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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

January 13, 2014

Boost Your NAD And Fix It All?

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Posted by Derek

Here's a paper from a few weeks back that I missed during the holidays: work from the Sinclair labs at Harvard showing a new connection between SIRT1 and aging, this time through a mechanism that no one had appreciated. I'll appreciate, in turn, that that opening sentence is likely to divide its readers into those who will read on and those who will see the words "SIRT1" or "Sinclair" and immediate seek their entertainment elsewhere. I feel for you, but this does look like an interesting paper, and it'll be worthwhile to see what comes of it.

Here's the Harvard press release, which is fairly detailed, in case you don't have access to Cell. The mechanism they're proposing is that as NAD+ levels decline with age, this affects SIRT1 function to the point that it no longer constains HIF-1. Higher levels of HIF-1, in turn, disrupt pathways between the nucleus and the mitochondia, leading to lower levels of mitochondria-derived proteins, impaired energy generation, and cellular signs of aging.

Very interestingly, these effects were reversed (on a cellular/biomarker level) by one-week treatment of aging mice with NMN (nicotine mononucleotide edit: fixed typo), a precursor to NAD. That's kind of a brute-force approach to the problem, but a team from Washington U. recently showed extremely similar effects in aging diabetic rodents supplemented with NMN, done for exactly the same NAD-deficiency reasons. I would guess that the NMN is flying off the shelves down at the supplement stores, although personally I'll wait for some more in vivo work before I start taking it with my orange juice in the mornings.

Now, whatever you think of sirtuins (and of Sinclair's work with them), this work is definitely not crazy talk. Mitochondria function has long been a good place to look for cellular-level aging, and HIF-1 is an interesting connection as well. As many readers will know, that acronym stands for "hypoxia inducible factor" - the protein was originally seen to be upregulated when cells were put under low-oxygen stress. It's a key regulatory switch for a number of metabolic pathways under those conditions, but there's no obvious reason for it to be getting more active just because you're getting older. Some readers may have encountered it as an oncology target - there are a number of tumors that show abnormal HIF activity. That makes sense, on two levels - the interiors of solid tumors are notoriously oxygen-poor, so that would at least be understandable, but switching on HIF under normal conditions is also bad news. It promotes glycolysis as a metabolic pathway, and stimulates growth factors for angiogenesis. Both of those are fine responses for a normal cell that needs more oxygen, but they're also the behavior of a cancer cell showing unrestrained growth. (And those cells have their tradeoffs, too, such as a possible switch between metastasis and angiogenesis, which might also have a role for HIF).

There's long been speculation about a tradeoff between aging and cellular prevention of carcinogenicity. In this case, though, we might have a mechanism where our interests on on the same side: overactive HIF (under non-hypoxic conditions) might be a feature of both cancer cells and "normally" aging ones. I put that word in quotes because (as an arrogant upstart human) I'm not yet prepared to grant that the processes of aging that we undergo are the ones that we have to undergo. My guess is that there's been very little selection pressure on lifespan, and that what we've been dealt is the usual evolutionary hand of cards: it's a system that works well enough to perpetuate the species and beyond that who cares?

Well, we care. Biochemistry is a wonderful, heartbreakingly intricate system whose details we've nowhere near unraveled, and we often mess it up when we try to do anything to it, anyway. But part of what makes us human is the desire (and now the ability) to mess around with things like this when we think we can benefit. Not looking at the mechanisms of aging seems to me like not looking at the mechanisms of, say, diabetes, or like letting yourself die of a bacterial infection when you could take an antibiotic. Just how arrogant that attitude is, I'm not sure yet. I think we'll eventually get the chance to find out. All this recent NAD work suggests that we might get that chance sooner than later. Me, I'm 51. Speed the plow.

