Old Mice Made "Young"—May Lead to Anti-Aging Treatments

Stem cell injections prolonged lives of rapidly aging mice.

Christine Dell'Amore

National Geographic News

Published January 6, 2012

Aging mice can be made "young" again, according to findings one scientist initially found unbelievable.

The key is muscle-derived stem cells, which—like other stem cells—are unspecialized cells that can become any type of cell in the body.

When injected with muscle stem cells from young mice, older mice with a condition that causes them to age rapidly saw a threefold increase in their life spans, said study co-author Johnny Huard, a stem-cell expert at the McGowan Institute for Regenerative Medicine in Pittsburgh.

(See "Liposuction Fat Turned Into Stem Cells, Study Says.")

"I've been doing science for the last 20 years," Huard said. What "makes the story so amazing is that in the beginning, I didn't believe the result," he said.

"I bet that we mixed up the animals—you know, scientists are always skeptical."

"Tired" Stem Cells Reenergized

The study mice were genetically engineered to have a condition similar to a rare human syndrome called progeria, in which children age quickly and die young. (Learn more about the human body.)

The fast-aging mice typically die around 21 days after birth, far short of a normal mouse's two-year life span.

When scientists looked at the muscle stem cells of the fast-aging mice, they found what Huard called "tired" stem cells, which don't divide as quickly.

The team then examined mice that had aged normally and found their stem cells were similarly defective.

Curious if these deficient stem cells contribute to aging, Huard and colleagues injected stem cells from young, healthy mice into the fast-aging mice about four days before the older animals were expected to die.

To Huard's astonishment, the treated mice lived an average of 71 days—50 more than expected, and the equivalent of an 80-year-old human living to be 200, he said.

Not only did the animals live longer, they also seemed healthier, the scientists found.

(See "Drug Could Make Aging Brains More Youthful?")

Mysterious Secretions Make Cells Young

The "drastic" results bore out with repeated experiments, leaving the scientists to wonder how exactly the stem cells were working their magic, Huard said.

To find out, the team "tagged" stem cells injected into the fast-aging mice with a genetic marker that tracked where the cells went inside the body. Surprisingly, the team found only a few stem cells in the mouse organs, squashing a theory that the introduced cells were repairing organ tissues.

The scientists went back to the lab to test another idea: that stem cells secrete some kind of mysterious anti-aging substance.

The team put stem cells from the fast-aging mice on one side of a flask and stem cells from normal, young mice on the other side. The two sides were separated by a membrane that prevented the cells from touching.

Within days, the aging stem cells began acting "younger"—in other words, they began dividing more quickly.

"We can conclude that probably normal stem cells secrete something we don't know that seems to improve the defects in those aging stem cells," Huard said.

"If we can identify that, we have found an anti-aging protein that is going to be important" for people, said Huard, whose study appeared January 3 in the journal Nature Communications. http://www.nature.com/ncomms/journal/v3/n1/full/ncomms1611.html

Stem-Cell Research "Intriguing" but Preliminary

But other scientists are cautious about how soon the discovery may help people delay the aging process or treat age-related disease.

"They did a beautiful job of showing that, when they put the muscle stem cells in [the mice], they improved function," said Justin Lathia, an assistant professor of cell biology at the Cleveland Clinic's Lerner Research Institute.

But as far as people go, it's still not clear what exactly stem cells do in the body, as well as what the mysterious stem cell secretion really is, Lathia emphasized.

Jeremy Rich, chair of the department of Stem Cell Biology and Regenerative Medicine at the Cleveland Clinic, also pointed out that the study is limited to muscle stem cells. That means the research can't be generalized to include all stem cell types, which are often very different from each other.

Paul Frenette, a stem cell and aging expert at the Albert Einstein College of Medicine in New York, called the research "intriguing," but said one of the messages for "patients is not to get too excited."

"You see all these clinics that are popping up all over the world—even in New York—where they're injecting stem cells" into people to treat disease, even though such therapies have not been proven.

"I don't think people should run to the clinic right now to have injections of stem cells to live longer."

(See "'Stem Cell Tourists' Go Abroad for Unproven Treatments.")

Stem Cell Therapy to Help People "Age Well"?

Indeed, study co-author Huard noted that before any human anti-aging trials can begin, scientists need to repeat the experiment in normally aging mice to show whether these mice also live longer.

