Extending Healthy Lifespans? A Pill on the Horizon?

Resveratrol, the much-hyped ingredient found in red wine and sold widely as a nutritional supplement, is known to improve the health and extend the lifespan of mice. Can it do the same for humans? Without nasty side effects? And at what dose?

A study published today in Cell Metabolism helps unravel a few more of resveratrol’s mysteries. In particular, researchers have shed new light on how resveratrol works. Key to its effectiveness is a gene known as SIRT1, found in slightly different forms in species as different as yeast and humans. SIRT1 plays many roles, some tied to core metabolic processes. The new study shows that in mice, even a low dose of resveratrol interacts with SIRT1 to improve metabolism.

What makes this study especially interesting is that researchers had to create a special strain of mice in order to test whether SIRT1 is necessary for resveratrol to work. If mice have no SIRT1, they do not develop properly. So two graduate students, Nathan Price and Ana Gomes, developed a novel strain of mice with an unusual copy of the SIRT1 gene, one that could be switched off at adulthood.

By administering a drug (tamoxifen), researchers can “induce” or switch the SIRT1 gene on and off, a strategy that will likely be used in other studies. "This is a drug inducible, whole body deletion of a gene," David Sinclair, the study's senior author, said in a press release from Harvard Medical School. "This is something that's rarely been done so efficiently. Moving forward, this mouse model will be valuable to many different labs for other areas of research."

Photo by R. Cole-Turner

In this case, the switchable SIRT1 mouse provided proof that SIRT1 is key to resveratrol’s effectiveness. Why is that important? Because resveratrol is a complex molecule that interacts with the body in many unknown ways. While it may be beneficial, it may have unwanted side effects. So researchers are trying to design a more simple molecule that provides the benefits of resveratrol without all the risks. One strategy is to boost SIRT1 activity. By proving that SIRT1 is involved, this study provides support for that strategy, which is already being pursued by pharmaceutical firms.

"The results were surprisingly clear," said. "Without the mitochondria-boosting gene SIRT1, resveratrol does not work."

Are we any nearer a magic pill that slows aging or promotes longevity? Perhaps. The headline of the press release from the publisher, Cell Press, claims that this work “restores hope for anti-aging pill.” Remember, of course, that the work reported here is entirely with mice.

Even so, the paper itself concludes with this statement: “This model supports the enticing possibility of designing and developing potent small molecules that provide the health benefits of resveratrol by activating SIRT1 and downstream pathways to treat metabolic and other age-related diseases.”

The treatment of age-related diseases, including diabetes, is a huge target for pharmaceutical firms. But beyond that lies that even bigger market for human enhancement, specifically for enhancing the span of healthy decades.

The study, "SIRT1 Is Required for AMPK Activation and the Beneficial Effects of Resveratrol on Mitochondrial Function," appears in the May 1, 2012 issue of Cell Metabolism.

Spreading Farming, Spreading Genes

Agriculture probably originated in the Middle East about 11,000 years ago. Over the next six thousand years, it spread to other parts of the globe, including northern Europe, gradually replacing hunting and gathering as the primary means of human survival.

How did it spread? Were hunter-gatherers converted to the efficiencies of agriculture? Or did farmers from the south spread north, bringing their agriculture with them?

A new study suggests that farming spread because farmers moved. The movement was slow, taking five to six thousand years to reach Scandinavia. Early in the process, farmers of southern ancestry lived side by side with their more northerly human cousins, who still lived by hunting and gathering. Eventually, after a thousand years or so, farmers interbred with hunter-gatherers and farming became the dominant way of life.

The new study, which appears in the April 27 issue of Science, is based on an analysis of four skeletons, all found in Sweden and dating from about 5,000 years ago. Three were hunter-gatherers and one was a farmer. All of them lived their entire lives close to where they were buried, the hunter-gatherers in a flat grave and the farmer a stone megalith like the one pictured below.

Caption: Several hundred megalith tombs are known from the Falbygden area, including Gökhem and Valle parishes in Östergötland,Sweden.Credit: Göran Burenhult

"We know that the hunter-gatherer remains were buried in flat-bed grave sites, in stark contrast to the megalithic sites that the farmers built," said Mattias Jakobsson, a senior author from Uppsala University. "The farmer we analyzed was buried under such a megalith, and that's just one difference that helps distinguish the two cultures," Jakobsson said in a press release issued by the journal.

