About this Author
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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November 5, 2009
Posted by Derek
Resveratrol's a mighty interesting compound. It seems to extend lifespan in yeast and various lower organisms, and has a wide range of effects in mice. Famously, GlaxoSmithKline has expensively bought out Sirtris, a company whose entire research program started with resveratrol and similar compound that modulate the SIRT1 pathway.
But does it really do that? The picture just got even more complicated. A group at Amgen has published a paper saying that when you look closely, resveratrol doesn't directly affect SIRT1 at all. Interestingly, this conclusion has been reached before (by a group at the University of Washington), and both teams conclude that the problem is the fluorescent peptide substrate commonly used in sirtuin assays. With the fluorescent group attached, everything looks fine - but when you go to the extra trouble of reading things out without the fluorescent tag, you find that resveratrol doesn't seem to make SIRT1 do anything to what are supposed to be its natural substrates.
"The claim of resvertraol being a SIRT1 activator is likely to be an experimental artifact of the SIRT1 assay that employs the Fluor de Lys-SIRT1 peptide as a substrate. However, the beneficial metabolic effects of resveratrol have been clearly demonstrated in diabetic animal models. Our data do not support the notion that these metabolic effects are mediated by direct SIRT1 activation. Rather, they could be mediated by other mechanisms. . ."
They suggest activation of AMPK (an important regulatory kinase that's tied in with SIRT1) as one such mechanism, but admit that they have no idea how resveratrol might activate it. Does that process still require SIRT1 at all? Who knows? One thing I think I do know is that this has something to do with this Amgen paper from 2008 on new high-throughput assays for sirtuin enzymes.
One wonders what assay formats Sirtris has been using to evaluate their new compounds, and one also wonders what they make of all this now at GSK. Does one not? We can be sure, though, that there are plenty of important things that we don't know yet about sirtuins and the compounds that affect them. It's going to be quite a ride as we find them out, too.
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+ TrackBacks (0) | Category: Aging and Lifespan | Biological News | Drug Assays
October 5, 2009
Posted by Derek
As many had expected, a Nobel Prize has been awarded to Elizabeth Blackburn (of UCSF), Carol Greider (of Johns Hopkins), and Jack Szostak (of Harvard Medical School/Howard Hughes Inst.) for their work on telomerase. Blackburn had been studying telomeres since her postdoc days in the late 1970s, and she and Szostak worked together in the field in the early 1980s, collarborating from two different angles. Greider (then a graduate student in Blackburn's lab) discovered the telomerase enzyme in 1984. She's continued to work in the area, as well she might, since it's been an extremely interesting and important one.
Telomeres, as many readers will know, are repeating DNA stretches found on the end of chromosomes. It was realized in the 1970s that something of this kind needed to be there, since otherwise replication of the chromosomes would inevitably clip off a bit from the end each time (the enzymes involved can't go all the way to the ends of the strands). Telomeres are the disposable buffer regions, which distinguish the natural end of a chromosome from a plain double-stranded DNA break.
What became apparent, though was that the telomerase complex often didn't quite compensate for telomere shortening. This provides a mechanism for limiting the number of cell divisions - when the telomeres get below a certain length, further replication is shut down. Telomerase activity is higher in stem cells and a few other specialized lines. This means that the whole area must be a key part of both cellular aging and the biology of cancer. In a later post, I'll talk about telomerase as a drug target, a tricky endeavour that straddles both of those topics.
It's no wonder that this work has attracted the amount of attention it has, and it's no wonder either that it's the subject of a well deserved Nobel. Congratulations to the recipients!
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+ TrackBacks (0) | Category: Aging and Lifespan | Biological News | Cancer | Current Events
July 10, 2009
Posted by Derek
A new paper coming out in Nature is getting a lot of attention, and well it should. This is some of the more dramatic anti-aging news that's been reported to date. (The accompanying editorial is also surely the first time anyone's quoted "Stairway to Heaven" in Nature).
The work hinges on a kinase enzyme called TOR (you often see an "m" in front of it, for "mammalian"). TOR, in accordance with the best gotta-name-it-something traditions of biochemistry, stands for "target of rapamycin", by which you would deduce (correctly) that rapamycin was discovered well before TOR. Rapamycin's a complex natural product first isolated from bacteria in a soil sample from Easter Island (Rapa Nui) - right here, in fact. In the late 1980s and early 1990s it was (along with another macrolide immunosuppresant, FK-506) the subject of a huge amount of research. (Note that FK-506 and rapamycin, though similar, still have some major differences in mechanism - unraveling these was most definitely nontrivial). Both compounds have strong immunosuppressive properties - the hope was that one or the other might prove to be some sort of universal transplant drug, among other things.
Rapamycin isn't that, but it's still useful, particularly in kidney transplants. And since TOR is involved in a lot of important cellular processes (brace yourself), inhibition of it by rapamycin and synthetic molecules has been studied extensively for other actions. The most interesting (well, perhaps until now) has been as an anticancer therapy. That alone illustrates the trickiness of this area, since one problem with any immunosuppressive therapy is a significantly higher risk of cancer. Decoupling these two effects has occupied a lot of time and effort over the years; that last link should give you an idea of the magnitude of the task.
But rapamycin has also shown life-extending properties in simple organisms, and this latest paper extends this effect to mice. The NIH group studying this had their problems, though - just adding the compound to rodent chow wasn't enough to achieve useful blood levels. More formulation work had to be done to produce an encapsulated version that could make it past the upper gut, and by the time that was worked out, the large cohort of mice set aside for the experiment was. . .well, rather more aged than planned.
