In Human Cells and Live Mice Aging is Reversible

A new study reveals changes to gene activity that transpire with age can be reversed.

New research implies it is possible to slow or even reverse aging, at least in mice, by undoing changes in gene activity—the same kinds of changes that are the result of decades of life in humans.

As reported by a study published recently in Cell, by modifying genes that turn adult cells back into embryoniclike ones, researchers at the Salk Institute for Biological Studies reversed the aging of mouse and human cells in vitro, extended the life of a mouse with an accelerated-aging condition and successfully promoted recovery from an injury in a middle-aged mouse.

The study bolsters the scientific argument that aging is largely a process of so-called epigenetic changes, alterations that make genes more active or less so. Over the course of life cell-activity regulators get added to or removed from genes. In humans those changes can be triggered by smoking, pollution or other environmental factors—which dial the genes’ activities up or down. As these changes accumulate, our muscles weaken, our minds slow down and we become more susceptible to diseases.

The new study indicates the likelihood of reversing at least some of these changes, a process researchers believe they may eventually get to work in living humans. “Aging is something plastic that we can manipulate,” says Juan Carlos Izpisua Belmonte, the study’s senior author and an expert in gene expression at Salk. In their study Belmonte and his colleagues rejuvenated cells by turning on, for a short time frame, four genes that have the capacity to convert adult cells back into an embryoniclike state.

In living mice, they activated the four genes (known as “Yamanaka factors,” for researcher Shinya Yamanaka, the Nobelist who discovered their combined potential in 2006). This methodology rejuvenated damaged muscles and the pancreas in a middle-aged mouse, and extended by 30% the life span of a mouse with a genetic mutation responsible for Hutchinson–Gilford progeria syndrome, which causes rapid aging in children.

Because the Yamanaka factors reverse changes made to gene regulators, some scientists view the study as further evidence that aging is driven by epigenetic changes. “I do think that epigenetic reprogramming is the ultimate way to reverse aging,” says David Sinclair, a Harvard University geneticist and anti-aging researcher who was not involved in the study but is doing similar work. “My lab has a lot of evidence that the primary driver of what we call the hallmarks of aging is the epigenetic change.” Sinclair says his lab is preparing a paper explaining what causes these changes as we age.

The Salk study was conducted on middle-aged mice. But in theory, reprogramming epigenetics should work on mice and people at any age, remarks first author Alejandro Ocampo, adding that even cells from human centenarians could eventually be rejuvenated. He and Belmonte say they think they can improve the efficiency and results of the technique with more research—and that they can nullify the epigenetic changes responsible for aging by using easier-to-handle chemicals instead of the Yamanaka factors, hopefully advancing toward the potential of treatment for people.

Matt Kaeberlein, a molecular biologist at the University of Washington who studies aging but was not part of the work, says other researchers have found that the Yamanaka factors can rejuvenate cells—so in some ways this study is not astonishing. But Kaeberlein notes no one else had yet shown that the factors can treat age-related diseases in an animal by making the same changes. “That’s the wow factor,” he explains.

Kaeberlein says the study insinuates it may be possible not just to slow aging but to reverse it. “That’s really exciting—that means that even in elderly people it may be possible to restore youthful function,” he says. Plus, it is easier to imagine a treatment that makes changes to the epigenome than to consider going into every cell and changing its genes. He also notes that the results of the new study are very comparable to those seen when senescent cells—those that have lost function due to aging—are removed from an organism. It is not yet clear, he says, whether “this is another way to shut down or maybe reprogram senescent cells.”

Manuel Serrano, an expert on senescence at the Spanish National Cancer Research Center in Madrid, was not associated with in the new research but says he is impressed with the study and its results. “I fully agree with the conclusions. This work indicates that epigenetic shift is in part responsible for aging, and reprogramming can correct these epigenetics errors,” he wrote in an e-mail. “This will be the basis for future exciting developments.”

The study also demonstrated how fine the line can be between benefit and harm. When the researchers treated mice continuously, some developed tumors and died within a week. When the scientists reduced the treatment to two days out of seven, however, the mice benefited significantly. Sinclair says this should be taken as a note of caution by anyone trying to increase the human life span. “We’ve all been playing with fire,” he says, adding that this fine line will make it challenging to get a drug approved by regulatory agencies. “This is going to be what we spend the next 10 years figuring out: how to reprogram cells to be young again without taking it too far so they become tumors.”

