Resveratrol blocks weight gain in primate study

Gray mouse lemur

Resveratrol—a natural red-wine compound previously shown to protect mice against excess weight gain when fed a high-fat diet—has now been found to reduce seasonal weight gain in gray mouse lemurs in a primate model of obesity.

The study was published in BMC Physiology by a team of researchers from the Centre Nationale de la Recherche Scientifique, Museum National d’Histoire Naturelle, of Paris, who wrote that they had “demonstrated for the first time the short-term effects of resveratrol on the metabolism of an heterothermic [with varying body temperatures] primate.”

Gray mouse lemurs are a species of prosimian primate that can double in weight (seasonal fattening) within a matter of weeks. This increase in energy reserves is induced by the arrival of shorter days and longer nights (shorter photoperiod), which serves as a means of adapting to the long dry winters in its natural environment in Madagascar.

When given four weeks of resveratrol supplementation at the time of pre-winter fattening (200 milligrams per kilogram per day), the gray mouse lemurs exhibited the following “significant effects on energy metabolism”:

Reduction in seasonal body-mass gain associated with an increase in resting metabolic rate of 29 percent while decreasing food calorie intake by 13 percent.

Strong reduction of daily heterothermia expression (changes of body temperature relating to season) with no change in the daily amount of locomotor activity.

An increased secretion of glucose-dependent insulinotropic polypeptide (a gut hormone known to induce insulin secretion) levels that may play an additive role in limiting body-mass gain.

The researchers concluded that, “resveratrol activates energy expenditure by inducing an increase in resting metabolic rate and a decrease in torpor [temporary hibernation] patterns that play key roles in energy saving in this primate. Moreover, resveratrol had a satiety effect in this primate that reduced their spontaneous food intake.”

Resveratrol’s effects are potentially due to stimulation of SIRT1, one of family of sirtuin enzymes, that has a direct role in fat metabolism. Calorie restriction and, recently, intermittent fasting have also been shown to activate SIRT1 activity.

Mouse Lemurs to Humans

In a prepared statement, Fabienne Aujard, a co-author of the study, wrote, “The physiological benefits of resveratrol are currently under intensive investigation, with recent work suggesting that it could be a good candidate for the development of obesity therapies.”

When asked through e-mail about how the study related to humans, Aujard replied that the main point of the study is that the gray mouse lemur is a non-human primate, “This species is genetically closer to human. The data obtained with this lemur should be more easily extrapolated to humans compared to rodent studies.”

Investigation conducted in humans have mainly studied bioavailability in lesser amounts, not in the high amounts given to the lemurs (equivalent of a human weighing 70 kilograms taking 14 grams of resveratrol). At present, the maximum single dose studied in humans has been 5 grams (70 milligrams per kilogram for a human of 70 kilograms).

“However, despite being a primate, the mouse lemur’s organism is certainly very different from that of a human because of its size and its seasonality,” writes Aujard. “The mouse lemur is a small animal and, like all small mammals, it has a very active metabolism, thus, a very important nutrient metabolism. Therefore, we believe that the doses to be ingested by human to reach the same long-term effects will certainly be lower than that given to lemurs.”

The general recommendation for humans is between 50 to 500 milligrams daily, which is safe as supported by human clinical studies. Although this study shows promising results, it is not yet known whether or not resveratrol will influence fat metabolism or body composition in humans.

Source: Dal-Pan A, Blanc S, Aujard F. Resveratrol suppresses body mass gain in a seasonal non-human primate model of obesity. BMC Physiol 2010;10:11.

If You Ever Had Doubts About Our Ancestors Eating Shellfish, See Curtis Marean's Feature

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Anti-Aging with Aubrey de Grey

A couple of weekends ago I was in LA going to a meet-up with biomedical gerontologist Aubrey de Grey to discuss new research on aging. He talked about a new paper he co-authored with a few of his other biogerontologist colleagues.

So, I asked him to tell me more. Out of that meeting came a follow-up interview and this article published on KurzweilAI.net. Please read that article as it describes well why we must prevent a "Global Aging Crisis".

And for anyone who wants to read the entire interview with Aubrey and the efforts of the SENS Foundation, here it is below:

Q. Would you give a brief summary of the new paper of which you are listed as a co-author in Science Translational Medicine?

The essence of this paper is that we argue for a more balanced approach to the quest for interventions to postpone age-related ill-health. Specifically, we highlight the fact that there are three general strategies to consider:

- promotion of healthy lifestyles (through reduction in environmental toxins, medical control of disease risk factors, etc);

- interventions to slow down the lifelong aging process, i.e. the accumulation of various types of molecular and cellular damage that eventually contribute to age-related pathology; and

- interventions to repair that damage using (broadly defined) regenerating medicine

and we highlight the features and limitations of each approach. Our main conclusion, as reflected in the paper's title, is that there is a atrong case for increasing the emphasis on the "damage-repair" style of intervention, which hitherto has received much less attention from gerontologists and policy-makers than the others.

