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Tue, Sep 12 8:00am · Mayo Clinic researchers review the clinical potential of senolytic drugs on aging

Researchers are moving closer to realizing the clinical potential of drugs that have previously been shown to support healthy aging in animals. In a review article published online in the Journal of the American Geriatrics Society, Mayo Clinic aging experts say that, if proven to be effective and safe in humans, these drugs could be “transformative” by preventing or delaying chronic conditions as a group instead of one at a time.

The drugs being tested are called senolytic agents, because they target senescent cells. These are cells that have stopped dividing and secrete toxic chemicals that damage adjacent cells. Accumulation of senescent cells, which increases with age, is associated with chronic conditions, including diabetes, cardiovascular disease, most cancers, dementia, arthritis, osteoporosis, and frailty.

Researchers at Mayo Clinic’s Robert and Arlene Kogod Center on Aging  developed the first senolytic drugs to target these harmful cells. In a recent study led by The Scripps Research Institute, Mayo Clinic researchers and others confirmed that the senolytic drugs discovered at Mayo effectively clear senescent cells while leaving normal cells unaffected. The study, which was published in Nature Communications, also describes a new screening platform for finding additional senolytic drugs that will more optimally target senescent cells. The platform, together with additional human cell assays, identified and confirmed a new category of senolytic drugs, which are called HSP90 inhibitors.

James Kirkland, M.D., Ph.D., director of the Kogod Center on Aging, explains that the platform will help researchers quickly identify additional drugs that target aging processes, which he says will be useful as they move closer to clinical intervention. “We’ve moved rapidly in the last few years, and it’s increasingly looking like senolytic drugs, including the recently discovered HSP90 inhibitors, are having an impact on a huge range of diseases. We will need to continue to test whether there are more optimal drugs or drug combinations to broaden the range of senescent cell types targeted.”

As senolytic drugs and drug combinations are discovered, researchers then will need to test them in clinical trials. Dr. Kirkland and authors on the review article, “The Clinical Potential of Senolytic Drugs,” acknowledge the unique challenges of these trials in the field of aging, including the difficulty of testing long-term end points, such as life span and health span – the healthy, productive years of life. Outcomes such as effects on median or maximum lifespan cannot be tested feasibly in humans. That’s why Mayo Clinic and others are using new clinical trial paradigms, which include testing the effects of senolytic drugs on co-morbidity, accelerated aging like conditions, diseases with localized accumulation of senescent cells, potentially fatal diseases associated with senescent cell accumulation, age-related loss of physiological resilience, and frailty. The authors also call out a need for additional geriatricians with research training to lead future clinical trials.

“The emerging repertoire of senolytic drugs shows that they are having an impact on a huge range of diseases,” says Dr. Kirkland. “Our goal is to achieve the same success in humans as we have in preclinical animal models in efforts to prevent or delay the conditions associated with aging.”

Funding for the review article was provided by the National Institutes of Health; the American Federation for Aging Research; Aldabra Biosciences; The Connor Group; the Noaber Foundation, the Ted Nash Long Life Foundation, the Glenn Foundation; and Robert and Arlene Kogod Center on Aging, Mayo Clinic.

Additional authors on the review are:

  • Tamara Tchkonia, Ph.D., Mayo Clinic
  • Yi Zhu, Ph.D., Mayo Clinic
  • Laura Niedernhofer, M.D., Ph.D., The Scripps Research Institute
  • Paul Robbins, Ph.D., The Scripps Research Institute

The research for the study published in Nature Communications was supported by the National Institutes of Health; The Connor Group; the Noaber Foundation, the Ted Nash Long Life Foundation, and the Glenn Foundation; the American Federation for Aging Research; and Aldabra Biosciences.

