Uncovering clues about the aging process

Volume 8, Issue 1
Summary illustration - CPR Uncovering clues about the aging process

Summary

Researchers at the Mayo Clinic Robert and Arlene Kogod Center on Aging have created genetically engineered mice that are healthier than normal mice in their sunset years. Their findings, which made worldwide news, have revealed amazing insights about the aging process.

It had been only two days, but most of the cells in the lab dishes were dead or dying. Mayo Clinic researchers marveled at this. It was one of those rare, revelatory moments in science. In fact, it turned out to be one of the top scientific breakthroughs of the year.

The team followed up with animal studies and soon realized they were onto something with huge potential. Their experiments with mice had shown that they could delay the onset of age-related illness in the animals. The genetically modified mice exhibited no cataracts or curved spines. Instead, they had larger than normal muscle fibers, more fatty tissue and better exercise performance than did normal mice. It all had to do with those cells: senescent cells — cells related to aging. Mayo Clinic researchers had discovered how to eliminate those cells from the equation.

In a groundbreaking paper published in the journal Nature in late 2011, the Mayo Clinic researchers reported that their study showed that eliminating senescent cells prevents or delays some age-related disorders in genetically modified mouse models. Although the mice didn't live longer than average, they were healthier for more of their life span than were their normal counterparts. The study may someday lead to treatments that help people stay healthier as they age. As a very rough analogy, Mayo Clinic researcher Jan van Deursen, Ph.D., a Vita Valley Professor of Cellular Senescence and senior investigator on the study, likened the mice to a person who is 90 but seems more like a 70-year-old. Future studies may involve specific age-related diseases, such as Alzheimer's disease, heart attack, stroke, cancer and diabetes.

Kogod Center on Aging fosters research

Darren Baker, Ph.D., and Jan van Deursen, Ph.D.

Darren Baker, Ph.D., and Jan van Deursen, Ph.D.

Aging Center Director James Kirkland, M.D., Ph.D.

James Kirkland, M.D., Ph.D., Aging Center director and Noaber Foundation Professor of Aging Research

With an aging population, the United States faces increasing age-related health problems. By 2f030, nearly 1 in 5 Americans will be over age 65. More than 90 percent of people over 65 have at least one cataract, often requiring surgery to restore vision. And age-related loss of muscle mass and strength can lead to frailty, falls and other injuries.

The Mayo Clinic Robert and Arlene Kogod Center on Aging is an innovative center that's well suited to develop research and then translate it into clinical practice, where patients may benefit if age-related conditions can be delayed or better managed when they do occur.

"We view aging as a major driver of illness and health care costs," says James L. Kirkland, M.D., Ph.D., a co-author of the senescent cell study and director of the Kogod Center. "We're asking if we can reduce the period of illness toward the end of life."

Under the auspices of the Kogod Center, nearly 100 scientists and clinicians from all three Mayo Clinic campuses and every medical discipline contribute knowledge and innovation to age-related conditions. They range from the muscle research of Sreekumaran Nair, M.D., Ph.D., to the osteoporosis work of Sundeep Khosla, M.D., to the clinical and population studies of Nathan K. LeBrasseur, Ph.D., to the Alzheimer's research of Ronald C. Petersen, M.D., Ph.D.

"We need geriatricians who understand the basic science of aging and biologists who understand the clinical outcome," Dr. Kirkland says. "Our broad focus on aging can also streamline research. As we all work toward understanding the intersection between the fundamental mechanism of aging and clinical treatment to delay age-related diseases as a whole, we can have a much more significant impact than attacking each condition one at a time."

The Kogod Center on Aging also fosters global collaboration by hosting annual conferences that bring together international researchers and by bringing in international graduate students. For example, one of the authors of the Nature paper is Tobias Wijshake, a doctoral student at the University of Groningen in the Netherlands, who is doing half of his degree work at Mayo Clinic. "We hope that Tobias is only the first of many participants in a collaborative effort between the University of Groningen and Mayo Clinic," says Mayo cellular biologist Darren J. Baker, Ph.D., first author of the Nature aging paper.

Wijshake was eager for the opportunity. "I am very interested in aging research, and the van Deursen lab has a very good reputation," he says. "There's a chance to develop yourself here, so of course I wanted to come."

Mayo Clinic researchers credit these many opportunities for collaboration with promoting scientific discovery. "A center like Kogod creates a common goal. That's something dynamic," Dr. van Deursen says. "If you are a scientist, you come to your lab and you may have little connection with what's around you. You don't talk to the neighbors. Here at Mayo, you have a neighborhood. That's one of the values here — friends and colleagues who behave in a collegial fashion and offer reciprocal help."