But they went ahead with the experiment anyway, starting them off at 600 days old, which is roughly a 60-year-old human. Startlingly, the compound still extends life span, by about 14% in the female mice and 9% in the males. At ages where about 5% of the control mice were still alive, some 20% of the treated mice were still going. That's a very significant result, especially considering the late start. All in all, this looks like the most dramatic mid-to-later lifespan intervention that anyone's ever seen in a mammal. (Caloric restriction, for example, has been basically useless if started at the 600 day mark in mice, and no weight losses were seen here). There's a rapamycin study under way with mice in the prime of rodent life (starting at 270 days), and the preliminary results look quite similar (with again a stronger effect in the females).
The causes of death don't seem to have altered. A good sample of animals from both groups were checked by necropsy, and nothing significant was noted. That seems rather surprising, because the blood levels of the compound are (at least from what I can see) rather high. The paper mentions that the mice had 60 to 70 ng/mL rapamycin, and looking around, I find blood levels of 15 ng/mL mentioned as effective in tumor suppression in one mouse model, and the immunosuppressive doses seem to be similar. I'd be glad to hear from anyone who knows more about rapamycin dosing in mice, though; it's definitely outside my range of experience.
Are people going to run out and start taking the stuff? It wouldn't surprise me, although I'd have to say that that's a bad idea at the moment. There's an awful lot that we don't understand about the tradeoffs between aging, cancer, and the immune response, and I'd hate to end up on the wrong side of that bet. Jumping straight to humans is too big a leap for now, but remember - there are a lot of other mTOR inhibitors out there in development (try this paper for starters). If we can narrow down which pathways are important for lifespan (and believe me, there are people thinking hard about this right now, especially after this paper), then there could be some very interesting opportunities
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May 13, 2009
Posted by Derek
Now, this is an example of an idea being followed through to its logical conclusion. Here’s where we start: the good effects of exercise are well known, and seem to be beyond argument. Among these are marked improvements in insulin resistance (the hallmark of type II diabetes) and glucose uptake. In fact, exercise, combined with losing adipose weight, is absolutely the best therapy for mild cases of adult-onset diabetes, and can truly reverse the condition, an effect no other treatment can match.
So, what actually causes these exercise effects? There has to be a signal (or set of signals) down at the molecular level that tells your cells what’s happening, and initiates changes in their metabolism. One good candidate is the formation of reactive oxygen species (ROS) in the mitochondria. Exercise most certainly increases a person’s use of oxygen, and increases the work load on the mitochondria (since that’s where all the biochemical energy is coming from, anyway). Increased mitochondrial formation of ROS has been well documented, and they have a lot of physiological effects.
Of course, ROS are also implicated in many theories of aging and cellular damage, which is why cells have several systems to try to soak these things up. That’s exactly why people take antioxidants, vitamin C and vitamin E especially. So. . .what if you take those while you’re exercising?
A new paper in PNAS askes that exact question. About forty healthy young male volunteers took part in the study, which involved four weeks of identical exercise programs. Half of the volunteers were already in athletic training, and half weren’t. Both groups were then split again, and half of each cohort took 1000 mg/day of vitamin C and 400 IU/day vitamin E, while the other half took no antioxidants at all. So, we have the effects of exercise, plus and minus previous training, and plus and minus antioxidants.
And as it turns out, antioxidant supplements appear to cancel out many of the beneficial effects of exercise. Soaking up those transient bursts of reactive oxygen species keeps them from signaling. Looked at the other way, oxidative stress could be a key to preventing type II diabetes. Glucose uptake and insulin sensitivity aren't affected by exercise if you're taking supplementary amounts of vitamins C and E, and this effect is seen all the way down to molecular markers such as the PPAR coactivator proteins PGC1 alpha and beta. In fact, this paper seems to constitute strong evidence that ROS are the key mediators for the effects of exercise, and that this process is mediated through PGC1 and PPAR-gamma. (Note that PPAR-gamma is the target of the glitazone class of drugs for type II diabetes, although signaling in this area is notoriously complex).
Interestingly, exercise also increases the body's endogenous antioxidant systems - superoxide dismutase and so on. These are some of the gene targets of PPAR-gamma, suggesting that these are downstream effects. Taking antioxidant supplements kept these from going up, too. All these effects were slightly more pronounced in the group that hadn't been exercising before, but were still very strong across the board.
This confirms the suspicions raised by a paper from a group in Valencia last year, which showed that vitamin C supplementation seemed to decrease the development of endurance capacity during an exercise program. I think that there's enough evidence to go ahead and say it: exercise and antioxidants work against each other. The whole take-antioxidants-for-better-health idea, which has been taking some hits in recent years, has just taken another big one.
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+ TrackBacks (0) | Category: Aging and Lifespan | Biological News | Cardiovascular Disease | Diabetes and Obesity
June 6, 2008
Posted by Derek
Since it’s a favorite topic of mine, I really have to point out this study in PLoS ONE on resveratrol. A large collaboration looked at the gene transcription effects of dosing the compound in mice, compared to a normal diet and to a calorie-restricted one. I can’t do better than the first paragraph of the paper does at setting the scene:
” Caloric restriction (CR) retards several aspects of the aging process in mammals, including age-related mortality, tumorigenesis, physiological decline and the establishment of age-related transcriptional profiles. The wide scope of these actions, and the profound metabolic and hormonal shifts induced by CR has led to efforts at identifying natural or synthetic compounds that mimic the effects of CR in the absence of overt metabolic and endocrine disturbances or reduced caloric intake. Because most age-related diseases are likely to be secondary to the aging process itself, the discovery of such compounds could have a profound public health impact by reducing disease incidence and possibly extending the quality and length of the human lifespan.”