What is most significant in this study comes from an analysis of the human DNA extracted from the four skeletons. By studying their DNA, researchers found that the farmer belonged to a community with ancestral roots in the eastern Mediterranean, most closely resembling today's Greeks and Cypriots. The hunter-gatherers, on the other hand, were more like today’s northern Europeans, most closely resembling today's Finns. "What is interesting and surprising is that Stone Age farmers and hunter-gatherers from the same time had entirely different genetic backgrounds and lived side by side for more than a thousand years, to finally interbreed," Jakobsson said.

Caption: The skeleton belongs to a young female in her 20s, and can be dated to around 4,700 years ago. Credit: Göran Burenhult

"The results suggest that agriculture spread across Europe in concert with a migration of people," added Pontus Skoglund, also of Uppsala University. "If farming had spread solely as a cultural process, we would not expect to see a farmer in the north with such genetic affinity to southern populations."

The article, entitled "Origins and Genetic Legacy of Neolithic Farmers and Hunter-Gatherers in Europe," appears in the April 27 issue of Science, published by the American Association for the Advancement of Science.

Synthetic Biology: Is There Life beyond DNA?

Life as we know it is based on DNA and RNA. Could it have been otherwise? Might other worlds have life based on a different “genetic” system? We may never know for sure.

But we do know that synthetic biology is moving briskly toward the goal of engineered life beyond DNA and RNA.

Recall that in “DNA” and “RNA,” the “NA” part stands for “nucleic acids.” It’s the four nucleic acids that carry the genetic information in a chemical code. The “D” and the “R,” however, stand for sugars that hold the nucleic acids in place, allowing them to form pairs and to copy themselves. Can other sugars work as well?

Recent work in synthetic biology has led beyond DNA and RNA to xeno-nucleic acids or “XNAs.” Now, using six different forms of XNAs, an international team of researchers led by Vitor Pinheiro reports success in getting XNAs to store and propagate information. One of their XNAs actually “evolved” by responding to imposed selective constraints. Their work is published in the April 20, 2012 issue of the journal Science.

Caption: Courtesy--National Human Genome Research Institute

In a commentary on the research, Gerald F. Joyce writes in Science that this work has implications for the “understanding of life itself.” In addition, it opens new insight into the possible origins of life on our planet or else where in the cosmos.

At the same time, far more work lies ahead before synthetic biologists create XNA-based life. Pinheiro’s team was able to get their synthetic XNA “genes” to interact with DNA, but “they have not yet realized a synthetic genetic system.” One big challenge is in getting XNA sequences to copy themselves the way DNA does. Some XNAs can copy themselves to DNA and back again to XNA, but XNA-to-XNA copying is not reliable.

According to Joyce, however, “future studies are likely to yield improvements of the the various XNA-to-XNA copying reaction.” If that happens, synthetic biology will take yet another step toward “synthetic genetics.”

All this prompts a warning from Joyce: “Synthetic biologists are beginning to frolic on the worlds of alternative genetics but must not tread into areas that have the potential to harm our biology.” As ever, greater knowledge brings greater risks. More than ever, public awareness and careful thought are needed.

The research article, "Synthetic Genetic Polymers Capable of Heredity and Evolution" and the commentary, "Toward an Alternative Biology," are both published in the April 20, 2012 issue of Science, the journal of the American Association for the Advancement of Science.

A Million Years of Fire

One of our newest technologies has just shed new light on one of our oldest.

When did our human ancestors learn to control and use fire? Armed with the latest high tech tools, an international team of researchers has pushed the date back to 1 million years. That’s 300,000 years earlier than previous unambiguous dates.

The massive Wonderwerk Cave is in northern South Africa on the edge of the Kalahari. Previous excavations have shown extensive human occupation. Using the new techniques of micromorphological analysis and Fourier transform infrared microspectroscopy (mFTIR), researchers analyzed cave sediments at a far more detailed level than possible before.

Caption: This is a panoramic view of the entrance to Wonderwerk Cave, South Africa. Credit: H. Ruther. Usage Restrictions: None

In the cave sediments researchers found bits of ash from plants along with fragments of burned bone. Did the wind blow burning debris into the cave? The evidence—collected about 100 feet from the current opening of the cave—supports the conclusion that the fire burned in the cave. Also part of the proof: the surrounding surfaces are discolored.

