a TGF-β inhibitor that has been used in experiments to replace SOX2 during epigenetic reprogramming

Below is a link to an article on GSK3 inhibitors, natural and synthetic. Lithium is listed as one.

Page 24 of the downloadable pdf above says:

Purine consists of pyrimidine ring fused with imidazole ring. Chiron Corp developed
purine derivatives, which were probably the first synthetic molecules specifically reported as
GSK-3 inhibitors. The most active compound showed 63% inhibtion of GSK-3 activity at1
μM. In addition, Chiron Corp. also developed a number of other potent GSK-3 inhibitors
based on purine or pyrimidine motif like CHIR98014 (CT98014), CHIR98023 (CT98023),
CHIR99021 (CT99021) which inhibit GSK-3 selectively within the nanomolar concentration
range (Figure 5).

Page 32.

Currently Lithium is evaluated as a GSK-3 inhibitor in mild
cognitive impairment by University of Dundee in phase III clinical trial. The Wayne State
University and University of Sao Paulo have studies with lithium carbonate against GSK-3
for bipolar disorder, AD and cognitive impairment.


I’ve read about lithium extending lifespan in worms and flies.

Also affects kidney health:


What’s the saying? There are two sides to every story and somewhere in the middle there’s the truth. I feel as though both these men are at completely opposite sides of the spectrum. Sinclair is optimistic to a fault and seems prone to hyperbolic predictions, while Brenner is a perennial cynic, pessimist and all round sourpuss. I assume that it must be possible to induce cellular reprogramming chemically, and this at least seems like a first step in trying to work out what might induce it. So how long are we guessing it’s going to take the biohacker community to start skunkworking these combinations?


Yes - I take the comments and opinions from both of them with a large dose of skepticism.


I do think Charles Brenner has the edge in the arguments about SIR2.


Is this practicable for any of us? Shouldn’t there be mice-lifespan extension studies first akin to the ITP?

yes, and I would be very hesitant to take valproic acid,even though it’s a cheap patent free drug unless you want to look like a horse


Valproic acid is a derivative of valeric acid, a minor constituent of valerian. It also comes in salt form - betamethasone valerate, testosterone valerate.

The Sinclair team has only done it in cells; they are not even at tissue level. Seems to be more of a proof of concept.

We identify six chemical cocktails, which, in less than a week and without compromising cellular identity, restore a youthful genome-wide transcript profile and reverse transcriptomic age. Thus, rejuvenation by age reversal can be achieved, not only by genetic, but also chemical means.


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

The Editorial Board is a Who’s Who in longevity research. All the usual suspects are there -Blagosklonny, Barzilai, Campisi, Gordunova, Longo, Conboy, Horvath, Gudkov, Kapahi, Kirkland, among others.

Even the fave of many people here, is there - Attia.

Was Brenner not invited?


Aside from any science or discussion, it’s crazy how much Charles Brenner hates David Sinclair. Like a full 25% of his energy seems to be devoted to talking smack about David Sinclair and he’s been doing it for about 5-10 years.


Charles Brenner has some valid points, but I disagree with a lot that he says. His arguments about David Sinclair and the sirtuins are I think right.

Where Charles Brenner is good is that he will often (but not always) engage in a debate with people who don’t agree with him. David Sinclair (and Bryan Johnson) generally don’t. Bryan Johnson responds to abuse, but not critical rational argument.

It is in debating the science that we can move knowledge forward. Hence I prefer Charles Brenner’s approach to these issues.

Valproate is not an HDACi that I would be inclined to try in my initial list (I have tried 14 at some stage and have a small list (maybe 4-5) of additional ones I may try at some stage although I am likely to remain with the 14 for some time.


Sirtuins are the focus of many researchers. Sirt1 for Sinclair, Sirt3, Sandra Kaufmann declares as her new obsession, and Sirt6 for Vera Gorbunova. They are activated by harmless substances - fisetin and quercetin for Sirt1, Honokiol (magnolia) for Sirt3, and seaweed (wakame) for Sirt6.

I prefer to take the supplements, and experiment with my body. I respect scientists who prove by experimentation. I have no appetite for listening to some contentious debater. Debates prove nothing.

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The SIR2 genes are a subset of HDACs.

I have no appetite for listening to some contentious debater.

Charles Brenner has published a paper in which he explains why he thinks David Sinclair’s arguments on SIR2 are factually wrong.

Personally where there are scientific disagreements which are evidence based I like to read through them to work out what I think the truth is. On this particular point I think Charles Brenner is right.

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The problem with most of these substances is that they work well in perti dishes and on short lived flies. Quercetin has a ridiculous short half life, and your body metabolises this in no time.
I question the effect these have on humans. I think supplementing with Quercetin and Fisetin is useless. If you want Quercetin just eat apples, and eat a ton of strawberries if you want Fisetin. Seaweed is eaten a lot in Okinawa, but I doubt that this is the reason alone that they live a couple of years longer than the rest of the world.
The Sirtuin studies going on is helpful to answer some questions, but I think they are barking up the wrong tree. Solutions of slowing down aging lays elswhere.

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