That’s a fine list of things that everyone would like to avoid: cancer, decline, and death. And the last sentence makes a key point, that the age-related diseases are not inevitable, but can be attacked as a group by attacking aging itself. A few years back, that statement might not have made it into a scientific paper at this level, but it can now.
This study had three groups of male mice (in a hybrid strain derived from C57 black): a control group getting 84 kcal/mouse/week of food, a calorie-restricted group getting 25% less chow, and a group getting the first diet plus 4.9 mg/kg of resveratrol, both experimental diets starting at mouse middle age (14 months). This same group had already reported that starting CR at that point in that mouse strain leads to about a 13% increase in lifespan.
As a baseline, they checked the transcriptional changes in young versus old mice on the control diet. There were, for example, about a thousand genes in heart tissue (out of twenty thousand checked) with a highly significant change in their profile. Comparing old heart tissue from the controls to the old tissue from the CR group, 536 genes showed a highly significant difference due to caloric restriction. The resveratrol-treated group, meanwhile, showed the same level of change in 522 genes, from basically the same list.
They also looked at skeletal muscle and brain (neocortex) and found similar but definitely less dramatic effects. In muscle, CR only affected about a quarter of the age-related genes (as opposed to half in the heart), and resveratrol was very similar. In the brain tissue, CR was able to reverse the aging profile in only 19% of age-related genes, and resveratrol lagged with 13%. The take-home message there is that aging can be a different process in different tissues, and attempts to alter it are going to vary across those tissues as well. (Here's the figure covering all these).
Another interesting question is whether CR (or resveratrol) affect other genes that aren’t in the age-related group. The answer is “Oh, yes indeed”, with over seven hundred genes whose profile was altered by CR but are not directly altered by age alone. (Compare that to the thousand age-altered genes, five hundred of which are reversed by CR, and you can see that this could be a source of significant effects). Resveratrol treatment did an extraordinary job of mimicking this profile, affecting 745 of the same 747 genes. The same thing was found in the other tissues – 1164 non-age-related transcription changes were found in skeletal muscle from the CR mice, and resveratrol treatment affected all 1164 of them.
So resveratrol appears to be a pretty close mimic of caloric restriction – but it’s closest in the non-age-related genes, which is interesting. The thing is, there’s no guarantee that all these transcriptional changes are good – presumably a lot of the ones that reverse age-related changes are beneficial (although we don’t know that for sure), but the ones that aren’t involved in aging could be more of a mixed bag. The net effect of CR does seem to be beneficial, but there are a lot of ways to arrive at that end point, and resveratrol could be mimicking the bad as well as the good. Here’s an attempt at figuring out the functions of the various genes involved in each group.
Of course, a much more relevant measure of benefit is how the animals themselves are doing under these treatments. The paper looks at some measures of cardiac function in young and old control mice, as well as in the treatment groups, and find that both CR and resveratrol seem to protect against decline. That chart also shows some other physiological readouts, at least one of which is rather surprising.
There's a huge insulin-signaling component in this whole field of study - the putative target of resveratrol (the sirtuins) are thoroughly tangled up in insulin and insulin-related growth factor (IGF) pathways. Genetic manipulation of several genes in those areas has also shown powerful effects on lifespan and aging in model organisms. So one of the oddities here is that the CR diet showed an effect on IGF-1, but resveratrol didn't. And while both treatment groups showed increased insulin sensitivity, several markers of that (glucose transporters, for example) showed the expected changes in the CR group but not the resveratrol group.
So if resveratrol treatment really does increase lifespan in the same way that caloric restriction does, it could mean that the insulin signaling axis isn't as important in CR as people thought. That's a difficult conclusion to come to, given the other data in the field, so a more reasonable one might be that resveratrol is hitting those same pathways, but not in the same way that CR does. (The similar increase in insulin sensitivity in the two groups argues for that view). Supporting this view, the transcription factor Pgc-1alpha, which is known to be very important for a range of genes in insulin sensitivity, was upregulated in muscle in the CR group but untouched in the resveratrol group.
The weirdest thing about this whole study, though, to my mind was the finding that levels of the prototype sirtuin, SIRT1, were not elevated in either group. That's in direct contrast to results seen in rats and humans under caloric restriction. In fact, in this case SIRT1 levels actually went down in the CR mice. There are several potential conclusions, all of which will keep people busy for a good while: perhaps some (or most?) of the anti-aging benefits of either CR or resveratrol in all species are coming from something else other than the effect on SIRT1. That would sow confusion, for sure. Or perhaps this is only true in mice, but not in rats (or people), and the sirtuin pathway really is the answer in the other species - in that case, you have to wonder what's so special about mice, and just what those different pathways are that kick in with them.
No, this is a very interesting study, and a very hopeful one, but it also points out just how much we don't know. I'm sure many more surprises like this are on the way, both positive and negative ones. But the overall point is made: aging and its effects can be altered. We don't understand quite how it's happening, and there are a lot of things to be worked out, but we can do it. If we can get the details worked out, human history is going to go through the biggest inflection point since fire and agriculture.
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April 25, 2008
Posted by Derek
I don’t want to say that this is a trend, but I notice that GSK is saying that they’re going to leave Sirtris more or less alone as well (as Takeda has said they’ll do with Millennium). The researchers in both shops should feel good about that, and not only because they’ll be keeping their jobs. They’re getting a vote of confidence in the most meaningful way that a large company can give that to its employees: by paying you money and not messing with you.
Of course, these deals have two sides to them. I don’t know what it’s like in Takeda back in Japan – my contacts inside the Japanese pharmaceutical industry aren’t extensive. But I think that some of the people at GSK (where I do know a lot of people) are wondering just what motivated their company to spend $720 million on Sirtris rather than on them.