Q. Who are the other authors on the review and why is it meaningful to have them come together with you to co-author this paper?

Five of the other authors - Butler, Campisi, Finch, Martin and Vijg - are among the absolute top tier of biogerontologists, whose views are universally respected within the field. They have never previously expressed the above conclusion (or not nerly so unequivocally), even individually. Therefore, their voice here will make a huge impact on thinking about this issue, both within the field and beyond. Another author, Gough, is a policy veteran with great influence in the corridors of power. The remaining authors - Rae, Perrott and Logan - are involved in organisations that have been promoting the case for repair-style interventions for some years.

Q. What impact will this paper have on the SENS Foundation? Do you expect the paper to raise more awareness and possible funding for research into "pre-disease interventions" and "human regenerative engineering"?

I feel very confident that this will be of great benefit to SENS Foundation, yes. SENSF is the global spearhead of the application of regenerative medicine to aging, and we intend to leverage this paper considerably.

Q. Could you briefly describe "pre-disease interventions" and "human regenerative engineering" as addressed in your paper?

We don't go into many details in this paper concerning the specifics of the interventions, but in my work over the past decade I have identified seven major categories of molecular and cellular "damage" that I believe we need to repair (or in some cases obviate) in order to rejuvenate the aged body comprehensively, and ways to implement that repair. Very briefly, the interventions consist of stem cell therapies to combat cell loss, suicide gene therapy against death-resistant cells, non-human enzymes against intracellular "molecular garbage", vaccination against extracellular "molecular garbage", small-molecule drugs against spontaneous crosslinks in the extracellular matrix, nuclear copies of the mitochondrial DNA to obviate mitochondrial mutations, and a complex combination therapy (involving suppression of telomere elongation together with a variety of stem cell therapies) to pre-empt cancer.

Q. Many gerontologists do not share your ideals about ending aging, how does the new paper seek to change paradigms? What paradigm is ideal in gerontology?

The ideal is not to have only one paradigm. Those gerontolgists who favour "optimising metabolism" to slow down the creation of these various types of molecular and cellular damage, rather than regenerative medicine to repair the damage, are not wrong: their approach is intrinsically less powerful, but it's also very likely to be far easier to implement. As such, it provides a "bridge" to the regenerative approach; the greatest benefit to humanity in terms of lives saved and suffering averted will occur if both approaches are pursued equally aggressively.

Q. What is human healthspan extension? How is this different than life extension?

For practical purposes there is no difference, and this is something that needs to be understood far better by the general public and by policy-makers. We simply cannot plausibly extend lifespans very much by keeping people alive in the diminished state of health that most people currently endure for the last year or three of their lives. Significant life extension will therefore occur only if we can postpone age-related ill-health, i.e. extend the healthy part of our lives. With regenerative medicine, I believe we have a realistic prospect of postponing ill-health so well that we simply never attain it - we postpone it faster than time is passing.

Q. Why do you think more people in general need to become familiar with new paradigms such as human healthspan extension? How will this new paper seek to break pre-conceived notions about aging?

The core reason is the obvious, boring one: funding. Serious public-purse resources to develop regenerative medicine against aging will emerge only when there is public support for it, and that will occur only by educating the respected, mainstream scientific community to take the concept seriously. This paper is directed mainly at those people - the biogerontologists who have hitherto presumed that this approach is too difficult to be worth even considering, or who have not appreciated its potential.

Q. What advice would you give to university students and scientists who are interested in performing research in line with goals for slowing or ending aging and human healthspan extension?

The main advice is simply to read up on the relevant experimental work that has already been done. Virtually all my conversations with scientists who initially doubt the feasibility of regenerative medicine against aging gravitate rapidly to the discovery that their pessimism arises from simply not knowing about the relevant published work. My book "Ending Aging" is a good place to start, since it is a single source for all this information with hundreds of references to the primary experimental literature.

Q. What projects is SENS working on? What lies ahead from the research?

SENS Foundation's research direction is based on two main principles: prioritise the SENS components that are not being adequately pursued through other funding sources, and prioritise those that are the most challenging. These two principles naturally overlap a lot, since difficulty is a disincentive to work on something. Accordingly, we are pursuing most of the seven SENS strands at this time. We anticipate that this will continue.

Q. How can more funding help SENS with their goals for the future?

There are no surprises there: it all about the fact that biology is irreducibly expensive. In particular, as more and more of our research programs move from the cell culture stage into live mice, the expense rises sharply.

Q. What can people look forward to in the near future from greater funding into aging research? What are a few concrete examples of near-future benefits?