If that turns out to be true, Huard could imagine a scenario in which some of a person's stem cells are harvested at about age 20 and then injected back into his or her body at around age 50 or 55.

Stem cell therapies do already exist for conditions such as incontinence and heart problems, so he thinks "we're not that far [from applying] this approach clinically down the road."

But Huard warned that such a treatment would not mean a 55-year-old will suddenly look and feel 25 again.

"The goal of doing this research is not to [be like a] movie star with a ton of money [who wants to] look great for the rest of their lives," he said.

"The goal is, if you delay aging, maybe you can delay Alzheimer's or cardiovascular problems."

In other words, he said, such stem cell treatments would help people "age well."

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'Silver bullet' supplement could slow brain aging

January 4, 2012 By Andrew Baulcomb

Professor David Rollo and a group of researchers at McMaster may have found a "silver bullet" when it comes to slowing the aging of the brain.

The team's latest paper [LINK] documents a new dietary supplement that completely maintains learning ability in older mice.

"These findings are not just significant, they're remarkable," says Rollo.

The tests were conducted by Vadim Aksenov, a PhD candidate in the Rollo laboratory in McMaster's Department of Biology.

A complex nutritional supplement containing 30 ingredients, including vitamins such as B1, C, D and E, along with beta-carotene, ginseng, green tea extract, cod liver oil and other acids and minerals, was used in the test. It was designed to offset five mechanisms associated with aging.

For mice aged 20-31 months (roughly equivalent to a 70-80-year-old human), those without the mixture in their diet showed no ability to learn new information. However, those who had taken the supplement displayed learning abilities equivalent to young mice, and more effectively completed the task.

The trials focused on a region of the brain associated with Alzheimer's disease.

VIDEO:

http://www.youtube.com/watch?feature=player_embedded&v=rL3lgAG2RuE#!

Other findings revealed that brain mass was increased by up to 10 per cent as a result of taking the supplement. The function of the cellular furnaces that provide brain energy (mitochondria) was also increased.

But what does it all mean for humans?

"This diet was our first try, so the door is just opening up," says Rollo. "Whether these results will translate to humans remains to be seen."

A major goal in anti-aging research involves the reduction of poisonous "free radicals" and their associated damage, while also maintaining mitochondrial function and energy supply later in life. The new supplement does both.

Unlike stand-alone vitamins, pills or anti-aging products, the combination of ingredients is far more effective in maintaining brain function.

While human testing has yet to begin, Rollo is hopeful that the supplement may one day slow the progression of Alzheimer's, Parkinson's and other neurodegenerative diseases in older adults.

If human trials prove safe and successful, most of the aging population could access the ingredients at local health food stores.

Jiangang Long, Jiankang Liu, Henry Szechtman, Parul Khanna and Sarthak Matravadia were also involved in the study.

Provided by McMaster University

http://medicalxpress.com/news/2012-01-silver-bullet-supplement-brain-aging.html

The Healthy Skinny Pill

Tuesday, November 04, 2008

A new drug proves effective in fighting obesity and related diseases while increasing stamina in mice.

By Brittany Sauser

Marathon mice: Last year, scientists tested the health effects of resveratrol, a compound found in red wine, that targets the same pathway as the synthetic compound SRT1720. In both instances, mice fed these compounds have increased running endurance. The mouse on the right (fed resveratrol) runs for longer than the untreated mouse on the left.
Credit: Institut Clinique de la Souris, Illkirch, France

Multimedia Watch the testing of a mouse’s running endurance on a treadmill.

A pill that delivers the health benefits of diet and exercise without any of the effort is one step closer to becoming a reality. European scientists have found that mice fed a high-fat, high-calorie diet and prevented from exercising regularly can be protected from weight gain and metabolic disorders when given a drug that targets a gene linked to longevity. The treatment even increases the animals' running endurance.

The drug was developed last year by Sirtris Pharmaceuticals, based in Cambridge, MA, and preliminary studies of the compound showed it to be effective in treating mice models of type 2 diabetes, a disease that results in an impaired ability to produce or process insulin, the risk of which increases with age. Now scientists led by professor Johan Auwerx at Ecole Polytechnique Federale de Lausanne (EPFL), in Switzerland, have shown that the compound involved, known as SRT1720, also blocks weight gain and obesity-related disorders and increases muscle stamina.