It’s a fair question, even though I don’t have a problem myself with the Sirtris deal (as I said yesterday). But the sirtuins themselves are targets that anyone can work on, and you’d assume that a big outfit like GlaxoSmithKline could, if they wanted to, make a big push into the area and find some interesting things. So why didn’t they? The most obvious reason would be Sirtris had already done a good deal of that work, and it was more economical for GSK to buy it than to redo it. Another possibility is that the chemical space for drug-like hits in that area may not be very spacious, and that Sirtris may have already carved out a good piece of that real estate.
There’s also a bit of Glaxo history to deal with. The company had already, about fifteen years ago, decided to make a great big push into a promising new research area: nuclear receptors. They set up a whole research institute and did a huge amount of good science trying to figure out how these things worked, what they were good for, and how to get drugs that affected them. I got interested in the field in the late 1990s, and it became clear to me very quickly that Glaxo’s effort was the most serious of the bunch (and that included some really substantial research going on at Merck, Lilly and some other outfits). The company had teams of people who seemed to do nothing else than study the structures of these things, generate reams of X-ray data, synthesize huge lists of ligand molecules of every kind you could want, and so on. Just run "Glaxo nuclear receptor" through PubMed to see what I mean.
And what did it get them? From what I can see, not much. Avandia (rosiglitazone) is a nuclear receptor ligand (for PPAR-gamma), but its activity had already been discovered, and it was in clinical trials without a known mechanism. Figuring out how it worked was one of the Glaxo team’s early triumphs. But Avandia has turned out to be famously troublesome, and no others have come to market, despite multiple tries in the clinic. The huge amount of time and money the company spent generated a lot of interesting science, but appears (at least to me) to have brought in not one dime of revenue. (No doubt someone from GSK will correct me if I’m wrong).
So you can see how the company might be wary of starting a big internal effort to explore a massive, complex, and risky new field of biology. Politically and psychologically, it’s probably easier for them to structure this in terms of an acquisition.
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+ TrackBacks (0) | Category: Aging and Lifespan | Business and Markets | Diabetes and Obesity | Drug Industry History
April 24, 2008
Posted by Derek
Well, I’m back from a brief vacation, and catching up with the news. It looks like the big headline is GlaxoSmithKline’s offer for Sirtris: $720 million, which is a hefty premium (84%!) to what the company was trading for previously. Reckless waste of money, or canny deal?
I lean toward the latter, but I’ve long had a place in my heart for sirtuin research and its potential. It’s still a long shot, but it’s one of the most intriguing ones in the history of medicine. Actually, from one perspective, you wonder how long a shot it is: a biochemical pathway that seems to extend healthy life in yeast, roundworms, flies, and mice would seem to have some odds of doing the same thing in man. A lot of drug programs have been started with a lot less backing them up, albeit for rather less earth-shattering indications.
Of course, Sirtris hasn’t officially been targeting life extension drugs, at least not in the near term. A number of these potential life-extending biochemical pathways are tied up with insulin signaling, which makes sirtuin-targeted drugs a natural for diabetic therapy as well. Sirtris has reported encouraging data for just that indication. If a sirtuin-based drug is going to make it to market, that’s a good bet for how it’ll do it. I note, though, that the company has also applied for orphan-drug status for resveratrol itself for a rare muscle disorder. But they don’t own that parent compound, just its use in this case – the diabetes work is being carried on with second- and third-generation analogs that address some of resveratrol’s problems. (It’s not a particularly stable compound, for one thing).
Once one of these drugs is approved, it’ll have the biggest, strangest potential for off-label use that anyone has ever seen. Oh, that’s going to be something to watch. GSK is well aware of this – I’m not saying that it’s part of their business plan, but when you see their head of drug discovery talking to Forbes and tossing the word “transformational” around, you know that they’ve thought beyond a replacement for Avandia. The Wall Street Journal headlines it like it is: “Glaxo to Buy Sirtris in Bet on Antiaging Reseach”.
That’s the truth, all right, and it’s going to be fascinating to watch things develop. As I was saying here the other day, a drug for aging is a perfect example of something the FDA has absolutely no idea of how to approach. Well, it’s not just the FDA, come to think of it: how on earth would you design a Phase II trial for life extension? How long would it take? What’s your clinical endpoint? And further on, how long will you want to monitor your Phase III patients (recall Pfizer’s recent follow-up of Exubera trial participants? How long will it take before you could be sure that some horrible bargain wasn’t struck along the way?
That’s the lurking fear behind all this research, fit to give Leon Kass the shakes. Life extension tends to give some people the same “Things Man Was Not Meant to Know” shivers as (for example) germ-line genetic manipulation. I’m tempted to cue the theramin music in the background, but I can’t really make fun of this attitude, since I understand where the uneasiness is coming from. In all these cases, we’re looking at real alterations of what we think of as human. Personally, I think there’s room for improvement in what we think of as human, but I agree that we should reach for those improvements carefully. And I can see how the very thought could strike some people as coming close to crazy.
But we’re going to find out. That’s the real import of the GSK news: the money is there to find out what’s possible in this field. I’m happy to hear it. But then, I was a bit euphoric back in 2003 when this news started breaking, and I’ve never really lost that feeling. We shall see.
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January 21, 2008
Posted by Derek
Update: Prof. de Grey responds to Jim Hu's criticisms below
I didn’t note it at the time here, but back in November there was a very interesting paper in Nature that bears on aging and life extension. A group at the Hutchinson Center in Seattle did a survey of compounds, looking for whatever might show up that seemed to extend lifespan. (That’s just the sort of see-what-falls-out screen that C. elegans is good for, since the little beasts are so small, and they only live for about 20 days or so).