Comments (17) + TrackBacks (0) | Category: Aging and Lifespan | Biological News | Diabetes and Obesity

September 20, 2013

Google Versus Aging

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Posted by Derek

If you haven't heard that Google is now funding research into human aging and lifespan, they'll be very disappointed. There's been plenty of publicity, which I find sort of interesting, considering that there's not too much to announce:

The Time article—and a Google blog post released at the same time—provided scant detail about what the new company, called Calico, will actually do. According to Time, the company, to be based somewhere in the Bay Area, will place long-term bets on unspecified technologies that could help fight the diseases of aging.

Page did tell Time he thinks biomedical researchers may have focused on the wrong problems and that health-care companies don’t think long-term enough. “In some industries it takes 10 or 20 years to go from an idea to something being real. Health care is certainly one of those areas,” Page told Time. “We should shoot for the things that are really, really important, so 10 or 20 years from now we have those things done.”

The company’s initial investors are Google and Arthur Levinson, also chairman of Apple’s board and that of biotech company Genentech. Levinson, a trained biochemist, will be the CEO of Calico, which the The New York Times reported is short for California Life Company.

I'm fine with this. Actually, I'm more than fine - I think it's a good idea, and I also think that it's a good idea for the money coming into it to be long-term, patient money, because it's going to have to be. I think that human life span can probably be extended, although no one's ready to say if that's going to mean thirty extra years of being 40, or thirty extra years of being 90. If you know what Trimalchio says about seeing the Cumaean Sybil in the Satyricon, you'll have come across the problem before. (Trimalchio's an unlikely fount of wisdom, but he seems pretty much on target with that one).

Patience will be needed on several fronts. Biochemically, there are actually a number of ideas to follow up on, and while that's good news in general, it also means that there's a lot of work ahead. Not all of these are going to actually extend lifespan, I think it's safe to say, and sorting them out will be a real job. But that's the sort of problem that a lot of therapeutic areas have. Aging research has several others piled on top of it.

One of them it shares with areas like diabetes and cardiovascular disease: you're looking for a drug or therapy that the patient will be taking for the rest of their lives - their extended lives, if all goes well - so toxicology becomes a huge concern. Tiny safety concerns can become big ones over the decades. And that leads into another big issue, the regulatory one. How would one set up a clinical trial for an anti-aging therapy? How long would it run? How long would you have to work with the FDA to get something together? Keep in mind that the agency doesn't have any framework for making people better than normal. You'll note that despite the possible lifespan enhancement with the sirtuin compounds, GSK never really mentioned this possibility in their takeover of Sirtris. It was all about diabetes and other conditions that have defined clinical endpoints and a regulatory environment already in place.

The answer to that problem, then, is surely to pick some disease of aging and see if you can ameliorate it by attacking the aging process in general. It's a bit like a second derivative: in other therapeutic areas, you pick a biomarker, and you try to get approval based on an effect against it as a surrogate for the long-term benefits against the actual disease. In this case, though, you'd pick an actual medical condition, and hope to get approval using it as a surrogate against the meta-disease of aging itself. Those will not be short trials, nor easy to run, nor will it be easy to obtain statistical significance in them.

And I don't think we'll be seeing one of those for quite some time. Larry Page himself is 40, I believe, so if he's looking for a benefit that he might realize, he's almost certainly out of luck. As am I at 51. Page's ten or twenty year timeline seems very short indeed. If I find a wonder drug in my lab this afternoon, it won't be hitting the pharmacy shelves for about fifteen years itself. I hope I'm wrong about this, but I doubt if anything will be worked out enough to try before either of us are much further into old age, at which point you start to run into that Cumaean Sibyl problem. Unless, of course, you are fortunate enough to come up with something that actually turns the clock back a bit, but that's much less likely. Just slowing it down is enough of a feat already. I realize that this is more of my patented brand of "pessimistic optimism", but I can't make myself come up with any other opinion yet.

I thought seriously about titling this post "Gegen Den Tod Ist Kein Kräutlein Gewachsen", but I figured that would drive my traffic into the basement. That is, I'm told, one of the mottos of the old German herbalists, translating as "Against death does no simple grow". It's safe to assume, though, that anything that really does usefully treat aging will not be simple, so the Germans are probably still in the right.