In the study, scientists fed the mice a high-fat, high-calorie diet mixed with doses of SRT1720 for approximately 10 weeks. The mice were given 100 or 500 milligrams of fat per kilogram of body weight each day (a high dose even for humans). The mice did not exercise regularly, although the scientists tested the animals' exercise capacity, or endurance, by making them run on a treadmill. "The mice treated with the compound ran significantly longer," says Auwerx. The drug also protected the animals from the negative effects of high-calorie diets: metabolic disorders, obesity-related diseases, and insulin resistance. It even improved the mice's cholesterol.

It is significant that the drug mimics the effects of a calorie-restricted diet, since this has previously been tied to increased life expectancy, says William Evans, a professor of geriatric medicine, nutrition, and physiology at the University of Arkansas for Medical Sciences.

It's as if the couch-potato mice underwent a strict diet and exercise regime, says David Sinclair, a biologist at Harvard Medical School, in Boston, who is one of the cofounders of Sirtris but was not involved in the current study. The new study "is a major step forward, showing that we can design and synthesize potent, druglike molecules that could slow down the aging process," says Sinclair.

The effects of the compound are similar to those of resveratrol, a molecule found in red wine that has previously been shown to extend life span and have health benefits in mice. But SRT1720 is a thousand times more potent than resveratrol, meaning that it could be taken in smaller doses. A person would have to drink hundreds of glasses of wine to get the same health benefits from resveratrol, and, while supplements are available, it is unclear whether they are as effective. "Resveratrol will pretty soon look like ancient technology," says Sinclair.

The findings in the new study, which is published in the November issue of the journal Cell Metabolism, also answer a big scientific question: whether scientists searching for ways to combat aging have been targeting the right gene.

SRT1720, like resveratrol, works by targeting a gene known as sirtuin 1, or SIRT1, which many scientists believe plays a fundamental role in regulating life span. SIRT1 encodes for a class of proteins known as sirtuins, and it is a central controller of mitochondrial activity (mitochondria are the powerhouse energy providers to the cells). "Firing up mitochondria is one of the best treatments against diabetes and obesity because you burn off extra energy instead of storing it," notes Auwerx.

However, unlike the new compound, resveratrol is not specific to SIRT1, and thus many experts have questioned whether the effects of resveratrol in mice were mediated by SIRT1 activation or by some other pathway.

The fact that another chemical activates the same gene and produces similar effects strongly suggests that the metabolic benefits can be attributed to SIRT1, says Leonard Guarente, an MIT biologist whose lab first discovered the sirtuin 1 gene. He is on Sirtris's advisory board but wasn't involved in the study. "This is a very important finding, and [it] means that [SIRT1 activators] are good candidates for lead compounds [in] antidiabetic drugs in humans," Guarente says. SIRT1 could also be a target for other diseases related to aging, he adds, "which would be a silver bullet."

"The scientific community is focusing on mitochondria as the most important organelle in muscle that affects the risk of diabetes, hypertension, and the loss of physical function in elderly people," says Evans. "The compound may be one additional help or aid that we could use to treat these conditions. It is an exciting, new development."

Sinclair says that a cousin molecule of SRT1720, which is even more potent, is currently in human trials and will enter clinical studies for the treatment of diseases like type 2 diabetes in 2009. "We could know as early as next year if the same types of benefits we see in mice, we see in humans," he says.

Source

Nano Carrier Targets Cell Sites

Thursday, September 18, 2008

Researchers find a new way to precisely target cancer drugs.

By Katherine Bourzac

Tiny target: A new targeted nano carrier selectively brings a cancer-killing drug to the mitochondria, the drug’s subcellular site of action. In these fluorescent images, yellow indicates that the drug is inside the mitochondria. Cell nuclei are stained blue. Credit: Volkmar Weissig

Most drugs work by affecting a particular organelle within cells, but it's difficult to get a therapeutic compound to the right place inside a cell. Now researchers have succeeded in targeting a cancer-killing drug to a part of the cell called the mitochondrion by packaging it in a nano carrier. The highly targeted version of the drug increased its efficacy in tests in mice, even at relatively low doses, shrinking tumors and extending survival.