”The analysis pushes the timing for the human use of fire back by 300,000 years, suggesting that human ancestors as early as Homo erectus may have begun using fire as part of their way of life," anthropologist Michael Chazan said in a press release from the University of Toronto.

According to the paper, "Through the application of micromorphological analysis and Fourier transform infrared microspectroscopy (mFTIR) of intact sediments and examination of associated archaeological finds— fauna, lithics, and macrobotanical remains—we provide unambiguous evidence in the form of burned bone and ashed plant remains that burning events took place in Wonderwerk Cave during the early Acheulean occupation, approximately 1.0 Ma. To date, to the best of our knowledge, this is the earliest secure evidence for burning in an archaeological context."

Caption: Interior of Wonderwerk Cave. Images courtesy of M. Chazan.

"The control of fire would have been a major turning point in human evolution," says Chazan. "The impact of cooking food is well documented, but the impact of control over fire would have touched all elements of human society. Socializing around a camp fire might actually be an essential aspect of what makes us human."

How important are fire and cooking for human evolution. A recent book, Catching Fire: How Cooking Made Us Human by Richard Wrangham, argues that cooking is essential to our humanity. Now in the paper published on April 2, the team concludes that its study “is the most compelling evidence to date offering some support for the cooking hypothesis of Wrangham.”

Their work is published as “Microstratigraphic evidence of in situ fire in the Acheulean strata of Wonderwerk Cave, Northern Cape Province, South Africa,” in the April 2, 2012 issue of the Proceedings of the National Academy of Sciences.

Planets by the Billions

New calculations suggest that there may be as many as 60 billion habitable planets just in our own Milk Way galaxy, maybe more. At least 100 of these planets may be as close as 30 light-years away.

Researchers at the European Southern Observatory (ESO) carefully sampled 102 red dwarf stars in the southern skies. Red dwarfs are very common in our galaxy. Based on observations and calculations, the ESO team estimates that approximately 40% of the red dwarf stars are orbited by planets. What’s more, these planets are in what astronomers call the “habitable zone,” meaning they are neither too close nor too far from their sun. In particular, it means that the temperature may be right for liquid water to exist on the planet’s surface.

The ESO project is the work of an international team using observations with the HARPS spectrograph on the 3.6-metre telescope at ESO's La Silla Observatory in Chile. It is published in the March 28 issue of Astronomy & Astrophysics.

Caption: This artist's impression shows a sunset seen from the super-Earth Gliese 667 Cc. The brightest star in the sky is the red dwarf Gliese 667 C, which is part of a triple star system. The other two more distant stars, Gliese 667 A and B appear in the sky also to the right. Astronomers have estimated that there are tens of billions of such rocky worlds orbiting faint red dwarf stars in the Milky Way alone. Credit: ESO/L. Calçada. Usage Restrictions: None

"Our new observations with HARPS mean that about 40% of all red dwarf stars have a super-Earth orbiting in the habitable zone where liquid water can exist on the surface of the planet," says Xavier Bonfils in a press release issued by ESO.

"Because red dwarfs are so common — there are about 160 billion of them in the Milky Way — this leads us to the astonishing result that there are tens of billions of these planets in our galaxy alone," according to Bonfils.

"The habitable zone around a red dwarf, where the temperature is suitable for liquid water to exist on the surface, is much closer to the star than the Earth is to the Sun," says Stephane Udry, another member of the ESO team.

Red dwarfs, however, may pose a special challenge to life. According to Udry, "Red dwarfs are known to be subject to stellar eruptions or flares, which may bathe the planet in X-rays or ultraviolet radiation, and which may make life there less likely." In the more technical language of the scientific publication, “The main difference from earth are a significantly higher mass and a different stellar environment, which potentially can have caused divergent evolutions.”

All the more tantalizing, of course. As one of the ESO scientists puts it, "Now that we know that there are many super-Earths around nearby red dwarfs we need to identify more of them using both HARPS and future instruments. Some of these planets are expected to pass in front of their parent star as they orbit — this will open up the exciting possibility of studying the planet's atmosphere and searching for signs of life," concludes Xavier Delfosse.