Update: a reader has sent along more information on that quotation. It actually goes back to Latin (cue various readers holding their heads and moaning). It goes ". . .contra vim mortis non est medicamen in hortis", and is part of the declamations that are more or less Quintilian's work on Roman court cases and rhetoric (thus often ascribed to "pseudo-Quintilian").

Comments (85) + TrackBacks (0) | Category: Aging and Lifespan

August 29, 2013

A New Pathway For Memory

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Posted by Derek

As someone who will not be seeing the age of 50 again, I find a good deal of hope in a study out this week from Eric Kandel and co-workers at Columbia. In Science Translational Medicine, they report results from a gene expression study in human brain samples. Looking at the dentate gyrus region of the hippocampus, long known to be crucial in memory formation and retrieval, they found several proteins to have differential expression in younger tissue samples versus older ones. Both sets were from otherwise healthy individuals - no Alzheimer's, for example.

RbAp48 (also known as RBBP4 and NURF55), a protein involved in histone deacetylation and chromatin remodeling, stood out in particular. It was markedly decreased in the samples from older patients, and the same pattern was seen for the homologous mouse protein. Going into mice as a model system, the paper shows that knocking down the protein in younger mice causes them to show memory problems similar to elderly ones (object recognition tests and the good old Morris water maze), while overexpressing it in the older animals brings their performance back to the younger levels. Overall, it's a pretty convincing piece of work.

It should set off a lot of study of the pathways the protein's involved in. My hope is that there's a small-molecule opportunity in there, but it's too early to say. Since it's involved with histone coding, it could well be that this protein has downstream effects on the expression of others that turn out to be crucial players (but whose absolute expression levels weren't changed enough to be picked up in the primary study). Trying to find out what RbAp48 is doing will keep everyone busy, as will the question of how (and/or why) it declines with age. Right now, I think the whole area is wide open.

It is good to hear, though, that age-related memory problems may not be inevitable, and may well be reversible. My own memory seems to be doing well - everyone who knows me well seems convinced that my brain is stuffed full of junk, which detritus gets dragged out into the sunlight with alarming frequency and speed. But, like anyone else, I do get stuck on odd bits of knowledge that I think I should be able to call up quickly, but can't. I wonder if I'm as quick as I was when I was on Jeopardy almost twenty years ago, for example?

(If you don't have access to the journal, here's the news writeup from Science, and here's Sharon Begley at Bloomberg).

Comments (7) + TrackBacks (0) | Category: Aging and Lifespan | The Central Nervous System

July 26, 2013

How Rapamycin Extends Lifespan: Not By Slowing Down Aging

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Posted by Derek

A few years ago, there came the interesting news that rapamycin looked as if it prolonged lifespan in mice. That result is robust; it's been replicated. Now a large multicenter effort in Germany has looked closely at this effect, and they have many more details about what's going on.

The big question is: does rapamycin extend lifespan through some general effect on aging, or does it work through a non-aging mechanism (by perhaps suppressing tumor formation)? Now, many people wouldn't find that much of a distinction - would you like a drug that makes you age more slowly, or would you like one that keeps you from getting cancer? The answer would probably be "Yes". But it's a question that very much matters biochemically.

And it turns out that it's the latter. This new paper does a very careful examination of many phenotypes of aging, on both whole-animal and tissue levels, and finds that rapamycin treatment does not really seem to affect age-related changes. What changes they did see on rapamycin treatment were also present in young mice as well as older ones, making them less likely to be an underlying cause of the effect. They now believe that the compound's effect on lifespan is entirely, or almost entirely, due to the lower rate of fatal neoplasms.

Comments (8) + TrackBacks (0) | Category: Aging and Lifespan

July 23, 2013

Resveratrol: What's It Do For Mitochondria?