Over the past several years, researchers have had great success using antibodies and other molecules to target drugs to cells of particular tissue types. But once a drug gets inside the right cell, it's easy for it to get lost. Drugs are tiny compared with cells, and their charge, weight, and tendency to interact with water all determine where in the cell a drug ends up. "You have to design it such that it finds its way," says Volkmar Weissig, a professor of pharmacology at the Midwestern University College of Pharmacy, in Glendale, AZ, who developed the new targeted therapy with Vladimir Torchillin, director of the Center for Pharmaceutical Biotechnology and Nanomedicine, at Northeastern University, in Boston.

Subcellular targeting "is one of the biggest promises nanotechnology offers," says Jerry Lee, a project manager at the National Cancer Institute's Alliance for Nanotechnology in Cancer. The new research, he says, "offers early proof of concept of being able to target not only to cancer cells, but to pick and choose where in the cell to target."

Weissig and Torchillin developed a nano carrier to deliver a drug called ceramide to the mitochondria of cancer cells. The researchers enclosed ceramide within a sphere of lipids similar to those in many drug-delivery systems. This lipid envelope, which is too large to pass through the walls of healthy blood vessels, has a tendency to passively accumulate in tumors. (Tumor blood vessels have large gaps that allow the lipid-coated drugs in.) In order to actively target the drug to its subcellular site of activity, Weissig and Torchillin decorated the lipid envelopes with a molecule known to accumulate in the mitochondria.

In animal tests, the approach shows good efficacy, says Joseph DeSimone, a professor of chemistry and chemical engineering at the University of North Carolina at Chapel Hill. DeSimone is taking a different approach to intracellular targeting: he recently found that it's possible to control where in the cell nanoparticles accumulate by varying their shape. Overall, he says, "methods for accessing intracellular targets are extremely important to pursue."

Unhealthy mitochondria play a role in obesity and many diseases, including diabetes and degenerative diseases of the nervous system and muscle. And in theory, the nano-carrier system could be used to carry a wide variety of drugs to the mitochondria, says Weissig. However, since the carrier relies on leaky blood vessels to get to its target cells, it's not likely to be used to treat a wide variety of other diseases. Inflammatory diseases like arthritis, which also causes leaky blood vessels, are another possible application.

The nano-carrier technology was recently licensed by Telomolecular, a company in Rancho Cordoba, CA. Weissig says that the company will use it to develop an anticancer drug that works in the mitochondria. Although the system was proved using ceramide, Telomolecular will test other cancer drugs as well, says Weissig.

Source

UC Santa Barbara Chemist Goes Nano with CoQ10

July 24, 2008


Bruce Lipshutz, professor of chemistry at UC Santa Barbara.
Click for downloadable image
Bruce Lipshutz,
professor of chemistry
at UC Santa Barbara.

(Santa Barbara, Calif.) – If Bruce Lipshutz has his way, you may soon be buying bottles of water brimming with the life-sustaining coenzyme CoQ10 at your local Costco.

Lipshutz, a professor of chemistry at UC Santa Barbara, is the principal author of an upcoming review, "Transition Metal Catalyzed Cross-Couplings Going Green: in Water at Room Temperature," which will be published in Aldrichimica Acta in September. In it, Lipshutz and post-doctoral researcher Subir Ghorai discuss how recent advances in chemistry can be used to solubilize otherwise naturally insoluble compounds like CoQ10 into water.

Never heard of CoQ10? Lipshutz says you're not alone. "If you don't know anything about it," Lipshutz said during a recent interview, "that's not surprising to me. Much of the public hasn't heard of it." But he's on a mission to correct what he views as a major oversight. "In a sense, I'm just a messenger. People need to not only know about CoQ10, they need to take it."

Like vitamin C, CoQ10 is a compound that's vital to our survival. It's a coenzyme that our cells synthesize, albeit in 21 steps, and it's in every cell. This contrasts with a vitamin, such as vitamin C, which is not made by the body. Both CoQ10 and vitamin C are "compounds of evolution," Lipshutz said. "Everybody accepts the importance of vitamin C. The reason the public does not fully appreciate it is that there's no Linus Pauling for CoQ10. There is no champion."

Pauling, a Nobel Prize-winning scientist, was also an advocate for greater consumption of vitamin C. "CoQ is not really in that category of public awareness yet," Lipshutz said.

While the body produces its own CoQ10, that production decreases with age. "Nature gave us, through 2.5 billion years of evolution, a number of fundamental anti-aging, free-radical scavengers that helped us to survive, on average, only to about 40 years of age, until modern medicine came along," Lipshutz said.