They screened 88,000 compounds - by far the largest direct survey ever run for longevity, as far as anyone knows, but (I should point out) still a tiny run by industrial standards. But they came up with a few hits: 1083 compounds made the first cut (roundworms still alive longer than they should be), and 115 of those repeated with statistical significance. 13 compounds increased lifespan by 30 to 60%. Interestingly, I don't think that they list all of them in the paper, but they did note that one of the strong hits looked very much like a known hit set of serotinergic antagonists.
They ran a set of analogs through the assay, and had a high hit rate. All the compounds that worked were 5-HT2 antagonists, such as marketed drug mianserin, although they each have some other activities as well. (It should be noted that the reuptake inhibitors, the Prozac/Zoloft type compounds, had no effect). But the 5-HT2 subtype, particularly 5-HT2c, has long been regarded as important in food intake, so the guess is that these compounds also tie into the whole caloric restriction story for aging. Restricting food intake and giving one of these drugs at the same time didn't add anything, the group found. It may be that these compounds set off metabolic signals that tell the roundworms that they’re short of food, even they they really aren’t, and thus do a sort of fake caloric restriction on them. At any rate, mutant nematodes that can't make serotonin showed no lifespan extension with exposure to these compounds, so one way or another, it seems to be involved.
Now, I wouldn’t advocate running out and trying this on a human being just yet, though, since we’ve come up with several higher brain functions for our serotinergic receptors that roundworms don’t have much call for. There’s also the question of what this strategy would feel like in a higher animal: would you want to live longer, but always feel as if you were starving, for example? I know that the people who are trying CR on themselves say that this isn’t the case, at least after the first few weeks or months (!), but there’s no telling what would happen with a pharmacological approach.
What this study does point out, though, is something that I think that a lot of people haven’t really caught on to yet: first, it’s increasingly clear that there are deep connections between metabolism and lifespan. All sorts of genes related to food intake and insulin signaling affect how long model organisms live, and there’s every reason to expect that the same is true of us.
Second, the settings for our lifespans may not be optimal – or what we’d now consider optimal. There’s every reason to expect that this relationship has been under very heavy selection pressure. Evolutionarily, this would be the balance between reproductive fitness and everything else an organism might do, and evolutionarily, reproductive fitness is going to be the big winner every time. But there’s no reason that we necessarily have to accept whatever tradeoffs were made during the development of our species.
We’re going to have to be very careful, of course. There may be all kinds of catches to extending lifespan – susceptibility to cancer and other diseases being the first one that everyone thinks of. But ever since our brains became large and complex enough for language and culture, and ever since we started growing our own food, we’ve been altering the evolutionary bargains that all other species have had to make – predator/prey relationships, availability of food, and so on. We may yet be able to draw a black line through another paragraph of the contract, and make it stick.
I don’t think that many people realize that this is possible, or that it’s an area of active research. Most of the large drug companies, in fact, seem to be staying away from it for now, content to let the smaller ones take on the (considerable) risks. Some people may not be able to get past Aubrey de Grey’s hair, and may have decided the whole subject is out on the fringe. But, increasingly, I don’t think it is. This stuff could work, eventually, and if it does, it’ll be one of the biggest inflection points in the history of the species.
Update: Jim Hu has more to criticize about de Grey than his hair - see here and here, for starters. Of course, as Jim himself points out in the comments, criticizing de Grey isn't the same as criticizing research on aging. Perhaps de Grey's high profile is doing as much harm as good for the field. . .
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September 24, 2007
Posted by Derek
It’s been a while since I talked about sirtuins, but the field has not been quiet. The latest data is a paper in Cell which set off a strong move in the stock of Sirtris, the company closely tied to the labs involved.
SIRT1 had already been the focus of a huge amount of attention in the aging/cancer field, but this paper seems to validate two other members of the family, SIRT3 and SIRT4. It’s mostly the story of NAD+, a very fundamental molecule indeed in cellular metabolism. There’s been some evidence (and a lot of speculation) that NAD+ levels are regulated quite differently in the mitochondria as opposed to the rest of the cell, but getting hard data on this pathway hasn’t been easy.
What is known is that apoptosis (programmed cell death) can depend on NAD+ levels. An enzyme called PARP-1 depletes NAD+ levels when it’s activated, and sets off a chain of events leading to apoptosis. Recently it was shown that there’s a PARP-1 fraction inside mitochondria, and given their central role in energy production, this gave room to wonder if an apoptosis signal could be set off from in there as well. On the flip side, NAD+ is synthesized (in mammals, anyway) though a pathway involving the enzyme Nampt. It’s also present in mitochondria, along with another NAD-pathway enzyme called Nnmat, so all the machinery is presumably there to up- and downregulate mitochondrial NAD+.
And so it does. The Cell paper looked at NAD+ levels inside mitrochondria for the first time, and found that they change greatly in response to nutrient levels. Fasted animals (and cells) greatly increased their mitrochondrial NAD+, which makes sense.
At first the authors were puzzled, when they found that although Nampt protected cells from genotoxic stress, it didn’t seem to affect how low the NAD+ levels in the cells went. Overexpression, underexpression – they all went down to the same low levels. It was only when the looked inside the mitochondria that they found where the NAD+ was being maintained.
So mitochondria can hold normal NAD+ levels even after they’ve fallen in other cell compartments. As far as the authors can tell, this is because of local synthesis, although it’s possible that the mitochondria also import all that they can get their hands on under such conditions. But the fact that levels of mitochondrial Nampt also rise along with the NAD+ argues for biosynthesis.
