More resveratrol hoopla

Resveratrol is in the news. Again.

My last major note about resveratrol is here, way back last September. How time flies. I also mentioned it more briefly here, in May, in connection with cancer. (Where its effect may involve facilitating apoptosis of tumor cells.)

But resveratrol's now back in the news again, so I guess it's time for an update.

As you recall, resveratrol seems to have a number of properties that confer health benefits. For example, it is thought to be an antioxidant, an anti-inflammatory, and perhaps to activate sirtuin enzymes, which may help produce an effect similar to calorie restriction.

The big question is whether you can get the benefits from the amount of the stuff you can get in a dose of reasonable size, for a reasonable price, and without having to drink gallons of wine per day (not a great idea).

Now we have recent reports of two more research results dealing with resveratrol. One suggests a benefit in countering obesity, and the other concerns anti-aging properties that mimic calorie restriction.

Here's the finding on obesity, the relation to which of resveratrol I cannot recall having heard bandied about before:

Red Wine's Resveratrol May Help Battle Obesity (6/16/08)

Resveratrol, a compound present in grapes and red wine, reduces the number of fat cells and may one day be used to treat or prevent obesity, according to a new study.

Past research found that resveratrol protected laboratory mice that were fed a high-calorie diet from the health problems of obesity, by mimicking the effects of calorie restriction. Researchers at the University of Ulm in Germany wanted to know if resveratrol could mimic the effects of calorie restriction in human fat cells by changing their size or function. The German team used a strain of human fat cell precursors, called preadipocytes. In the body, these cells develop into mature fat cells. ...

In the cell-based study, they found that resveratrol inhibited the pre-fat cells from increasing and prevented them from converting into mature fat cells. Also, resveratrol hindered fat storage.

One would certainly expect effects like that, if they can be reproduced in living humans, to be helpful in countering obesity. But there were two other beneficial effects as well:

[R]esveratrol reduced production of certain cytokines (interleukins 6 and 8), substances that may be linked to the development of obesity-related disorders, such as diabetes and clogged coronary arteries. Also, resveratrol stimulated formation of a protein known to decrease the risk of heart attack. Obesity decreases this substance, called adiponectin.

We've discussed both of these subjects before: IL-6 and inflammation were discussed here, while adiponectin was discussed here and here.

But the intriguing connections don't even stop there. Another report on the same research suggests that the effects related to fat cells may be mediated through sirtuin proteins:

Red wine component resveratrol might fight obesity, lab tests show (6/16/08)

Resveratrol’s mechanism of action is not entirely clear, but the compound seems to activate at least one member of a family of proteins called sirtuins. While also poorly understood, some sirtuins show up in fat cells.

Previous work showed that low levels of sirtuins allowed fat cells to add fats and to proliferate freely from nascent to mature stages, a recipe for weight gain. Conversely, that work also showed that an increase in sirtuins — in that case the compound Sirt2 — kept stem cells from maturing into full-fledged fat cells and inhibited mature fat cells from filling with fats.

In the new study, resveratrol’s good effects failed to emerge in either nascent or mature fat cells engineered to lack a sirtuin called Sirt1, Wabitsch said.

As potential therapeutics, “the sirtuins are a new class in the armamentarium of diabetes and pre-diabetes management,” says Henry Anhalt, a pediatric endocrinologist at Animas Corp. in West Chester, Pa., who wasn’t involved in this study. Sirtuins seem to curb the risk of obesity, cardiovascular disease and inflammation, all of which have been correlated with development of diabetes and its complications. The finding that resveratrol seems to work through a sirtuin (Sirt1) opens up new research opportunities, he says.

As previously noted, I've had a lot to say about sirtuins, which you can refer to here.

The second recent study, which appeared about two weeks before the one just discussed, involved experiments with mice that explicitly compared the effects of resveratrol and calorie restriction:

Substance In Red Wine, Resveratrol, Found To Keep Hearts Young (6/4/08)

[T]he researchers report that low doses of resveratrol in the diet of middle-aged mice has a widespread influence on the genetic levers of aging and may confer special protection on the heart.

Specifically, the researchers found that low doses of resveratrol mimic the effects of what is known as caloric restriction - diets with 20-30 percent fewer calories than a typical diet - that in numerous studies has been shown to extend lifespan and blunt the effects of aging.

