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DBL%20Hendrix%20small.png College chemistry, 1983

Derek Lowe The 2002 Model

Dbl%20new%20portrait%20B%26W.png After 10 years of blogging. . .

Derek Lowe, an Arkansan by birth, got his BA from Hendrix College and his PhD in organic chemistry from Duke before spending time in Germany on a Humboldt Fellowship on his post-doc. He's worked for several major pharmaceutical companies since 1989 on drug discovery projects against schizophrenia, Alzheimer's, diabetes, osteoporosis and other diseases. To contact Derek email him directly: derekb.lowe@gmail.com Twitter: Dereklowe

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March 14, 2014

A Sirtuin Activator Extends Lifespan in Normal Mice

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Posted by Derek

If you haven't seen it, the Sinclair group and numerous co-workers at the NIH and elsewhere now report that the SIRT1 activator SRT1720 extends the lifespan of mice on a diet of normal chow, and they see a number of good metabolic indicators - increase fat oxidation, decrease fat mass, increased insulin sensitivity, and so on.
SRT1720.png
There are several things to note about this effect, though. The mice were started on the compound at six months of age, and the compound was supplemented in chow to a dose of 100 mpk, which was maintained from there on out. (I don't have any allometric tables to hand, but it's safe to say that this would translate to a daily multigram dose in humans Absolutely wrong: it's about 8.8 mpk, a 600mg dose or so. Good thing I'm not a clinician). The lifespan extension was mean lifespan (up 8.8%) - they saw a trend towards extended median lifespan, but it didn't reach significance. (That sounds, at first, like there were some long-lived responders in the treatment group). There was no difference in 90th-percentile survival, which as the authors note, is consistent with the idea of the compound delaying age-related illness. There was also a high-fat-fed group of mice, supplemented in the same fashion, and consistent with earlier reports, these had their mean lifespan extended over 20%.

Blood markers of liver and kidney function seemed to hold up fine. Other than less steatitis (fatty tissue inflammation) in the liver, histology didn't appear to show any major changes (good or bad) in the treated mice compared to controls, especially considering that the treated mice were older when assayed. Gross pathology was also the same, which is worth noting because SIRT1 pathways have been implicated in slowing down some cancer phenotypes but speeding up others. Getting down to DNA microarrays, the most altered genes were found in liver and muscle tissue, and were associated with lower levels of inflammation.

This paper is not going to clear up the sirtuin controversies, but it is interesting and worthwhile. 100mpk, q.d. for life, is a hard and heavy dose, though, and if SRT1720 really is an efficacious sirtuin activator (a point subject to plenty of disagreement in the literature), then it's worth wondering if the pathway is really within range of therapeutic effects in humans. Resveratrol has been studied in a human trial, but resveratrol is polypharmacologic, to the point that in vivo data with it are probably only capable of telling us about the effects of resveratrol itself.

A couple of the authors on this new paper have their affiliations listed as "Sirtris, a GSK company", but there's no such thing any more. When last heard from, GSK was continuing sirtuin work on its own, but if there have been any notable announcements from them, I've missed them. What a selective SIRT1 activator does, long-term in normal humans, no one yet knows. Will anyone, ever?

Comments (16) + TrackBacks (0) | Category: Aging and Lifespan


COMMENTS

1. pharmacologyrules on March 14, 2014 7:53 AM writes...

I would hesitate to take a single dose result and extrapolate to 'safe to say' human dose. What is %F in mouse and other species, what is hepatic clearance, where is this dose on the dose response curve, is there a food effect, what is the activity in mouse versus human?

Permalink to Comment

2. Jeff on March 14, 2014 7:53 AM writes...

Your headline made me spew coffee all over my monitor: just this morning we caught a mouse under the kitchen sink. My wife's mission for me is to shorten the lifespan of mice, not to extend it...

Permalink to Comment

3. bhip on March 14, 2014 8:24 AM writes...

Perhaps mouse PK data at this dose exists in other publications (??) but SRT1720 could also safely be described as polypharmacologic (this link leads to off target screening data from Pfizer http://www.jbc.org/content/early/2010/01/08/jbc.M109.088682/suppl/DC1).
At 10 uM, SRT1720 inhibits (greater than 85%) a couple serotonin receptors, A3 (everything hits A3), alpha 2c, all the muscarinic receptors, MCH1, PDE2, some transporters, etc.
Granted, while this compound was not developed, it certainly doesn't suffice as a squeaky clean tool that would be required to interrogate such a complex biology.

Permalink to Comment

4. barry on March 14, 2014 8:56 AM writes...

how "normal" is your standard lab mouse? They've been inbred for generations to be highly standardized to each other. But that means there's a huge "founder effect".

Permalink to Comment

5. Paul Brookes on March 14, 2014 8:59 AM writes...

As I've iterated on comments here before, the politics surrounding this molecule will pretty much ensure it's not going anywhere as a clinical candidate...

First, the issue of availability for validation by academia. We approached Sirtris to obtain it, they said "no but you can make yourself it because we published the synthesis". We made it (actually a contract org-syn made it). It didn't behave as expected, so we went back and asked for some of Sirtris' special magic pixie dust-infused SRT1720, to which they responded "the method is published, maybe you messed up the synthesis". Of course, the only way we can ever find out if the synthesis was messed-up (1H-NMR, 13C-NMR and MS/MS all checked out) is to compare it with the "genuine" molecule. We've since had it made again by a different company and again it didn't work, and again Sirtris refused to hand over any of their material. Then of course the company imploded and the whole Westphal back-door resveratrol thing came up, and communication with the outside world ceased. Magically, Sinclair seems to still have access to this molecule, and he is alone in that privilege. Nobody else can get hold of it.