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Posted by Derek

I've been meaning to blog about this new paper in PLOS Biology on resveratrol's effects on mitochondria. It's suggesting that the results previously reported in this area cannot be reproduced, namely the idea that resveratrol increases mitochondrial biogenesis and running endurance. In fact, says this new paper, the whole mechanistic story advanced in this field (resveratrol activates SIRT1, which activates the coactivator PGC1, which cranks up the mitochondria) is wrong. SIRT1 has, they say, the opposite effect: it decreases PGC1 activity, and downregulates mitochondria.

That's an interesting dispute, and leads to all kinds of questions about who's wrong (because someone certainly appears to be). But there's another issue peculiar to this new paper. It now says that there are no reader comments, but for a couple of days there was one, which went into detail about how various Western blots appeared to have been performed sloppily and with confusing control lanes. I have no idea how well substantiated these objections were, and I have no idea why they have disappeared from the paper. It's all quite peculiar.

Comments (15) + TrackBacks (0) | Category: Aging and Lifespan

April 24, 2013

A New Book on Longevity Research

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Posted by Derek

The University of Chicago Press has sent along a copy of a new book by DePaul professor Ted Anton, The Longevity Seekers. It's a history of the last thirty years or so of advances in understanding the biochemical pathways of aging. As you'd imagine, much of it focuses on sirtuins, but many other discoveries get put into context as well. There are also thoughts on what this whole story tells us about medical research, the uses of model animal systems, about the public's reaction to new discoveries, and what would happen if (or when) someone actually succeeds in lengthening human lifespan. (That last part is an under-thought topic among people doing research in the field, in my experience, at least in print).

Readers will be interested to note that Anton uses posts and comments on this blog as source material in some places, when he talks about the reaction in the scientific community to various twists and turns in the story. (You'll be relieved to hear that he's also directly interviewed almost all the major players in the field, as well!) If you're looking for a guide to how the longevity field got to where it is today and how everything fits together so far, this should get you up to speed.

Comments (17) + TrackBacks (0) | Category: Aging and Lifespan | Book Recommendations

April 9, 2013

New Sirtuin Inhibitors

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Posted by Derek

And since that last post was about sirtuins, here's a new paper in press at J. Med. Chem. from the Sirtris folks (or the Sirtris folks that were, depending on who's making the move down to PA). They report a number of potent new sirtuin inhibitor compounds, which certainly do look drug-like, and there are several X-ray structures of them bound to SIRT3. It seems that they're mostly SIRT1/2/3 pan-inhibitors; if they have selective compounds, they're not publishing on them yet.

I should also note, after this morning's post, that the activities of these compounds were characterized by a modified mass spec assay! I would expect sirtuin researchers in other labs to gladly take up some of these compounds for their own uses. . .

Note: I should make it clear that these are more compounds produced via the DNA-encoded library technology. Note that these are yet another chemotype from this work.

Comments (17) + TrackBacks (0) | Category: Aging and Lifespan | Chemical News

March 12, 2013

Resveratrol Gets Some Details Cleared Up

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Posted by Derek

I've been meaning to write on this paper, from David Sinclair and co-workers, on the mechanism of resveratrol action. The backstory is so long and convoluted that you're going to have to set aside some time to catch up if you're just joining it (paging back through this category archive will give you some play-by-play). But the basics are that resveratrol came on the scene as an activator of the enzyme SIRT1, which connection was later called into question by work that showed a lot of artifacts in the assay conditions used to establish it.

This new paper may well clear some of that up. The fluorescent tagged peptides that were producing the false positive may well be mimicking the natural protein partners, if this analysis is correct. SIRT1, as it turns out, recognizes a hydrophobic domain in the same region of each, which can be the fluorescent tag, or native hydrophobic amino acids themselves.

So it appears that resveratrol (and other synthetic sirtuin activators) are acting allosterically on the protein. This work found a single SIRT1 amino acid mutant (E230K) that doesn't affect SIRT1's catalytic activity, but does completely mess with resveratrol's ability to activate it (the other compounds in this class show the same effect). That makes for a neat story, and it would resolve several questions about the molecular mechanism of action.