This research sharpens results that have previously been found, and also shows that the required dose of resveratrol may not be unreasonable:

Previous research has shown that resveratrol in high doses extends lifespan in invertebrates and prevents early mortality in mice given a high-fat diet. The new study, conducted by researchers from academia and industry, extends those findings, showing that resveratrol in low doses and beginning in middle age can elicit many of the same benefits as a reduced-calorie diet.

"Resveratrol is active in much lower doses than previously thought and mimics a significant fraction of the profile of caloric restriction at the gene expression level," says Tomas Prolla, a UW-Madison professor of genetics and a senior author of the new report.

Another way this research differs from earlier work is that it looks specifically at the expression of genes known to be affected by aging in several important tissue types:

The group explored the influence of the agent on heart, muscle and brain by looking for changes in gene expression in those tissues. As animals age, gene expression in the different tissues of the body changes as genes are switched on and off.

In the new study - which compared the genetic crosstalk of animals on a restricted diet with those fed small doses of resveratrol - the similarities were remarkable, explains lead author Jamie Barger of Madison-based LifeGen Technologies. In the heart, for example, there are at least 1,029 genes whose functions change with age, and the organ's function is known to diminish with age. In animals on a restricted diet, 90 percent of those heart genes experienced altered gene expression profiles, while low doses of resveratrol thwarted age-related change in 92 percent. The new findings, say the study's authors, were associated with prevention of the decline in heart function associated with aging.

Another report stresses the overlap between the effects of calorie restriction and of resveratrol:

Red wine compound seen protecting heart from aging (6/4/08)

Using a method that permits simultaneous analysis of thousands of genes at the same time, the researchers found a huge overlap in the genes whose activity were changed by resveratrol and caloric restriction.

They looked at the heart, brain and muscles, and said that the effect of resveratrol was strongest in the heart but did prevent some aging-related changes in the other tissues.

A similar news release on this research mentions an upcoming Phase I human clinical trial that will study the effects of resveratrol on older humans:

Substance in red wine found to keep hearts young (6/5/08)

Resveratrol is currently sold over-the-counter as a nutritional supplement with supposed anti-cancer, anti-viral, anti-inflammatory and anti-aging benefits, although few scientific studies have verified these claims in humans. That may soon change: Researchers at the University of Florida hope to explore the effects of resveratrol on older people in a phase 1 clinical trial, set to begin this summer.

The study will assess the supplement's effects on memory, physical performance, inflammation and oxidative damage.

It also calls attention to the possible longevity-promoting effects of resveratrol on the mitochondria of cells:

Mitochondria, the tiny power plants that keep a cell functioning, are especially vulnerable to the oxidative damage that accumulates during the aging process.

"In animal studies, (resveratrol) seems to promote mitochondrial health," said Todd Manini, also a principal investigator of the upcoming trial and an assistant professor of aging and geriatrics in the UF College of Medicine. "Mitochondria are everywhere: They're in the brain, in the muscle, the liver. So it could have kind of a global impact on many different organ systems."

New York Times science writer Nicholas Wade (who, in earlier articles, had questioned the necessary dosage of resveratrol, see here) has a cautionary article that puts this research into context of other work on resveratrol and sirtuins. Among other points, he notes that there is still plenty of room to question whether resveratrol, or something similar, will actually have health benefits in humans, for example:

New Hints Seen That Red Wine May Slow Aging (6/4/08)

Dr. Auwerx, who used doses almost 100 times greater in his treadmill experiments, expressed reservations about the new result. “I would be really cautious, as we never saw significant effects with such low amounts,” he said Tuesday in an e-mail message.

Another researcher in the sirtuin field, Dr. Matthew Kaeberlein of the University of Washington in Seattle, said, “There’s no way of knowing from this data, or from the prior work, if something similar would happen in humans at either low or high doses.”

More news reports about this:

• Red Wine Compound Helps Heart, May Slow Aging (6/5/08)
  
• Study boosts wine chemical hopes (6/4/08)
  

Update, 7/16/08: There's more recent news about resveratrol here.