Both Sinclair and Kaeberlein indicate they wish Belmonte’s lab had demonstrated that a normal mouse could live longer after the gene tinkering—instead of just reversing an aging-related illness.

Belmonte, like some other anti-aging researchers, says his initial goal is to increase the “health span”—the number of years that someone remains healthy. Extending life span, the number of years someone remains alive, will likely take longer to achieve. Most major killers, including heart disease, cancer and Alzheimer’s, are diseases of aging that become far more common past middle age. “This is not just a matter of how many years we can live but how well we can live the rest of our life,” Ocampo says.

Belmonte says his team is also trying to determine if aging is a process that occurs concurrently throughout the body. Or, as he puts it, “Is there some tissue that regulates aging—and when that goes bad, the entire organism goes bad?” He says they currently think the brain’s hypothalamus—known as the seat of control for hormones, body temperature, mood, hunger and circadian rhythms—may also act as a mechanism of aging.

Other methods that have been discovered to have anti-aging benefits in animals include calorie restriction, the drug rapamycin and parabiosis—the practice of giving old mice a blood supply from younger ones. The fact that these diverse strategies all seem to work suggests there may be more than one way to age, and that multiple complementary therapies may be necessary to significantly extend longevity, Kaeberlein says.

Some compounds such as resveratrol, a substance found in red wine that seems to possess anti-aging properties in high concentrations, appear to delay epigenetic change and protect against damage from epigenetic deterioration, Sinclair says. These approaches can reverse some aspects of aging, such as muscle degeneration—but aging returns once the treatment stops, he adds. With an approach like the one Belmonte lays out in the new study, theoretically “you could have one treatment and go back 10 or 20 years,” he says. If aging starts to catch up to you again, you simply get another treatment.

“This work is the first glimmer that we could live for centuries,” Sinclair says, adding that he would happily do so himself: “Forty-seven years went by pretty quickly.”

Alternatives to Resveratrol: The Anti-Aging NAD Trend

Ever wonder why children are bursting with boundless energy all day long?  The answer is: young Mitochondria.

Mitochondria fuel our cells, providing them with energy originated from bacteria that colonized other cells about 2 billion years, they become fickle as we age. A prominent hypothesis regarding aging states that decaying of Mitochondria is a major expediter of aging. While it’s not clear why our Mitochondria diminish as we age, data implies that it can cause everything from heart failure to neurodegeneration, in addition to a noticeable decrease in energy.

Current research states it may be possible to reverse mitochondrial decay with dietary supplements that boost cellular levels of a molecule called NAD (Nicotinamide Adenine Dinucleotide). But caution is advised: While there’s promising test-tube data and animal research about NAD boosters, no human clinical trial results have been published yet.

NAD is a pillar of energy metabolism, among other roles, and its dwindling level with age has been linked to mitochondrial deterioration. Supplements containing Nicotinamide Riboside, or NR, a precursor to NAD that’s found in trace amounts in milk, could help improve NAD levels. In support of that idea, half a dozen Nobel Laureates and other renowned scientists are collaborating with two small companies offering NR supplements.

The NAD trend gained popularity at end of 2013 with a high-profile paper by Harvard’s David Sinclair and colleagues. Remember, Sinclair achieved fame in the mid-2000s for research on yeast and mice that implied the red wine ingredient Resveratrol mimics anti-aging effects of calorie restriction. This time his lab made headlines by reporting that the Mitochondria in muscles of elderly mice were restored to a youthful state after just a week of injections with NMN (Nicotinamide Mononucleotide), a molecule that naturally occurs in cells and, like NR, increases levels of NAD.

Of note: Muscle strength did not increase in the NMN-treated mice—the researchers hypothesized that one week of treatment wasn’t enough to accomplish that in spite of signs that their age-related mitochondrial deterioration was reversed.

NMN isn’t available as a consumer product. But Sinclair’s report generated enthusiasm about NR, which was already on the market as a supplement called Niagen. Niagen’s manufacturer, ChromaDex, a publicly traded Irvine, Calif., company, sells it to various retailers, which market it under their own brand names. In the wake of Sinclair’s paper, Niagen was praised by the media as a possible chartbuster.