And the protective effects of all this NAD+ work through SIRT3 and SIRT4. Their activity is limited by the amount of NAD+ around, so it makes sense that they get more active under stress, when NAD+ levels are up. siRNA knockdowns of all seven sirtuins showed that only the 3 and 4 subtypes – which are localized in the mitochondria – are the players.
All this makes Nampt look like the yeast gene called PNC-1, which is on the yeast and roundworm pathway to make NAD+. PNC-1 has been shown to be involved in extending lifespan in such creatures, so if the human homolog has been found, the immediate question is whether it has the same effects. Its changes in fasting rats suggest a link with the caloric restriction route to lifespan extension. Overall, you have to think that if we’re not onto the relevant pathways, we’re very close indeed.
Thus the spike in Sirtris stock. It came back down as various analysts make cautious noises today, but until the company gets some Phase II data, publications like this one will be what moves things around. If you’re interested in a wild and speculative ride, they’re worth a look. Don’t expect a dull time, though – there’s an awful lot about this stuff that we don’t know.
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November 1, 2006
Posted by Derek
Back in 2003, I wrote about the paper that identified the natural product resveratrol as an activator of the sirtuin deacetylase pathway. This may well be the common thread between a host of studies on life-extending genes in model organisms and the much-publicized phenomenon of life extension through caloric restriction. In other words, if you want to live longer, but don't feel like taking in a third fewer calories, it's possible that activating sirtuin might do the job for you, and resveratrol is the prototype activator.
Three years ago, after first pointing out that many companies might want to run screens for sirtuin activators, I went on to speculate:
Second, there is no reason to think that resveratrol itself is an optimized molecule. It's a great starting point, but as a medicinal chemist I can see several things I'd like to do to it immediately. Hey, fellow chemists, let's talk shop here. . .(list of possible structural modifications follows - DBL). . .Believe me, thousands of folks like me are looking at this structure today and having these exact thoughts, and some of them are going to act on them (if someone hasn't already.)
Third, this compound is surely being given to higher animals as we speak. I can see no reason not to start feeding it to mice in a long-term study. Mice live around two years - let's try for three! After all, it's already been given to rodents in other studies. (And those are just papers from the last year or two!) But as far as I can tell, none of these have allowed the mice to age to their full normal lifespan under resveratrol dosing. Time to find out!
Well, in an unusual development for my predictions, all of this is coming true. This summer, David Sinclair (who leads one of the major efforts in this area - another is led by his former boss, Leonard Guarente) published an interesting review of resveratrol's in vivo effects. Now his group reports in Nature that resveratrol does indeed have effects in mice - very powerful effects indeed. When put on a high-fat diet, normal mice gain weight, develop diabetes and liver problems, and die early. But on the same diet along with resveratrol, the mice (although they do put on weight) show improved glucose and insulin levels, better liver function, and significantly increased lifespan. Their activity and motor abilities appear to mimic normal-diet mice, even into their extended old age. (Here's their press release if you don't have a Nature subscription).
And on top of this, Sinclair's company has let it be known that they have developed improved molecules based on resveratrol, and are now taking them into the clinic. The first one is called SRT501, and I'd be very interested to know its structure. But remember that compound code - you're going to be hearing about it again.
These are still early days. There may be penalties to pay for messing around with longevity (increased cancer rates are only the first thing that come to mind). But there may also be a revolution in progress here, something that will make the future quite different from what we've been imagining it will be. G. K. Chesterton would be happy - scroll down here for a discussion of the game of "Cheat The Prophet". Is anyone ready for Cheat the Reaper?
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November 20, 2005
Posted by Derek
I've written before about the gene known as SIR2. Overexpression of it (or its homologs in different animals) extends lifespan in a range of organisms, and there's been a tremendous amount of research on these over the last few years. A good deal of evidence has linked them to the known life-extending effects of caloric restriction. In mice, for example, Sirt1 is involved in nutrient sensing and fat mobilization.
It suggests a pretty neat package, but the ribbon on it is unraveling. I wrote about Sir2/Sirt1 here a couple of years ago, where I said "An extra copy of the gene lengthens life; deletion shortens it." Well, in yeast cells that appears to be true, when you measure lifespan by how many times the cells can divide before burning out.
But what if you measure lifespan by the amount of time the cells can live when they're not dividing? That's the subject of a new paper in Cell from Valter Longo's group at USC, which they have given the provocative title "Sir2 Blocks Extreme Life-Span Extension." Yep, deleting it actually extends the non-dividing lifespan of the yeast, and combining that with caloric restriction increases it even more. These yeast cells have some problems, though, some of which can be ameliorated by further mutations in the IGF-1 pathway (itself heavily implicated in metabolic rate and lifespan). Yeast with combined Sir2 and IGF mutations, under caloric restriction, live longer by up to sixfold, a startling increase.
So what about higher organisms? Well, there appear to be some very similar findings in mice - maybe. Earlier this year, Frederick Alt's lab at Children's Hospital in Boston deleted Sirt1 in mouse cells and found, quite to their surprise, that the cells were extremely vigorous indeed. Such cell lines start to break down after a certain number of passages (cell divisions), but the Sirt1 knockouts just keep rolling along.
They then tried growing the cells under oxidative stress, but they plowed right through that, too. That led to the thought that Sirt1 might be some sort of checkpoint, which would normally limit cell division under such DNA-damaging conditions. But the Sirt1-deleted cells showed no signs of greater DNA degradation than normal lines. They're quite robust.
This is all extremely interesting, but you may have noticed that I pulled a fast one here. In these mouse cell lines, it appears that replicative life span has increased when Sirt1 is taken out - but with Sir2 deletion in yeast that's not the case at all. There it's replicative life span that takes the hit, and non-replicating (chronological) life span that's increased. How do we reconcile these blatantly contradictory findings? I've no idea, but it's a safe bet that several high-powered labs are currently working overnight shifts to answer that question.