Further reading:

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice – abstract and complete technical article describing the mouse study

Low-dose resveratrol as a calorie restriction mimetic – 6/12/08 blog post with further comments on the mouse study and associated issues

Tags: resveratrol, sirtuins, aging, longevity, calorie restriction

IGF-1, calorie restriction, exercise, and longevity

Loyal readers here (both of you) may recall that back here I mentioned the hormone IGF-1 and promised to deal with it more throughly. The occasion was that IGF-1 is a growth factor, like BDNF.

Basically, a growth factor is a protein for signaling between cells. Growth factors typically bind to specific receptors on a cell's surface, in order to promote cell survival, growth, or proliferation.

The following recent news item now gives me an excuse to make good on my promise:

Hormone May Hold Key To Helping Elderly Men Live Longer (5/27/08)

Elderly men with higher activity of the hormone IGF-1--or insulin-growth factor 1--appear to have greater life expectancy and reduced cardiovascular risk, according to a new study.

IGF-1 is a hormone similar in molecular structure to insulin. It is released from the liver and plays an important role in childhood growth and continues to have anabolic effects in adults. ...

Subjects with the lowest IGF-1 function had a significantly higher mortality rate than subjects with the highest IGF-1 bioactivity. These results were especially significant in individuals who have a high risk to die from cardiovascular complications.

So, does that mean we need to find ways to increase our body's IGF-1 production in order to extend lifespan? Well, not necessarily. It's more complicated than that, as we'll see shortly.

Any hint of longevity enhancement, of course, is something worth paying attention to, but in the case of IGF-1, there's a lot more to the story. It's actually kind of a big deal for several additional reasons.

To begin with, the full name of the hormone is insulin-like growth factor. It is so-named because, as the news item mentions, its molecular structure is similar to that of insulin.

But that's just the beginning of the similarity. Both IGF-1 and insulin affect metabolism. In fact, IGF-1 can bind to the same receptor that insulin does, although a lot less strongly. That, and the not coincidental structural similarity to insulin suggest that perhaps, sometime far back in evolution, the same gene may have coded for some ancestor of both insulin and IGF-1.

If you take into account a striking fact about the IGF-1 receptor, this hypothesis of a common origin for insulin and IGF-1 becomes even more intriguing. The fact is that the (gene for the) IGF-1 receptor is a homologue of the daf-2 gene of the nematode Caenorhabditis elegans (as is the gene for the insulin receptor also). In fact, DAF-2 (the protein product of daf-2) is the only insulin-like receptor in nematodes, so biologists now regard daf-2 as the ancestor of the mammalian receptors for IGF-1 and insulin.

I first mentioned this relationship back here, and went into more detail here, in connection with understanding the effect of sirtuin proteins on aging and longevity of C. elegans.

But the "coincidences" don't stop there. The important function of a receptor is the effect it has, when activated, upon signaling downstream inside the cell. All of the receptors we're talking about here are of the sort called tyrosine kinase receptors. Let's unbundle that term. Tyrosine is one of the 20 amino acids that make up proteins. A kinase is a type of protein enzyme whose function is to attach phosphate groups to specific kinds of amino acids in other proteins. This process is called phosphorylation. When another protein of the right sort is phosphorylated, it becomes able to act as a tyrosine kinase itself, and go on to affect yet other proteins.

This whole process is called signal transduction. The process begins (in the case here) with a receptor tyrosine kinase, which is a cell surface receptor protein that is also a tyrosine kinase – for example DAF-2, and the receptors for IGF-1 and insulin. There may be a number of intermediate steps, but the eventual result is the phosphorylation of a transcription factor, which enters the cell nucleus and facilitates the transcription of certain genes in order to produce new proteins.

In C. elegans, DAF-16 is the transcription factor that is activated by signaling mediated by DAF-2. We discussed DAF-16 in the aforementioned posts here and here. DAF-16 belongs to a family of transcription factors called forkhead box proteins. We have discussed these before too, or rather the subclass called FoxO transcription factors.

We're getting pretty far into the technical weeds here, so if you want more details on this stuff, refer to the earlier posts.

To make the long story short, the effects of the external signaling hormones like insulin and IGF-1 ultimately result from proteins coded for by the genes expressed because of the appropriate transcription factors that were activated by the signaling cascade. There are probably many proteins involved, and sorting them all out, figuring out how they collectively affect longevity, is very much an ongoing project.