In addition to Dr. Kirkland, others on the research team are:

  • Heike Fuhrmann-Stroissnigg, The Scripps Research Institute
  • Yuan Yuan Ling, The Scripps Research Institute
  • Jing Zhao, The Scripps Research Institute
  • Sara McGowan, The Scripps Research Institute
  • Yi Zhu, Ph.D., Mayo Clinic
  • Robert Brooks, The Scripps Research Institute
  • Diego Grassi, The Scripps Research Institute
  • Siobhan Gregg, University of Pittsburgh School of Medicine
  • Jennifer Stripay, University of Pittsburgh School of Medicine
  • Akaitz Dorronsoro, The Scripps Research Institute
  • Lana Corbo, The Scripps Research Institute
  • Priscilla Tang, The Scripps Research Institute
  • Christina Bukata, The Scripps Research Institute
  • Nadja Ring, International Centre for Genetic Engineering and Biotechnology
  • Mauro Giacca, International Centre for Genetic Engineering and Biotechnology
  • Xuesen Li, The Scripps Research Institute
  • Tamara Tchkonia, Ph.D., Mayo Clinic
  • Laura Niedernhofer, The Scripps Research Institute
  • Paul Robbins, The Scripps Research Institute

Mayo Clinic and Drs. Kirkland, Tchkonia and Zhu have a financial interest related to this research.

Thu, Aug 24 8:00am · UNTANGLING ALZHEIMER'S--Mayo Clinic's approach

Families living with Alzheimer’s disease woke to devastating newspaper headlines recently: Another highly touted drug failed in clinical trials.

Drugmaker Eli Lilly’s EXPEDITION3 trial tested an antibody, a molecule used by the immune system to fight off disease, called solanezumab.

This experimental drug sought to remove harmful proteins in the brain that become building blocks for amyloid, a molecular hallmark of Alzheimer’s disease. Like a garden mildew that deprives a leaf of key nutrients, amyloid proteins form into sticky clumps of plaque that kill brain cells, preventing the formation of new memories.

Not faulting the drugmaker for its efforts, media reports of the trial results nevertheless expressed varying degrees of desperation, revealing the high stakes nature of finding a true cure for Alzheimer’s disease. Without an effective intervention, the number of Americans age 65 and older living with Alzheimer’s is estimated to nearly triple, from 5.2 million today to 13.8 million in 2050, according to the Alzheimer’s Association. Meanwhile, U.S. health care costs related to the disease are expected to increase by 360 percent to more than $1 trillion, putting Medicare, Medicaid and the global economy in a vice grip.

Despite the setbacks and statistics, one person maintaining his optimism is Mayo neurologist Ronald C. Petersen, M.D., Ph.D. In addition to directing the Mayo Clinic Alzheimer’s Disease Research Center, Dr. Petersen has been appointed to numerous national and international advisory boards charged with finding an answer to what he calls the defining disorder of our generation.

With that insider perspective, Dr. Petersen has a clear message for patients and families who read the latest Alzheimer’s news with trepidation: Don’t give up hope.

KNOWING MORE, TRYING MORE

Ronald C. Petersen, M.D., Ph.D., is the Chester and Debbie Cadieux Director of Mayo Clinic Alzheimer’s Disease Research Center and the director of the Mayo Clinic Study of Aging. He is recognized as a Mayo Clinic Distinguished Investigator and holds the Cora Kanow Professorship in Alzheimer’s Disease Research.

“We know so much more about the biology of the disease than we formerly did — that is, we know about amyloid protein, how it’s deposited, where it is, and now, to a large extent, how to get rid of it,” Dr. Petersen says.

He notes that several clinical trials planned or underway take different approaches to targeting the root causes of Alzheimer’s disease. Like the Eli Lilly trial, some clinical trials involve antibodies that attack amyloid protein at different points in its development. Other trials investigate enzyme inhibitors that prevent the amyloid development process altogether.

While amyloid has received the most attention from biotech companies, Dr. Petersen acknowledges that the recent string of drug failures may result in more treatments that target a protein called tau. If amyloid is a garden mildew caked onto a plant’s leaves, tau is an invasive weed that forms tangles in the brain and blocks necessary nutrients from getting to brain cells. The affected areas are generally critical to memory development.

Exploring new ideas is a good thing, according to Dr. Petersen. He says that the research community will benefit from diversifying its treatment strategies to address the complexity of Alzheimer’s disease.

“Alzheimer’s is not a single cell that has failed and could be replaced and cured with stem cells,” Dr. Petersen says. “Alzheimer’s is a system failure in the brain.”

But there’s another question, one that’s vitally important for a disease that doesn’t usually strike until after age 65: How can research predict if and when that system will fail?