So much for mouse cells - how about whole mice? Well, as hardy as some of their cells may be, the Sirt1 knockout is a pretty hard animal to prepare, because most of the mice don't survive. The ones that do appear fairly normal, but have a complex phenotype, which includes decreased fat mass and body weight. (Alt's group is also trying to interfere with Sirt1 in adult animals, bypassing all the developmental roles that make the standard knockouts so hard to work with).
The big question now, given all these divergent cell findings, is: will these guys live longer, or not? And what happens to them when you put them on a limited-calorie diet? Are they going to act like the replicative-aging models, or the chronological aging ones? (We'll leave the yeast-mouse contradiction out of it for a while). Perhaps the two mechanisms will fight each other to a standstill, leaving the animals with plain ol' normal lifespans, but with some tissues acting much younger than the whole-body age and some acting much older. Mice generally live around two years. I wonder just how many months ago these lifespan studies started. . .
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September 19, 2005
Posted by Derek
There's been a lot of news in the aging-research area about the Klotho gene (and its associated protein) the last few years. Now there's a recent paper in Science that is bringing it back into the spotlight.
I won't go into all the details - that link and this one will give you some good background - but the short form is that adding an extra Klotho gene extends mouse lifespan by up to 30%. (It was already known that deleting the gene shortened lifespan drastically - the paper we're seeing now is the result of an immediate effort to take the system in the opposite direction. Aging research takes a long time!)
Some of the most interesting anti-aging genes that have turned up in roundworms and flies have to do with insulin (and insulin-related growth factor, IGF) signaling. This team of researchers thought that the Klotho protein might fall into the same category, and they were right: the protein seems to lower insulin sensitivity by affecting signaling through the insulin and IGF receptors.
Here's where my drug-discovery radar started pinging. These receptors are part of a family that carries their own kinase along to phosphorylate themselves, and that's a key even in their signaling cascade. This new work noted that Klotho suppressed autophosphorylation of the receptors, and that makes sense, considering the downstream effects. It's very interesting to note that compounds that affect the IGF receptor kinase are already being developed. They're potential anticancer agents, and a number of companies seem to be working on them.
Now, I'm not aware of anything that's been developed to inhibit the insulin receptor kinase, mainly because no one has seen a market for giving people a sort of quick-acting type II diabetes. But it's certainly possible that such a compound could be discovered, if someone were to look. What would the effects be of lower doses of such kinase inhibitors in normal humans? Could one get the effect of the Klotho hormone through that route, or does it cause other things to happen through its own pathways?
I think someone's going to be tempted to find out. Intense work is doubtless in progress in this area, and there will be many more things to be discovered. But if the insulin/IGF story continues to hold up, I don't see what's going to stop people from trying this out on themselves or on others. It's probably the nearest thing in the whole field to being realized in practice. And if it doesn't happen here, it might take place somewhere else with more. . .relaxed clinical standards. Worth keeping an eye on. . .
UPDATE: ". . .I just wish I understood more than every third word." Well, that was a kind of condensed post, I have to admit. I was a bit short on time, and it's a pretty knotty subject, even for the people who work in it. But I promise that I'll come back to it and try for a from-the-bottom-up backgrounder. And I'll try to get to it before we all need life-extension drugs. What's that? You say we all need them now?
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August 1, 2002
Posted by Derek
I've written about the idea that aging is related to oxidative damage (most recently on June 3.) There's a lot of support for it, and the documented life-extending properties of caloric restriction are thought by many to be tied into this hypothesis. CR has worked in (for example) fruit flies and rodents, and some slow-moving experiments suggest that it works in larger animals up to primates. The less you eat, the less you metabolize, the fewer reactive oxygen species you generate, and the less damage you do to your cellular machinery. It makes a lot of sense.
Too much sense, I suppose. As is the relentless way of science, the waters have been thoroughly muddied by a report in the July 18 issue of Nature (a summary is here.) [Note added on August 1: these links don't seem to work without a subscription to Nature. I'll see if I can find free ones and post those.] These researchers studied yeast, using the number of divisions a cell can go through as a measure of lifespan. Some of their earlier work supported the CR trend, since they found that yeast grown in reduced-glucose conditions went on dividing for 30% longer.
They were even able to tie this effect to the presence of a particular gene, SIR2. That codes for a histone deacetylase, which would puts it squarely in the gene transcription / regulation area. There's a lot to write about those, of course, but for those who don't follow the field, the short story is that DNA needs to be wound and unwound from histone proteins in order to be transcribed into RNA. Acetylation and deacetylation of the histones is one of the key switches for those processes, although there are others. And there are things that regulate them, and things that regulate the regulators, and things that modulate the effect of the regulation of the thing that cancels the actions of the. . .ah, cell biology. Nothing like it.
But when they looked at things more closely, they found that the calorically-restricted yeast actually have three times the respiration rate! So much for the simple hypothesis. A closer look showed that a key factor is the way that yeast can switch back and forth between respiration (when there's enough oxygen) and fermentation (when there isn't.) Carbon dioxide is the waste product of the first process, which yields more bang for the buck. And as the world well knows, ethanol is the waste product of the second one. Grow yeast under conditions where they do both, and you've got beer. When there's just enough food to survive, it seems, the yeast switch entirely over to respiration for its greater efficiency.
As it turns out, not only do the CR yeast respire faster, but if you mutate them to where they can't respire at all, caloric restriction doesn't increase life span. So what about all the foul free radicals produced by all that respiration? The CR yeast were shown to be more sensitive to free radical sources (which usually means that their existing machinery for detoxifying such things is already stretched near its limit) but these cells showed no increase in the usual suspects (like superoxide dismutatase.)