A large percentage of the body is made up of water, "but there are also the lipophilic portions of our cells that make up the non-aqueous part," Lipshutz explained. At some point in our evolution, the water-soluble antioxidant vitamin C was produced in vivo, or what would technically be "coenzyme C." Eventually, "a mutation took place that now prevents humans from making it," he said. "However, evolution chose not to mutate out CoQ10."

If one doesn't get vitamin C, the consequences can be dire. "It's essential for several cellular processes. For example, everyone knows about scurvy," Lipshutz said. "You can last 30 days, maybe 60 days, as your cells deteriorate."

On the other hand, CoQ10 – much of which is in the mitochondria of our cells – is essential for cellular respiration and ATP (adenosine triphosphate) production. "You wouldn't last 30 minutes without CoQ10," he said. "Thus, evolution teaches us that CoQ10 is as important as vitamin C. But who's teaching this to our aging population? Nobody."

Lipshutz has a history of CoQ10 research at UCSB. Initially, he retooled the chemistry that would produce the supplement via synthesis instead of fermentation, which is what Japan used to become the world leader in CoQ10 production. But China's entry into the CoQ10 market only a few years ago changed everything.

"The price of CoQ for over 30 years was about $1,600 per kilo as produced by the Japanese," Lipshutz said. "The Chinese came along and, for the time being, have dramatically altered the market by deciding at the government level that they were going to own this important area of dietary supplements. CoQ10 can now be purchased for as little as $400 a kilo, which in principle is great news for consumers."

When the supply of CoQ10 grew faster than demand, Lipshutz went into the lab to study what else could be done with this life-enriching compound. After all, CoQ is now readily available. At Costco or drug stores, you can buy CoQ10 formulated into softgels that deliver the nutrient in various strengths. It's marketed as helping to provide a boost in energy as well as a healthy heart. But, Lipshutz notes, you absorb only10-15 percent of CoQ10 in the softgel form. How, he asked, could this become more available and bioefficient?

"The future is not about access to CoQ10 anymore," he said. "It's not about, ‘Do we have the best synthesis?' or ‘Can we compete with the Chinese?' It's about getting it into water, so that we can get it into our mitochondria."

Quite a challenge since CoQ10 is water insoluble. The answer? Go nano.

"We do it with nano-micelle-forming technology," Lipshutz said. He starts by putting a known, inexpensive molecule called PTS into water, which spontaneously forms a nanosphere about 25 nanometers (one nanometer is equal to one billionth of a meter) in diameter. This sphere has a lipophilic portion tied to a hydrophilic portion through a linker. The lipophilic portion, which is actually vitamin E, goes to the center. "The vitamin E portion associates in the middle with itself because it doesn't have any solubility, any energy-lowering interactions, with the water around it," Lipshutz said. "But the external or hydrophilic portion associates with water.

"So, on the outside is the water-loving portion, while the lipophilic, or grease-loving portion, is on the inside. When you add the CoQ, it says, ‘Where would I rather be?' Since like dissolves like, the CoQ10 goes inside the micelle. It's 25 nanometers and it's crystal clear. And, it's stable at room temperature."

That's nanotechnology. It delivers twice the amount of the compound into the bloodstream, and the concentration in water can be adjusted, he said. This approach can be applied to a broad range of nutraceuticals, including omega-3s, carotenoids like lutein and beta-carotene, and resveratrol. "We can also take pharmaceuticals, like Taxol, an anti-tumor agent, and put them into just water or saline using this PTS," he said.

By taking advantage of this micellar technology, synthetic chemistry can also be done inside the nano-containers. That translates into doing chemistry in pure water, and at room temperature. "That's green chemistry," Lipshutz said.

The amount of heat usually needed in reactions, and the waste created by organic solvents, are dramatically reduced. Lipshutz hopes that when his processes are looked at on a much larger scale, a savings of metric tons of solvent, currently released into the environment, will be realized.

"We aim to get organic solvents out of organic reactions," he said. "And we're already looking into next-generation possibilities. All of our green chemistry has come out of being able to put CoQ10 and other dietary supplements into water."

Lipshutz sees this as his most significant contribution to an already illustrious career as an organic chemist.

"It's an opportunity to affect every person on the planet," he says proudly.

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