Raffaele Reports — 22 November 2011
Intrigue of the Sleeper Cells

In early November, researchers at the Mayo Clinic’s anti-aging institute announced a landmark study.      They’d figured out a way to rid the aging body of  “senescent” cells—those that are old and broken-down, no longer able to multiply—and the results were dramatic: The participants in the study were able to run longer and stayed remarkably healthy and vital right up until the end of their lives. They didn’t even get cataracts.

Of course, the participants in question were mice.

Still, the findings, reported in the journal Nature on November 2, are legitimately groundbreaking, even if they’re not applicable to humans just yet.  The New York Times, for one, ran the story on its front page. “The findings raise the prospect that any therapy that rids the body of senescent cells would protect it from the ravages of aging,” wrote science writer Nicholas Wade, adding the million-dollar caveat: “But many more tests will be needed before scientists know if drugs can be developed to help people live longer.”

Many more tests, indeed. As Mr. Wade cautioned in a follow-up article today, even if the results are replicated by other researchers, “The experiment was just in mice, and it cleared the cells with a technique that cannot be applied to people.”

So perhaps we should describe this development by borrowing from Stephen Colbert’s notion of “truthiness.” The Mayo study is, shall we say, landmarky.

It’s certainly a long leap between mice and man, and in a study of aging the leap may be even longer because our lives are–especially when the mice are genetically engineered to live fast and die young. Nonetheless, there is some very compelling and highly important news here: The Mayo study marks the first time researchers have been able to completely remove senescent cells from a living creature and demonstrate a cause and effect on aging. The mice didn’t live longer, but they lived far healthier and avoided the infirmities of old age through the last part of their lives. In human terms, it was the equivalent of the difference between spending one’s last decade in failing health and declining function and being strong and vital until the end.  “Their healthspan was extended,” one of the Mayo researchers said of the mice.

A major dose of proof that senescent cells

are culprits in the unregulated inflammation

associated with the diseases of aging

It’s been half a century since a biologist named Leonard Hayflick identified the phenomenon of senescent cells. It had always been assumed that human cells multiply indefinitely, but Hayflick found when he cultured them in his lab that they divided only about 50 times before breaking down. Since cell division is the key to the tissue renewal that in turn keeps us healthy, it’s not surprising that researchers in recent years have established correlations between senescent cells and both aging and cancer.

Unquestionably, the Mayo study will further our understanding of senescent cells. Perhaps, eventually, it will even lead the way to a method of intervening in their deleterious effects, allowing us to forestall the diseases of aging. Indeed, the study dovetails with some of the most striking aspects of the biomarker approach I use in my clinical practice. Senescent cells have been shown to have a particular relationship with the aging of the immune system. And researchers have found that a cell can become senescent when its telomeres—the protective cap at the ends of the cell’s chromosomes—become too short, something that comes with age. These are two of the six biomarkers I use to help assess and improve the way my patients are aging.

We humans have different kinds of senescent cells, and one of the most-studied are called cytotoxic T cells. They have been shown to secrete many inflammatory molecules that cause deterioration of tissue function, and their accumulation with age has been associated with many aspects of the aging process, as well as an increased mortality rate after age 65.

Since 2007, I have been measuring my patients’ senescent T cell counts as a biomarker of how well their immune systems are aging. This coincides with the emergence of new knowledge about the importance of telomere length to aging and how telomeres in turn depend on an enzyme called telomerase. In 2010, collaborating with a group of eminent telomere researchers, I conducted an observational study of my patients who took TA-65, a natural telomerase activator, along with a regimen of nutritional supplements. After one year, we found a 20 percent reduction in senescent cytotoxic T cells in patients who had  a high accumulation of them. These results were published in Rejuvenation Research

While this was not a placebo-controlled trial, it does add credence to the concept that one can reduce senescent cells in particular tissues. We’re now planning two randomized controlled trials to test the effect of TA-65 in older adults and in late-stage cancer patients. (We’re also analyzing our data on other biomarkers of aging performed on the same patient group to see if there was an effect in other aspects of the aging process such as arterial stiffness, bone density, blood glucose and cholesterol levels.)

Senescent cells may not be able to divide

but it seems they still can conquer

Though senescence is generally defined as advanced age and diminished function, it turns out that senescent cells are anything but. Yes, they’re old but they’re still quite active–and not in a good way.  There’s been accumulating evidence that senescent cells play a major role in the chronic and unregulated inflammation common to tissue in older people—“inflammaging,” as it’s been dubbed. Research has shown that some cells become senescent in early adulthood, when the immune system is young and healthy enough to clear them out—an ability that diminishes with age. And the ultimate consequence is age-related diseases ranging from Alzheimer’s to cancer.

But as is often the case, the proof  has been in the eye of the beholder. In an article last year in Cell, for instance, Judith Campisi of the Buck Institute for Age Research posed the question this way:  “Does aging drive inflammation, or does something else cause chronic inflammation, which in turn drives aging?”

The great immediate value of the Mayo Clinic study is that it’s the closest thing we have to a definitive answer to that question. It’s a major dose of proof that senescent cells are culprits in this chronic inflammation of aging. The researchers used mice genetically engineered to age quickly and die young, and treated them with a drug that made their senescent cells self-destruct. The mice whose senescent cells were eliminated were able to run much longer on a treadmill than a control group, and  showed other beneficial effects indicated an intervention in the aging process—a lengthening of healthspan, if not lifespan. That’s a pretty big deal.

The next step for the researchers is to try the method on normal mice and see if they do live longer than those left with their senescent cells. The gene-altering and cell-removal technique can’t be used in people. Instead, researchers will likely aim at better understanding the mechanisms of senescent cells and developing drugs to block their adverse effects, neutralizing them. Unfortunately–you could say unfathomably–three weeks after publishing their initial study, the Mayo researchers were denied funding from the National Institutes of Health for the next phase of research. They’re hopeful of getting private funding.

NIH funding decisions emerge from a rigid peer-review system that allows one dissenter to derail a grant application or even an entire line of scientific inquiry. But the promise of research into senescent cells and aging is hard to argue with. The Mayo study was partially funded by the National Institute on Aging’s Division of Aging Biology, and its director, Felipe Sierra, found the results stirring. “This area has been developing for the last 50 years,” he said. “It’s getting extremely exciting.”   JMR

 

Left: Fat cells of untreated mouse. Right: Much healthier fat cells with senescent cells removed. The fat cells are associated with skin aging.

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THE MAYO CLINIC STUDY: “Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders.” By Darren J. Baker, Tobias Wijshake, Tamar Tchkonia, Nathan K. LeBrasseur, Bennett G. Childs, Bart van de Sluis, James L. Kirkland & Jan M. van Deursen. Nature, Vol. 478 No. 7370, Nov. 3, 2011.

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Joseph Raffaele, MD is an expert in Age Management Medicine, and founder of PhysioAge Medical Group, in New York City. He is also a world-renown speaker, writer, and instructor in Age Management techniques.

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