In early February, Elysium Health, a startup cofounded by Sinclair’s former mentor, MIT Biologist Lenny Guarente, joined the NAD game by debuting another supplement with NR. Christened Basis, it’s only offered online by the company. Elysium is taking precautions with regards to scientific credibility. Its website boasts a dream team of advising scientists, including five Nobel Laureates and other big names such as the Mayo Clinic’s Jim Kirkland, a leader in Geroscience, and Biotech pioneer Lee Hood. Currently, there isn’t a startup with more stars on its roster.

Shortly thereafter, ChromaDex reaffirmed its first-comer status in the NAD game by revealing that it had conducted a clinical trial validating that “a single dose of NR resulted in statistically significant increases” in NAD in humans—the first evidence that supplements could truly boost NAD levels in human beings. Details of the study won’t be out until it’s reported in a peer-reviewed journal, the company said. (ChromaDex also brandishes Nobel credentials: Roger Kornberg, a Stanford professor who won the Chemistry prize in 2006, chairs its scientific advisory board. He’s the son of Nobel Laureate Arthur Kornberg, who, ChromaDex proudly notes, was among the first scientists to study NR some 60 years ago.)

The NAD results merge into a related story about enzymes called Sirtuins, which Guarente, Sinclair and other researchers have implicated as key players in conferring the longevity and health benefits of calorie restriction. Resveratrol, the wine ingredient, is thought to stimulate one of the Sirtuins, SIRT1, which appears to help protect mice on high doses of Resveratrol from the negative effects of high-fat diets. An abundance of other health benefits have been attributed to SIRT1 activation in hundreds of studies, including several small human trials.

This is the NAD correlation: In 2000, Guarente’s lab reported that NAD fuels the activity of Sirtuins, including SIRT1—the more NAD there is in cells, the more SIRT1 does beneficial things. One of those things is to induce formation of new Mitochondria. NAD can also activate another Sirtuin, SIRT3, which is believed to keep Mitochondria functioning properly.

The Sinclair group’s NAD paper garnered attention in part because it demonstrated a unique way that NAD and Sirtuins work together. The researchers discovered that cells’ nuclei send signals to Mitochondria that are needed to maintain their normal operation. SIRT1 helps insure the signals get through. When NAD levels drop, as they do with aging, SIRT1 activity falls off, which in turn makes the crucial signals fade, leading to mitochondrial dysfunction and all the ill effects that go with it.

NAD boosters might work collaboratively with supplements like Resveratrol to help revitalize Mitochondria and stave off diseases of aging. Elysium is banking on this potential synergy—its NR-containing supplement includes a Resveratrol-like substance called Pterostilbene (pronounced tero-STILL-bean), which is found in blueberries and grapes.

Why choose Pterostilbene in lieu of Resveratrol?

While Resveratrol has dominated the anti-aging spotlight over the past decade, nameless researchers in places like Oxford, Miss., have quietly shown that Pterostilbene is a kind of extra-robust variant of Resveratrol. The Pterostilbene molecule is virtually identical to Resveratrol’s, with the exception of a few variances that make it more “bioavailable” (animal studies indicate that about four times as much ingested Pterostilbene gets into the bloodstream as Resveratrol). Test-tube and rodent studies also suggest that Pterostilbene is more powerful than Resveratrol when it comes to enhancing brain function, staving off various kinds of cancer and preventing heart disease.

Elysium isn’t the only Pterostilbene merchant. As a matter of fact, ChromaDex also provides Pterostilbene for supplements separately from Niagen.

Prior to Sinclair’s paper, researchers had shown in 2012 that when given doses of NR, mice on high-fat diets gained 60% less weight than they did on the same diets without NR. Furthermore, none of the mice on NR exhibited signs of diabetes, and their energy levels improved. The scientists reportedly characterized NR’s effects on metabolism as “nothing short of astonishing.”

The dearth of human data is cause for hesitation.  Despite Nobel Laureates involvement, it’s advisable to wait until more is known before rushing out to purchase some NR.  There’s a good chance more data will be revealed, based on the mounting excitement about NAD.

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