The story is interesting to understand because longevity is one of its main themes. In addition to the news item already mentioned, there's more recent news with the same theme. Here are summaries of some of these research announcements:

When It Comes To Living Longer, It's Better To Go Hungry Than Go Running, Mouse Study Suggests (5/14/08)

It is once again verified that a low-calorie diet can extend the lifespan of rodents. This benefit is beyond what can be achieved with a higher-calorie diet offset by exercise. However, rats that consumed the most calories, and has less longevity, also had the highest levels of IGF-1. Rats that consumed the fewest calories had the best longevity and the lowest levels of IGF-1. Exercise could only partially counteract the higher IGF-1 levels and reduced longevity of rats on a high-calorie diet. In this study, IGF-1 levels were inversely correlated with longevity. This is a "live-fast, die-young" scenario, which is especially typical of rodents, but not necessarily of humans.

More on this study: here

Shorter Women May Have Very Long Lives: Gene Mutation Found (3/4/08)

This study focused attention on the (adult) daugheters of especially long-lived Ashkenazi Jews. A control group consisted of daughters of the same age as the others, but whose families had no history of unusual longevity. The finding was that female children of long-lived individuals (aged 95-110) were on average 2.5 cm shorter than female controls. It was also found that both the centenarians and their daughters were much more likely than the controls to have mutations in the genes for their IGF-1 receptors. However, the daughters also had blood plasma levels of IGF-1 that were 35% higher than the levels in the control group. The interpretation is that the higher IGF-1 levels were due to an attempt to compensate for disruption of IGF-1 signaling due to irregularities of the receptor proteins. This would be consistent with a number of animal studies in which reduced IGF-1 signaling correlates with increased longevity.

More on this study: here, here, here

Interestingly enough, IGF-1 had already been recognized to have an effect on body size – in mice and dogs. The dog research is described here:

One gene between tiny dogs and giant ones? (10/13/06)

Nate Sutter, a geneticist at the National Human Genome Research Institute in Bethesda, Maryland, wanted to know the reason why big dogs, such as Irish wolfhounds, can grow up to 50 times larger than other members of their own species, such as chihuahuas. So he started out looking at large and small dogs of one breed — the Portuguese water dog. ...

The team found that one of the few differences in these Portuguese water dogs occurred in a gene called 'insulin-like growth factor 1', or Igf-1 .

This is one of many genes already known to influence the size of mice: when Igf-1 is knocked out, the animals grow up to be mini-mice.

(The article is subscription-only, but you can find another reference to it here.)

The researchers went on to do further analysis of the IGF-1 gene in many different dog breeds of all sizes, and also in foxes and wolves. They found that almost all of the small breeds had the same variant of the IGF-1 gene as the small Portuguese water dogs had, while almost none of the large breeds had that variant. The team concluded that the IGF-1 variant in small breeds is responsible for the difference because it reduces production of the growth factor.

This should also explain what dog people have always known – that small breed dogs generally live longer than large ones.

Here's a later report of the same research:

What Makes Little Dogs Small? Researchers Identify Gene Involved In Dog Size (4/5/07)

In their study, researchers explored the genetic basis for size variation among dogs by comparing the DNA of various small dog breeds, including Chihuahuas, Toy Fox Terriers and Pomeranians, to an array of larger dog breeds, including Irish Wolfhounds, Saint Bernards and Great Danes. Their investigation found that variation in one gene - IGF-1, which codes for a protein hormone called insulin-like growth factor 1 - is very strongly associated with small stature across all dog breeds studied.

Further reading:

Scientists Explore Queen Bee Longevity (5/8/07) – press release describing research on various factors, including IGF-1 signaling, in queen bee longevity

Mechanisms of lifespan regulation by IGF-I (2/25/08) – blog post that considers some of the paradoxical effects of IGF-1 that may be beneficial in some ways but also shorten lifespan

Not so fast, daf-2: IGF-I is all kinds of good for you (1/23/08) – another blog post on the paradoxical effects of IGF-1

IGF-1 attenuates cardiac aging (11/15/06) – blog post about research on cardioprotective properties of IGF-1

It’s not easy being wee: Does IGF-1 deficiency slow down the brain? (8/30/06) – one more blog post on paradoxical effects of IGF-1

A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs – 4/6/07 research article in Science (sub. rqd.)