“A big criticism is that we’re starting too late in the disease process,” Dr. Petersen says. In many clinical trials, patients already must have documented presence of amyloid in the brain and clinical symptoms of Alzheimer’s disease to meet enrollment criteria. At that point, the damage in the brain may be irreversible, rendering promising therapies useless.

“It’s as if we’re lowering your cholesterol as you’re having a heart attack, not 10 to 15 years earlier,” Dr. Petersen says. “Because of the possibility that some of these drugs actually work but are being used too late in the disease process, the field is looking toward earlier and earlier intervention.”

EXPERTISE IN DEMAND

As pressure mounts to find the optimal treatment window for Alzheimer’s disease, scientists are turning to Mayo Clinic for expertise that is now in high demand: Mayo’s unmatched research capabilities in prediction and prevention.

To design more effective clinical trials and recruit the right patients, scientists need risk models that predict who will develop Alzheimer’s disease and at what point in their life span. These risk models require imaging and biological data on large populations of people as they age over time.

Because of a unique medical records linkage system in Olmsted County, Minnesota, Mayo Clinic can conduct this population-level research through the Mayo Clinic Study of Aging. The study recruits a random sample of local study volunteers from 30 to 90 years old to better understand amyloid, tau and other dementia-related biomarkers long before an individual becomes symptomatic.

Information from the Mayo Clinic Study of Aging that is becoming more valuable to the research community includes population data on individuals who are just barely below certain biomarker-positive thresholds — for example, patients who today would test negative for amyloid but eventually become amyloid positive in a defined time frame.

“This is where a lot of Mayo’s research comes into play: Where in the life span do things start to go wrong? We can then relay this information to the therapeutic community. Given this person with this background, you need to intervene at age 50, 55 or 60.”

A SILVER LINING

Coupling the progress in new therapies with growing momentum behind early intervention, Dr. Petersen sees a silver lining in the solanezumab trial. “Consider that the solanezumab trial enrolled people who had documented amyloid in the brain.

That was one of the first studies to do that,” Dr. Petersen says. “Thanks to advances in biomarker development, going forward, almost all studies will ask patients, ‘Do you have the target that the drug is shooting at?’ If yes, then the question will become, ‘When should we intervene?’ Already, trials are moving earlier and earlier.”

As clinical trials become more sophisticated, definitive cures for Alzheimer’s disease will come into view, Dr. Petersen believes.

“For instance, if research showed antibodies really work, we’d develop a vaccine against Alzheimer’s disease. That way, patients don’t need invasive and expensive infusions for the rest of their life starting at age 45 or so,” Dr. Petersen says. “With a vaccine, the body develops its own antibodies — just like it does with the polio vaccine.”

With no shortage of imagination or perseverance, the research community will push forward, Dr. Petersen concludes. And the day will come when newspapers hail a different headline: a long-awaited turning point in the journey to end Alzheimer’s.

TRANSLATIONAL SCIENCE SUPERSTARS

Left to right: Walter A. Rocca, M.D., Michelle M. Mielke, Ph.D., Clifford R. Jack, M.D., Ronald C. Petersen, M.D., Ph.D., David S. Knopman, M.D., Rosebud O. Roberts, M.B., Ch.B., Bradley F. Boeve, M.D., Val Lowe, M.D.

Ronald C. Petersen, M.D., Ph.D., is quick to point out he’s no lone track star when it comes to achieving Mayo Clinic’s leading reputation in Alzheimer’s disease research.

If anything, Mayo’s physicians and scientists who study Alzheimer’s and dementia function like an all-star relay team. With each lap around the track, experts in neuropathology, basic science, genetics, neuroimaging and population science pass discoveries seamlessly to one another so each can apply the rigor of their specialty to advance potential breakthroughs across the ultimate finish line: patient application.

This is called translational science, and it makes much of Dr. Petersen’s work in population science possible. For instance, studying amyloid and tau in Mayo Clinic Study of Aging participants has required significant advances in neuroimaging so researchers can see the progression of these proteins over time in living people as they age. Those advances in neuroimaging are built off the work of basic scientists who reveal the true nature of disease culprits like amyloid, tau and genetic factors.