I believe the main benefits we can expect to see in the coming few years will come from public health advances, and possibly from drugs to optimise metabolism. These will act, as I noted above, as a "bridge" to allow more people to survive in a healthy state for long enough to be able to benefit from the regenerative approach that SENS Foundation is pursuing.

Michael Holick on Vitamin D

Michael Holick, MD, PhD, of Boston University Medical Center says he’s “just one of the many scientists” exploring vitamin D, but he easily can be considered the world’s foremost authority on the sunshine vitamin.

In the 1970s, it was Dr. Holick who first isolated the major circulating form of vitamin D in plasma, 25-hydroxyvitamin D, as well as the active form produced by the kidneys.

He was also one of the first scientists to warn the medical community about the potential implications of widespread vitamin D insufficiency. When asked about the prevalence of low vitamin D status, he answers that it’s the “most common medical condition in the world, believe it or not.”

Dr. Holick has championed the cause of bringing vitamin D into the limelight for decades, writing numerous scientific papers as well as two popular books on the subject of vitamin D and health.

Getting D Facts from Dr. Holick

While seeking the latest findings from vitamin D research, I caught up with Dr. Holick and sought out his advice on sun exposure, vitamin D supplementation and vitamin D’s potential ties to weight management, insulin resistance and heart health.*

Q: Dr. Holick, thank you for taking the time to update us on vitamin D research. Elvis Presley once said, “Truth is like the sun. You can shut it out for a time, but it ain’t going away.” Don’t you think this quote represents the vitamin D story?

A: Amen. Elvis was right on target. Our sun has been demonized for 40 years unchallenged. It’s quite remarkable that it’s part of the psyche of the world. But it’s caused a major problem, which is worldwide vitamin D deficiency [or insufficiency] and markedly increased risk of chronic disease for children and adults.

You can instantly make vitamin D, but if you’re avoiding the sun as most people do it puts you at high-risk of deficiency. Why is that? It’s been demonized for so long because the dermatologists have come out with the big “C” word [melanoma skin cancer from sun exposure]. And there’s no question that skin cancer is on the rise. The major reason is because back in the ’60s people used to put baby oil on and bake in the sun. Right? Now, all of the sudden, that’s starting to haunt them later in life. It increased their risk of non-melanoma skin cancer.

But often what people don’t realize is that melanoma, the most deadly cancer—which is also what they lump together with skin cancer from the sun—most melanomas occur on the least sun-exposed areas. Occupational sun exposure decreases your risk of developing melanoma. There was a study done in a group in Texas that if you had the most sun exposure as a child and young adult and you did get melanoma, then you were more likely to survive it.

Q: Would you comment on vitamin D being a hormone, and the oldest hormone?

A: Well, the reason why we say that [it's the oldest hormone] is because I asked the question several years ago. If you take phytoplankton—there’s a phytoplankton species called Emiliani huxleii has been identified as one of the oldest phytoplankton species that has been unchanged for 750 million years. When we looked at that organism, it made a huge amount of vitamin D when it was exposed to sunlight.

It’s a hormone you make in your skin, then it’s inactive. It has to go to your liver to get hydroxylated to 25-hydroxyvitamin D, which is the major circulating form, the form you should ask your doctor to test for vitamin D status. Then it goes to your kidneys where it’s activated to 1,25-dihydroxyvitamin D, then it goes to your bone and intestines and kidneys.

Q: As a hormone, we also know now that it has a greater role on the body besides speeding up absorption of calcium for bone health. There is a link to cardiovascular health, right? What’s the state of the science?

A: As for the heart, we know that vascular smooth muscle cells have vitamin D receptors and we know that vitamin D seems to play a role in regulating blood pressure, regulating heart muscle cells in their growing activity, regulates to some degree the strength of the heart in terms of its pumping ability. That’s why it’s not at all surprising that just two years ago out of the Framingham heart study it shows that if you are vitamin D deficient you [are not providing optimal support for cardiovascular health].

Q: How does vitamin D’s relationship to heart health affect you if you are overweight?

A: This issue for obese people is particularly important because vitamin D is fat-soluble and is incorporated in your body fat. We showed many years ago that if you take an obese person and give him an oral dose of vitamin D or put him in a [UVB] tanning bed, it only raises his blood level to less than 50 percent than what a normal-weighted individual does and we’re talking about a BMI [Body Mass Index] of greater than 30. He needs two to three times more [of vitamin D than a person of normal BMI].

We know that obese people have more aches in their muscles, which is definitely due to vitamin D deficiency. They have muscle weakness. They’re fatigued. They just don’t want to go. It’s in part due to the deficiency. We also know that fat cells have a vitamin D receptor. There’s some evidence—we’re doing some research right now—that suggests that maybe vitamin D helps keep fat cells in check.