Dr. van Deursen, one of the most distinguished scientists in the field of aging, began his career in his native Netherlands and joined Mayo Clinic in 1999. His mentee, Dr. Baker, started as a technician in Dr. van Deursen's lab and earned his doctorate in 2008. Their work is typical of the mentoring relationships that help drive Mayo Clinic's highly successful research culture.

"Mayo promotes mentoring," Dr. van Deursen says. "A mentoring program, where you can go all the way from a lab technician to a primary investigator, is quite unique. It fits the Mayo philosophy."

Technical wizardry

Mouse cells forced into senescence either by high cancer-promoting signals or exhaustion of proliferation ability turn green and actively express galactosidase.

Mouse cells forced into senescence either by high cancer-promoting signals or exhaustion of proliferation ability turn green and actively express galactosidase.

The clever development of the transgenic animal at the heart of this research on aging is the result of collaboration, hard work and stunning technical wizardry. Dr. Kirkland's work has made significant contributions to the team effort. He has devoted much of his career to understanding the mechanisms underlying changes in senescent cells in fat tissue that promote inflammation and accelerate aging. To prove that these cells really do accelerate aging, they would need to be eliminated from the body and the responses observed.

In 2002, during a study of tumors in lab animals, Dr. Baker noticed that mice bred to be deficient in a protein called BubR1 seemed to age faster than normal, developing cataracts and hunched spines. It was a crucial observation by the then-lab technician, leading to the discovery that declining levels of BubR1 play a role in aging. The van Deursen lab then engineered a BubR1-deficient mouse model that aged five times faster than normal.

The aging mice produced high levels of a tumor-suppressing molecule called p16Ink4a. Further tests in 2008 (Nature Cell Biology) yielded another significant finding: Higher production of p16 accelerates cellular senescence in lab mice. Cellular senescence occurs when cells age to the point that they no longer undergo cell division. The immune system regularly sweeps out these dysfunctional cells but becomes less effective at doing so over time.

"These senescent cells were known to accumulate in the body of a mouse and a human," Dr. van Deursen says. "But what they were actually doing there — whether and how they would contribute to aging — was still unresolved."

Age-defying outcomes

Mouse cells forced into senescence either by high cancer-promoting signals or exhaustion of proliferation ability turn green and actively express galactosidase.

Cells forced into senescence by rosiglitazone, as evidenced by galactosidase expression, are selectively killed in engineered cells with the addition of the synthetic drug AP20187.

Aging mouse.

The aging mouse.

The 2008 study pointed to cellular senescence as a prime suspect in aging. "We started to ask whether eliminating these p16-expressing senescent cells would be beneficial," Dr. Baker says.

The Mayo Clinic team's next feat of technical wizardry was to create a new gene that accelerates cellular senescence. The gene, called INK-ATTAC, is turned on exclusively in cells where p16 is turned on. Researchers inserted the new gene into the chromosomal material of the rapidly aging BubR1-deficient mice. The outcome, they said, was astounding. These transgenic lab mice age rapidly and have senescent cells that can be eliminated at any time by administering a drug that triggers the cells to kill themselves. The results, reported in the Nature paper, showed that the mice seemed to defy some characteristics of aging — they maintained muscle mass, performed better in exercise tests, and didn't develop cataracts or lose fatty tissue.

"We started the experimental intervention at an early age when a senescent cell would be eliminated as soon as it arose," Dr. Baker says. "So the mice couldn't accumulate these senescent cells."

To determine if aging could be slowed or stopped in mice after it has already begun, the researchers studied 5-month-old mice — the equivalent of middle age in mice — that showed signs of aging. After their interventions to eliminate senescent cells, the cataracts in these mice remained unchanged. However, muscle fiber increased and treadmill performance improved. As with their other experiments, clearing the senescent cells didn't extend life span, but it did improve health.

"The cause of death doesn't seem to be influenced by the removal of senescent cells," Dr. Baker says. "But the health span, the time of life when the animals are healthy and more active, is longer when we remove the cells."

Much work remains before this research can be translated into treatments that benefit humans. Although the mice showed no negative effects from removal of senescent cells, the research was conducted in a pathogen-free lab environment, Dr. Baker notes. Not enough is understood about senescent cells to determine whether removing them from humans might have adverse consequences, and how those consequences might be overcome.

"Eventually, there may be ways to target senescent cells in human beings and eliminate them," Dr. Baker says.

Adds Dr. van Deursen: "Before this study, this was a mysterious group of cells. Now, it's become a little clearer what senescent cells actually do, and how they contribute to the aging process."

The mouse-aging study was supported by the Ellison Medical Foundation, the Noaber Foundation, the Mayo Clinic Robert and Arlene Kogod Center on Aging and the National Institutes of Health. Drs. van Deursen and Kirkland share equally in the intellectual property.