The article, "The HARPS search for southern extra-solar planets XXXI. The M-dwarf sample", by Bonfils et al. appears in Astronomy & Astrophysics on March 28.

Stem Cell Update: Important Research Breakthrough

Another important step has just been taken toward achieving the medical promise of stem cell research. For the first time, researchers at the Max Planck Institute for Molecular Biomedicine in Münster, Germany, have reprogrammed skin cells directly into multipotent stem cells.

Over the past five years, stem cell researchers have learned how to induce or reprogram skin cells to become pluripotent stem cells—cells capable of becoming any type of cell in the body. The result: induced pluripotent stem cells or iPSCs. Scientists have also discovered how to reprogram cells to become precursor or progenitor cells. Precursor cells have a much narrower range of potential for development. They are able to become one very specific type of cell in the body.

Expanding on previous work, the latest breakthrough achieves a kind of “goldilocks” or just-right level. Working with mice, the team led by Hans Schöler discovered how to reprogram fully differentiated skin cells into neuronal stem cells (NSC)s. Unlike pluripotent cells, NSCs are far more suitable for clinical use. And now, with this breakthrough, the Max Plank Institute team has learned how to reprogram or induce NSCs or iNSCs.

And unlike precursor or progenitor cells, iNSCs are capable of multiplying and diffentiating once they are implanted. When researchers implanted their iNSCs into mouse brains, iNSCs generated new cells that began to take on some of the characteristics of ordinary developing brain cells.

Caption: This is an immunofluorescence microscopy image of the induced neural stem cells (iNSCs) using antibodies against two neural stem cell markers SSEA1 (red color) and Olig2 (green color). Credit: MPI for Molecular Biomedicine

The field of stem cell research has faced many obstacles, some moral and some medical. The main moral objection is that the prime source of human pluripotent cells is the human embryo, and many object to the destruction of the embryo for medical purposes. One of the medical challenges is that implanted cells are likely to be rejected by the immune system, much as transplanted organs are rejected unless immunosuppressant drugs are given.

Unless, of course, the source of the cells is from the patient’s own body. That’s why this achievement is important. If this technique can be applied to human cells—and there’s no reason to think it can’t—then someday it may be possible to take a small sample of cells from a patient’s skin, convert them to iNSCs, and then implant them in the patient’s brain to repair damage from disease or injury.

Not only does the iNSC discovery use the patient’s own cells as the source. It also by-passes the pluripotent stage. That fact should help researchers avoid creating cancer or other problems.

According to Schöler, "pluripotent stem cells exhibit such a high degree of plasticity that under the wrong circumstances they may form tumours instead of regenerating a tissue or an organ."

"Our research shows that reprogramming somatic cells does not require passing through a pluripotent stage," Schöler said in a press release issued by the Max Plank Institute. "Thanks to this new approach, tissue regeneration is becoming a more streamlined—and safer—process."

The article, "Direct Reprogramming of Fibroblasts into Neural Stem Cells by Defined Factors," appears in the March 22 issue of Cell Stem Cell.

Space Age View of Stone Age Settlements

Thousands of early human settlements have been located using computers and satellite images, according to a paper published on March 19 in the Proceedings of the National Academy of Sciences.

Researchers used computers to analyze satellite images of a 23,000 square kilometer region in the Upper Khabur Basin of northeastern Syria. The finding? They believe they can identify 14,312 possible sites of human settlements dating back eight thousand years. The region, a relatively small 100 miles square, was nearly 3% occupied at various points over the intervening millennia.

Harvard archeologist Jason Ur collaborated with MIT researcher Bjoern Menze to develop a system that identified settlements based on a several factors. Old sites tend to leave mounds that show distinctive shapes and colors from the collapse of building materials such as mud bricks.

“With these computer science techniques, however, we can immediately come up with an enormous map which is methodologically very interesting, but which also shows the staggering amount of human occupation over the last 7,000 or 8,000 years,” Ur said in a press release issued by Harvard.

"What's more, anyone who comes back to this area for any future survey would already know where to go," he continued. "There's no need to do this sort of initial reconnaissance to find sites. This allows you to do targeted work, so it maximizes the time we have on the ground."

The article, “Mapping patterns of long-term settlement in Northern Mesopotamia at a large scale,” appears in the March 19 issue of PNAS.