Second, as mentioned above the molecule doesn't do what it's supposed to do (i.e. in accordance with existing scientific knowledge). We have shown quite conclusively that knockout of SIRT1 ablates protection by ischemic preconditioning (as do pharmacologic inhibitors of SIRT1). In addition the SIRT1 over-expressing mouse is resistant to cardiac ischemic injury. Notably, short-term pharma' inhibition of SIRT1 abolishes the protection seen in the over-expressor, so that protection is not due to long term adaptation. The activity of the molecule is required during the short time frame of the ischemic injury itself. All of this is published (PMIDs 20823277 & 21856913). So, it would seem logical to suggest that activating SIRT1 with SRT1720 should be cardioprotective, but it doesn't do shit (see supplemental data in that first paper). There's actually another paper (PMID 23024374 from Ji Li's lab in Buffalo), where they showed a protective effect of SIRT1, but here's the rub - it still works in the knockout mouse. Two reputable labs, opposite results, no comment from anyone connected to SRT1720.

Third, word on the street is SRT1720 was toxic as shit in primates. Hence the rather cryptic words of Sinclair in an interview with the NY Times (http://www.nytimes.com/2011/08/19/science/19fat.html?_r=0) regarding their pursuit of other candidates. In particular, he says SRT2104 is "more suitable for human consumption". Hmmm... wonder what that could mean?

Permalink to Comment

6. Erebus on March 14, 2014 9:09 AM writes...

@1-

There are some fast-and-loose rules for that. PMID: 17942826, "Dose translation from animal to human studies revisited"


For mice, it basically boils down to:
Dm * (3/37) = Dh

Where Dm is the mouse dose in mg/kg, and Dh is the corresponding human equivalent dose. The reasoning behind this is perhaps overly general, but it holds up quite well for most practical intents and purposes.

...So 100mg/kg/day/mouse corresponds to roughly 8mg/kg/day in humans. Still a large dose. Not multigram, though, if that dose-translation study is to be believed.

Permalink to Comment

7. anon the II on March 14, 2014 9:32 AM writes...

I give a lecture on medicinal chemistry each year to pharmacology students at a private college in Durham, NC. One of the things I tell students is that when they see an article on some amazing property of resveratrol, they can safely not only ignore that article but they can ignore any future work from that author.

Permalink to Comment

8. annonie on March 14, 2014 10:25 AM writes...

The paper, and your posting, ignores previous comments about the lack of selectivity of this & other agents that are so-declared as sirtuin activators. If this type of study was done by any major pharmaceutical company, and described with such glowing results in a review by senior scientists, the study and the people would be thrown out of the organization.

Permalink to Comment

9. neo on March 14, 2014 11:03 AM writes...

Even if Erebus' simple allometry holds, it's 8.8mpk qd, not 8.8mg. That's still a good 600mg daily dose in an average human.

Permalink to Comment

10. anananon on March 14, 2014 12:08 PM writes...

Who cares if the target is right? It does seem to increase life span.. at least in this study. I'd say that is interesting in its own right. The most interesting question now is how does this happen?

Permalink to Comment

11. Pee Kay genius on March 14, 2014 12:56 PM writes...

Sorry guys.... You cannot scale a dose by using a "generic equation" and without mechanistic knowledge of metabolic pathways.
I'm surprised... In this forum, I did not expect that...

Permalink to Comment

12. Erebus on March 14, 2014 1:25 PM writes...

@11 - Have you read the study? Clearance pathways are important, but they're not the _entire_ picture. Many if not most of the other variables are scalable. And, importantly, 'generic equations' --like that one & like those based on BSA -- are often used to come up with human doses for Phase I clinical trials.

Permalink to Comment

13. Pee Kay genius on March 14, 2014 1:32 PM writes...

@12
It's a free country....

Permalink to Comment

14. Jose on March 15, 2014 6:37 AM writes...

Event times are never normally distributed, and so survival times should always be reported as medians, and not means. The p for the logrank is marginally significant (p = 0.0412), but there's no comment on what else was included in the Cox model to get the HR for SRT1720 treatment (HR = 0.73, 95% con-
fidence interval [0.59, 0.90], p = 0.0034).

Rule of thumb in epi- if the effect measure (OR, HR, IRR, etc.) is

Marginally significant with poorly defined analysis in lab animals= clinically wholly irrelevant.

Permalink to Comment

15. Jose on March 15, 2014 6:39 AM writes...

Event times are never normally distributed, and so survival times should always be reported as medians, and not means. The p for the logrank is marginally significant (p = 0.0412), but there's no comment on what else was included in the Cox model to get the HR for SRT1720 treatment (HR = 0.73, 95% CI [0.59, 0.90], p = 0.0034).

Rule of thumb in epi- if the effect measure (OR, HR, IRR, etc.) is

Marginally significant with poorly defined analysis in lab animals= clinically wholly irrelevant.

Permalink to Comment

16. Jose on March 15, 2014 9:44 AM writes...

strange html issues....

Rule of thumb in epi- if the effect measure (OR, HR, IRR, etc.) is less than 2 or so, it is very likely to be an artifact of the experimental design. The HR above is 1.37 (95% CI- 1.1 to 1.7).

Marginally significant with poorly defined analysis in lab animals= clinically wholly irrelevant.

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