The free-radical production and protection pathways are clearly more complicated than they seemed. (And, of course, anyone who buys superoxide dismutase tablets at a health food store is clearly a fool, but that's been obvious long before this paper came out.) What would make the story neat and clean is if the SIR2 histone deactylase turned out to be regulating unknown genes that are involved in detoxifying free radicals. That's probably too rational, but it's the first thing to check.
Does any of this apply to larger things than yeast? No one knows yet if mammals on CR diets respire more (although I'll bet that folks are checking as we speak.) SIR2 works the same way in roundworms (C. elegans, the biologist's friend,) and there are homologous genes in higher animals. It's part of some highly conserved metabolic pathway, whatever it is. If we can get our hands on it, there may be hope for an extended life span during which we could actually have a pizza every so often.
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June 3, 2002
Posted by Derek
Another useful paper (Science 296, 1276) has come out on the mechanisms of aging. Ever since the 1950s, the idea of accumulating free radical damage has been a strong contender, to the point that it's been absorbed into popular culture. All the free radicals needed for this damage to take place are produced by our own metabolism: oxygen is pretty fierce stuff to handle.
There's a good amount of evidence that this theory is at least partially correct (such as the existence of enzymes like superoxide dismutase, SOD, whose only function in life is to get rid of one of those reactive oxygen-derived species.) And now there's more. The latest work involves mice with a mutated form of a particular helicase protein called Xpd. This is an important part of the DNA-RNA transcription machinery, and it's also important for a variety of DNA repair, nucleotide excision. The dual function makes sense; both processes involve unwinding the double helix so enzymes can bind to it directly.
There's a human genetic disease, trichothiodystrophy (TTD) that involves alterations in Xpd function, and the research group was trying to come up with a mouse syndrome that would mimic it. They got it, but the mice also shown signs of accelerating aging (gray hair, osteoporosis, loss of appetite, shorter life span.)
That would seem to be the end of the story: if you can't repair DNA damage, you age quicker. But another experiment has already been done to completely knock out a closely related protein called Xpa, and that knockout completely wipes out the ability to do nucleotide-excision repair. But those knockout mice don't show signs of premature aging! So what's going on?
One way to find out would be to take those Xpa-knockout mice and introduce the Xpd mutation into them. This group tried that experiment, and got the same premature aging, but in much more severe form. What might be happening, then, is that the total effect of DNA damage on gene transcription might be the aging factor. If you can still read off the DNA, damaged or not, then cell activity can still muddle on (as in the Xpa knockouts that don't show premature aging.) If your gene transcription keeps getting stalled out, as in the Xpd mutants, then you're in trouble. The cells involved end up dying (by programmed cellular suicide, apoptosis) or damaged. If you have both mutations at once, the defective DNA that accumulates is unwound and exposed for even longer periods, setting both those processes in motion even faster.
We're getting closer to making a coherent picture out of this - other knockout experiments shed some light on it, and others are no doubt in progress. As for what to do about it, that's a different question. The close association of aging with DNA damage means that there may well be a tradeoff between oncogenesis and aging - you can keep your cells alive for a long time, at the risk of developing cancer, or you can have them kill themselves off at the first sign of trouble, which helps to cause aging. We'll have to tread carefully, but there would still seem to be some wiggle room in there.
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May 14, 2002
Posted by Derek
There's an interesting article on aging in the latest issue of Current Biology. The researchers used gene-chip assays, which look at over 13,000 genes simultaneously for signs of up- or down-regulation, in populations of aging fruit flies.
Fruit flies share a rather unnerving number of similar genes with other animals (all the way up to us,) and their short live span makes the attractive for this kind of study. What makes this one stand out is the amount of detail it goes into.
The team checked the flies at different time points, in multiple populations, and under conditions of normal aging and caloric restriction. That last technique - basically, living close to starvation - has been shown in increase life span in many species. There are some people trying it as well (you have to be pretty careful with your nutritional balance, and the question always comes up about how wonderful excess life span can be if you can't eat anything. . .)
This study also controlled for how much the various genes tend to vary. You can see some genes tripling in activity, and it means nothing, because they vary naturally even more than that. Others are so steady that almost any change (up or down) is news.
Gene chips have been all the rage for a few years now, and they're getting more powerful all the time. But not too many people control their experiments with them as well as this group did, which often makes it hard to figure out what the data are telling you. In this case, though, they saw about 800 genes that were definitely associated with age-related changes. Half of those changed whether the flies were calorically restricted or not.
Some of them were things that had already been picked up by other studies. But there are quite a few new ones (enzymes and proteins that inhibit them, proteins involved at the cell nucleus, and others) that no one had fingered before. This paper will be a road map for some time to come for those looking at aging.
And many are, or will be. I think that over the next ten to twenty years, this is a field that could really take off. What use is a longer lifespan if you spend your extra ten (or 20, or 30) years as an eighty-year-old? Let's add those extra years to the twenties, thirties, and forties instead.
This is just the sort of research that probably sends Francis Fukuyama up the wall, to judge from his recent book and op-eds. (There's been a huge pile of commentary in the Blogosphere about all this, which I assume people have seen.) It's true that changing the human life span will probably lead to all sorts of disruptions - but we've done it before. The last hundred years has been a huge experiment in lengthening the average life expectancy, but because it was done by improving mortality rates and nutrition, no one had any room to object. In the same way, no one objects to the long, slow genetic engineering that humans have been doing with their crops and domestic animals. It's just when things get more efficient that the alarm bells start to go off. . .
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