But it leaves open the bigger questions: is SIRT1 a human drug target? Do activators exert beneficial effects, and do different ones have different profiles in living systems? There's already plenty of evidence for some of these; the problem is, the evidence points both ways (much of this is summed up and linked to in this post). Resveratrol itself is not, I would say, an appropriate molecule to answer the detailed questions (other than "What does effects does resveratrol itself have?"). It does not have particularly good pharmacokinetic properties, for one thing, and it is known to hit a lot of other things besides SIRT1 (Sinclair himself has referred to it as a "dirty molecule", and I agree).

So it's the follow-on sitruin activators that GSK has that are the real vehicles for answering these very interesting (and potentially important, and potentially lucrative) questions. A quick look at Clinicaltrials.gov shows that work has been done on SRT2104 and SRT2379, but many of these studies have been complete for a year or two now. (Here's the one that's listed as ongoing - it and several others have an anti-inflammatory bent). All we can deduce is that at least two SRT compounds are being (or recently have been) evaluated in the clinic. Fierce Biotech has a bit more from Sirtris CEO George Vlasuk:

About those clinical trials: GSK's massive investment in Sirtris has yet to lead to a drug or a prime-time drug candidate. Sirtris has ended clinical development of multiple synthetic compounds after initial human studies, Vlasuk said. And his team is hunting for the precise mechanism for activating SIRT1 in hopes of creating more potent compounds than resveratrol to treat diseases.

Hmm. I thought that maybe this new Science paper was the precise mechanism. But maybe not? The story continues. . .

Comments (9) + TrackBacks (0) | Category: Aging and Lifespan

August 29, 2012

Caloric Restriction Flops?

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Posted by Derek

Nature is out today with a paper on the results of a calorie-restriction study that began in 1987. This one took place with rhesus monkeys at the National Institute of Aging, and I'll skip right to the big result: no increase in life span.

That's in contrast to a study from 2009 (also in rhesus) that did see an extension - but as this New York Times article details, there are a number of differences between the two studies that confound interpretation. For one thing, a number of monkeys that died in the Wisconsin study were not included in the results, since it was determined that they did not die of age-related causes. The chow mixtures were slightly different, as were the monkeys' genetic background. And a big difference is that the Wisconsin control animals were fed ad libitum, while the NIA animal were controlled to a "normal" level of calorie intake (and were smaller than the Wisconsin controls in the end).

Taken together with this study in mice, which found great variation in response to caloric restriction depending on the strain of mouse used, it seems clear that this is not one of those simple stories. It also complicates a great deal the attempts to link the effect of various small molecules to putative caloric restriction pathways. I used to think that caloric restriction was the bedrock result of the whole aging-and-lifespan research world - so now what? More complications, is what. Some organisms, under some conditions, do seem to show longevity effects. But unraveling what's going on is just getting trickier and trickier as time goes on.

I wanted to take a moment as well to highlight something that caught my eye in the Times article linked above. Here:

. . .Lab test results showed lower levels of cholesterol and blood sugar in the male monkeys that started eating 30 percent fewer calories in old age, but not in the females. Males and females that started dieting when they were old had lower levels of triglycerides, which are linked to heart disease risk. Monkeys put on the diet when they were young or middle-aged did not get the same benefits, though they had less cancer. But the bottom line was that the monkeys that ate less did not live any longer than those that ate normally. . .

Note that line about "benefits". The problem is, as far as I can see (Nature's site is down as I write), the two groups of monkeys appear to have shown the same broad trends in cardiovascular disease. And cardiovascular outcomes are supposed to be the benefits of better triglyceride numbers, aren't they? You don't just lower them to lower them, you lower them to see better health. More on this as I get a chance to see the whole paper. . .

Comments (13) + TrackBacks (0) | Category: Aging and Lifespa