Tags: IGF-1, calorie restriction, longevity, aging

Sirtuin news

Back in November we had a series of posts about sirtuin proteins. This included an overview, with a particular focus on the relevance to calorie restriction and longevity, especially in light of recent research announcements at the time. This was followed by a couple of posts (here, here) on background history.

Now is a good time to return to that thread and continue the discussion of sirtuins, because of additional related research announcements, including especially this:

Sirtris Announces Positive Results with Proprietary Version of Resveratrol, SRT501, in a Phase 1b Type 2 Diabetes Clinical Study (1/7/08)

Sirtris Pharmaceuticals, Inc. ... announced today that the Company's first product to enter the clinic, SRT501, was found to be safe and well-tolerated, and was found to significantly lower glucose in an oral glucose tolerance test conducted as part of a 28 day Phase 1b clinical study in patients with Type 2 Diabetes.

This 28-day Phase 1b study was designed to assess the safety, tolerability and pharmacokinetics of once-daily, orally administered doses of either 2.5 g or 5 g of SRT501 in patients with Type 2 Diabetes who were naive to other diabetes drug treatments. Both doses of SRT501 were found to be safe and well-tolerated, and pharmacokinetics, a measure of drug levels in the blood, were identical at days one and 28, suggesting no drug accumulation. There were no serious adverse events and no dose-related adverse events. Importantly, SRT501 showed a statistically significant improvement in an oral glucose tolerance test on day 28 at two hours and a trend towards lower fasting plasma glucose levels.

SRT501 is also being tested in patients with Type 2 Diabetes in a Phase 1b BID (twice daily administration) study and in a Phase 2a study in combination with metformin, the current first-line therapy for Type 2 Diabetes. SIRT1 is the founding member of the human sirtuin family of enzymes which control the aging process. Specifically, SRT501 acts by increasing mitochondrial activity and therefore is targeted to address metabolic diseases, such as Type 2 Diabetes.

"This is the first time that a small molecule targeting sirtuins, the genes which control the aging process, has shown efficacy in a disease of aging," said Peter Elliott, Ph.D., Senior Vice President of Development at Sirtris.

OK, this is obviously a self-promotional PR piece from the drug developer. In particular, sirtuins aren't "the genes which control the aging process", merely some of them. However, if the claims hold up under further testing, especially the one stated in the last paragraph, this is an important validation of much prior research into the effect of sirtuins on longevity as a result of action in various cellular pathways. Our previous discussions reviewed some of this research conducted on model organisms like yeast and the nematode C. elegans.

More information: Resveratrol-like drug works in humans-Sirtris (1/7/08), Sirtris Anti-Aging Drug Generates Buzz, But May Already Be Old News (1/8/08)

This drug, SRT501, has been in human clinical trials for about a year and a half already. The initial trial (called "Phase 1") involved 85 healthy volunteers and began in June 2006 (see here). Results from that trial were reported in October 2006 (see here) and demonstrated that the drug was reasonably safe and well-tolerated.

SRT501 is a small molecule drug that achieves its effects by activating the mammalian SIRT1 NAD-dependent deacetylase enzyme, which has been investigated extensively for a decade (as discussed here). The drug is essentially just a proprietary formulation of resveratrol, the well-known component of red wine that has been shown to have lifespan-extending and anti-diabetes properties in several model organisms. (See here for an extended discussion, including reports of important research announced in late 2006.) SRT501, however, is a much more practical way to take advantage of resveratrol, compared to consumption of red wine, where hundreds or thousands of bottles of wine would be needed to achieve the same effect.

Perhaps the most important result shown by this newly reported result is that SRT501 actually seems to provide measurable beneficial effects of improved glucose tolerance and reduced blood glucose levels for humans with diabetes.

SIRT1 activators which are apparently much more powerful than SRT501 are under active investigation at Sirtris and in the laboratory of Sirtris co-founder David Sinclair. This has been documented in research that was published last November:

Sirtris unveils promising, novel SIRT1 activators for treating diseases of aging (11/28/07)

In November 2006, Sirtris scientists and Sirtris co-founder, Prof. David Sinclair from Harvard Medical School, published consecutive papers in the journals Cell and Nature showing that resveratrol, a SIRT1 activator found in red wine, could reduce the impact of a high fat diet, increase stamina two fold and significantly extend lifespan of mice. Unfortunately, it was estimated that a person would need to drink 1000 bottles of red wine to obtain an equivalent dose of resveratrol. Now, scientists at Sirtris have developed SIRT1 activating molecules that are chemically distinct from resveratrol and are 1000 times more potent.