Q: Really? By what mechanism is it that you think vitamin D could help keep fat cells in check?

A: It may regulate fat cell maturation. It may regulate fat cell fat accumulation. That’s brand new stuff that we’re taking a look at that we’ve not yet published on. We’re just beginning to look at it.

Q: Is there any relationship established between low vitamin D status and insulin sensitivity?

A: We think so. We know that from NHANES (National Health and Nutritional Examination Survey) that [there may be a relationship associated with insulin sensitivity].

Q: We’ve heard a lot about a new established relationship between vitamin D and the immune system. Would you comment on the mechanism by which vitamin D is involved?

A: Well we know is that your immune system is regulated by vitamin D. We know that the cell macrophages definitely gobble up infectious agents because of vitamin D, macrophages activate vitamin D locally, and it stimulates production of a defensive protein that kills infectious agents. A study was done to show that if you raise your blood level, that you have more activity of your macrophages in killing infective agents. If there’s anything out there that helps to support the immune system, it’s probably vitamin D.

Q: Do you agree that everyone should be checked for vitamin D status?

A: Well, that’s the problem. It’s not an unreasonable thing to do, but I can already tell you they’re deficient. We know almost everyone’s deficient. If a normal adult isn’t taking at least 1,500 to 2,000 IU from supplement and diet—and you can’t really get it from your diet—then we know you’re vitamin D deficient. And so, to try to screen everybody, all the obese people in the United States is such a huge cost burden.

In fact, Medicare is looking at this right now and wanting to control the doctors’ use of that assay. They do not want to use it as a screening tool. I don’t disagree with that. Because we know that you can very effectively correct vitamin D deficiency, treat it, and prevent it from occurring again, if you give the person enough vitamin D. So only if they have fat malabsorption syndrome, or has had gastric bypass surgery, or cystic fibrosis, IBD, or celiac sprue—all of those individuals should be tested because you can’t predict whether or not they’re going to be able to absorb the vitamin D that you give them as a supplement.

Q: What about older people? Does the requirement for vitamin D supplementation increase with older age because of declined absorption?

A: No it does not. That’s what everybody says. [Note: Elderly can absorb vitamin D as easily as younger people.] What does change with age is the ability to make it in your skin. We showed many years ago that if you compare a 70-year-old to a 20-year-old, the 70-year-old will have about a 70 percent reduced ability to produce vitamin D. But we also went on to show that you can take an older person and still have them exposed to sunlight or simulated sunlight and they make a lot of vitamin D. Your body has a huge capacity to make vitamin D. We showed that healthy adults in bathing suits getting a minimal erythermal dose get an equivalent to ingesting 20,000 IU of vitamin D.

Now you begin to understand why the 100 IU in a glass of milk or orange juice or the 400 IU in a multivitamin is probably one tenth of what we really need to satisfy our body’s requirements for heart health or for reducing risk diseases.

Q: Do you agree as other scientists have suggested that the average person should be getting at least 20 minutes of sunshine per day for adequate vitamin D intake along with supplementation?

Dr. Holick has been researching vitamin D since the 1970s.
A: I don’t know about 20 minutes a day because it depends upon time of day, season of the year, latitude, and your degree of skin pigmentation. What I tell people is, if you know that you’re going to be out in June at noon-time for 30 minutes, in Arizona, and you’re going to get a light sunburn to your skin, to go out 50 percent of that time.

Always protect your face, it’s the most sun exposed, the most sun damaged. But you can certainly expose your arms and legs and not worry about it, in my opinion. Abdomen, back, not a problem. The more skin you expose, the more [vitamin D] that you make.

Q: Do you expect the Institute of Medicine’s recommendations for Adequate Intake of vitamin D to change in the United States anytime soon to reflect findings of new research?

A: Yes, there will definitely be new Adequate Intakes. What you really care about though is not the AI recommendation, what you care about is the Upper Limit—that’s what prevents manufacturers from putting vitamin D into foods. The amounts that you can put in and the amounts that supplements can contain.

The safe upper limit right now is considered to be 2,000 IU for adults. The major manufacturers like Coca Cola or who make Minute Maid orange juice for example put only 100 IU in a glass, because if they put in any more then they start adding that up, drinking milk and taking a multivitamin, you’re over the 2,000 IU limit.

Then if you get some toxicity like a kidney stone, it doesn’t matter that it’s not due to the vitamin D, the lawyers will say that it is if you put more than you should’ve put in. So they need to increase it like to 10,000 IU in which case, then we can really have an impact on the entire U.S. population and the world’s population because they could now put more vitamin D in the food.

Q: Dr. Holick, this has been very interesting and I’m sure it will be interesting to our readers. Thank you for your time. Also, congrats on the new book. We’ll be ordering a couple of copies for our library.

A: Wonderful. Feel free to stay in touch