"The new drug candidates represent a significant milestone because they are the first molecules that have been designed to act on genes that control the aging process. For this reason, we feel they have considerable potential to treat diseases of aging such as Type 2 Diabetes," said Christoph Westphal, M.D., Ph.D., Chief Executive Officer and Vice Chair of Sirtris Pharmaceuticals. "The breakthrough in potency we have achieved with the novel chemical entities (NCEs) means that we can obtain the health benefits of resveratrol with a considerably lower dose."

Here's a useful professional assessment of these results: Sirtuin activators as anti-diabetes drugs, and beyond (11/29/07) More: Sirtris Drug May Slow Aging, Create 'Armstrong' Cells (11/28/07)

Additional information:

Gene Believed To Promote Long Life Linked To Cholesterol Flushing (10/12/07)

Research conducted in part by sirtuin-research pioneer Leonard Guarente has established one mechanism through which SIRT1 provides health and longevity benefits. The mechanism promotes flushing harmful buildups of cholesterol in macrophage cells of the immune systems of mice. This mechanism could explain part of the health benefits of SIRT1-activators such as resveratrol and calorie restriction.

Red Wine Ingredient -- Resveratrol -- Fights Diabetes In Mice (10/4/07)

Chinese researchers have reported that relatively low doses of resveratrol can improve insulin sensitivity in mouse cells, and they believe this effect is due to SIRT1 activation by resveratrol. Additionally, the researchers found that SIRT1 levels are reduced in insulin-resistant cells, and that increased SIRT1 activity improved insulin sensitivity

Sirtris Pharmaceuticals – Treating Disease by Modulating Sirtuins

This is a brief overview of Sirtris Pharmaceuticals drug development focus.

Tags: resveratrol, sirtuins, aging, longevity, calorie restriction, SIRT1, Sirtris, SRT501, diabetes

FoxO transcription factors

Transcription factors are proteins that help regulate genes. This regulation may involve either enabling the expression of a gene or preventing expression. In the first case, the transcription factor is an "activator", and in the second case a "repressor".

Transcription factors perform their function by binding to a particular portion of DNA that is specific to a given gene. When bound to the appropriate DNA segment, a transcription factor affects gene expression by either facilitating (activator) or inhibiting (repressor) the operation of RNA polymerase in transcribing the affected gene into messenger RNA. Usually more than one transcription factor must be present to affect gene transcription, and additional proteins (called "cofactors") may also be required.

To make things even more interesting, transcription factors usually affect multiple genes, which may be otherwise unrelated to each other.

A particularly important family of related transcriptions factors comprises what are called "forkhead box" proteins, or Fox proteins, for short. (The name refers to a sequence of 80 to 100 amino acids that are part of the protein and bind to DNA, and which was originally discovered in fruit flies (Drosophila).)

Among the genes that Fox proteins are involved with are genes related to cell growth, proliferation, differentiation, longevity, and embryonic development. So there are Fox proteins that are important for things like cancer and stem cells – and thus it's quite useful to know about them.

An important subfamily of Fox proteins are the FoxO proteins, and we'll discuss some recent examples in this note.

To begin with, perhaps the most recent example is this:

Molecular Signal That Helps Muscle Regenerate Discovered (12/19/07)

Muscle regeneration after injury is complex and requires a coordinated interplay between many different processes. Key players in regeneration are muscle stem cells, so-called satellite cells. They divide and produce many new muscle cells to fix the damage incurred by injury. A crucial regulator of muscle function and repair is a signalling molecule called calcineurin. It is activated by injury and controls the activity of other key proteins involved in differentiation and the response to damage.

It turns out that calcineurin works by inhibiting FoxO.

Using sophisticated molecular techniques, the scientists revealed that calcineurin accomplishes its effect on muscle by inhibiting another protein called FoxO. FoxO is a transcription factor, a protein that plays a crucial role in skeletal muscle atrophy through the induction of genes involved in cell cycle repression and protein degradation. Suppressing the effects of FoxO, calcineurin ensures that proliferating cells stay alive and keep dividing to produce enough cells to repair muscle damage.

In this case, the normal function of FoxO is to inhibit cell proliferation (as a check on cancer), but this needs to be bypassed (temporarily) to enable muscle regeneration.

This result follows the discovery a few months earlier of the way a specific FoxO protein (FoxO1) cooperates with another important developmental protein (Notch) to control muscle cell differentiation:

Building Muscle Requires Foxo1 (8/25/07)

The mechanisms by which Foxo proteins regulate metabolism are relatively well characterized. However, little was known about the mechanisms by which these same proteins regulate cellular differentiation.

New data generated by Domenico Accili and colleagues at Columbia University, New York, now indicates that Foxo1 cooperates with Notch to control muscle cell differentiation in vitro.

Overexpression of either a constitutively active form of Foxo1 or a constitutively active form of Notch was found to inhibit the in vitro differentiation of a mouse myoblast cell line.

Note that the preceding alludes to the involvement of FoxO proteins in regulation of metabolism. This comes about because they affect the insulin signaling pathway, and hence also glucose and lipid metabolism.

This function is what allows yet another well-known protein, mTOR, to play a role in "metabolic syndrome" – a group of disorders that includes insulin resistance, heart disease and high lipid levels. (mTOR is short for "mammalian target of rapamycin". It's a protein kinase that modifies other proteins by phosphorylation.) The same mechanism appears relevant also to the "Atkins diet" and the effects of calorie restriction.

Fly Genetics Reveal Key Workings Of Atkins Diet (8/8/06)

Using fruit flies bred with a newly created mutant form of the gene TOR (short for target of rapamycin), Oldham and his colleagues were able to determine how the TOR pathway interacted with other important regulators of insulin, glucose and lipid metabolism.

TOR is an ancient gene, found in nearly all animal and plant cells. The researchers discovered that their new mutant fly reduced TOR function, allowing them to observe what happens when TOR's influence is removed.

Reductions in TOR function lowered glucose and lipid levels in the body. They also blocked the function of another important insulin regulator, a factor called FOXO, which is known to be a critical mediator of insulin signals and therefore glucose and lipid metabolism.

As if all that weren't enough, FoxO proteins are also involved with cancer and stem cells:

Gene Knockouts Reveal FoxOs' Vital Functions In Cancer Defense, Health Of Stem Cells (1/25/07)

In an elegant, multiple-gene knockout experiment, a team of Boston scientists has discovered that a trio of molecules, called FoxOs, are fundamentally critical in preventing some cancers, maintaining blood vessel stability, and in keeping blood-forming stem cells healthy. ...

The researchers at Brigham and Women's found that mice engineered to lack genes for the FoxO1, FoxO3, and FoxO4 molecules had serious blood abnormalities. Without the FoxO gene-regulating molecules, the rodents' blood stem cells -- master cells that give birth to working blood cells while also renewing themselves -- divided too fast and "burned out." ...

In the companion paper, lead author Ji-Hye Paik, PhD, of Dana-Farber and colleagues from the DePinho lab report that the three FoxO molecules, known as transcription factors, normally function as tumor suppressors that override maverick cells threatening to grow too fast and form tumors. When FoxOs are eliminated, it may allow cancer to develop.

And even that's not the end of it. FoxO proteins are also involved in the increased levels of inflammation often associated with the aging process. (This phenomenon has been tagged with the neologism "inflammaging".) It has been hypothesized that inflammaging results from the effect of phosphorylated FoxO on another notorious transcription factor, NF-κB (which is heavily involved in inflammation). Some of the effects of calorie restriction may also be due to FOXO phosphorylation. Reference: Restricting inflammaging (11/12/07)

FoxO is also regulated (as is P53) by SIRT1 – so this is yet another relationship to calorie restriction. Reference: Unlocking the Secrets of Longevity Genes

Additional references (for the seriously interested):

An AMPK-FOXO pathway mediates longevity induced by a novel method of dietary restriction in C. elegans.

Ageing: When Less Is More

Tags: Fox proteins, transcription factor, longevity, aging, calorie restriction