And finally, pathologists who examine postmortem brain tissues find the initial genetic or biomarker anomalies that kick the entire team into action.

“People always talk about translational research — taking basic science findings from the laboratory and applying them in the clinic to patients,” Dr. Petersen says. “This is really what Mayo is built to do.”

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You can find out about more clinical trials on Mayo’s clinical trials website, including many trials focusing on Alzheimer’s disease.

Mayo Clinic is a nonprofit organization committed to clinical practice, education and research, providing expert, whole-person care to everyone who needs healing. This article was originally featured on the philanthropic site “You Are…the campaign for Mayo Clinic.”

Wed, Aug 23 9:00am · Researchers report link between cells associated with aging and bone loss

Mayo Clinic researchers have reported a causal link between senescent cells – the cells associated with aging and age-related disease – and bone loss in mice. Targeting these cells led to an increase in bone mass and strength. The findings appear online in Nature Medicine.

Low bone mass and osteoporosis are estimated to be a major public health threat for almost 44 million U.S. women and men 50 and older, according to the National Osteoporosis Foundation. Bone is a living tissue that is constantly being broken down and replaced. Osteoporosis occurs when the creation of new bone doesn’t keep up with the removal of old bone.

“While we know from previous work that the accumulation of senescent cells causes tissue dysfunction, the role of cell senescence in osteoporosis up to this point has been unclear,” says Sundeep Khosla, M.D., director of the Aging Bone and Muscle program at Mayo Clinic’s Robert and Arlene Kogod Center on Aging. “The novelty of this work for the bone field lies in the fact that, rather than targeting a bone-specific pathway, as is the case for all current treatments for osteoporosis, we targeted a fundamental aging process that has the potential to improve not only bone mass, but also alleviate other age-related conditions as a group.”

In the study, researchers used multiple approaches to target senescent cells in mice with established bone loss between 20 and 22 months of age. That’s the equivalent of over age 70 in humans. Approaches included using:

  • A genetic model where senescent cells can be killed off
  • A pharmacological approach, where senolytic drugs previously developed at Mayo Clinic eliminate senescent cells
  • A Janus kinase inhibitor – a drug that blocks the activity of Janus kinase enzymes – to eliminate the toxic products produced by senescent cells

“The effects of all three approaches on aging bone were strikingly similar,” says Dr. Khosla. “They all enhanced bone mass and strength by reducing bone resorption but maintaining or increasing bone formation, which is fundamentally different from all current osteoporosis drugs.”

The benefits on bone found in elderly mice were not evident in younger mice. That, coupled with the finding that the senolytic drugs were effective when given only intermittently, supports the link between senescent cells and age-related bone loss. Researchers administered a senolytic drug combination (dasatinib and quercetin) once per month to eliminate senescent cells.

“Even though this senolytic drug combination was only present in the mice for a couple of hours, it eliminated senescent cells and had a long-lasting effect,” says James Kirkland, M.D., Ph.D., director of the Kogod Center on Aging and co-corresponding author of the study. “This is another piece of the mounting evidence that senolytic drugs are targeting basic aging processes and could have widespread application in treating multiple chronic diseases.”

Drs. Kirkland and Khosla say that being able to administer the drugs intermittently poses less risk for side effects than with drugs that must be taken daily. Also, current therapeutics in the bone field that treat bone loss “work against themselves,” meaning that, if they decrease resorption, they also decrease formation. In this study, the senolytic drugs decreased bone resorption, while maintaining or increasing bone formation.

“With the aging of the population in the U.S. and around the world, age-related bone loss is going to continue to be an enormous public health problem, and patients with osteoporosis have a higher risk for other age-related comorbidities,” says Dr. Khosla. “By combining the knowledge of three separate labs and enlisting the expertise of several others in a true team science approach, we were able to collaborate and make these findings possible. We need to continue to pursue these potential interventions that target fundamental aging mechanisms as, hopefully, an eventual way to reduce the burden of fractures and other conditions, such as cardiovascular dysfunction, diabetes and frailty.”

The research was supported by the National Institute on Aging, The Connor Group, the Noaber Foundation, the Ted Nash Long Life Foundation, the Glenn Foundation, Robert and Arlene Kogod Center on Aging, Mayo Clinic, and the American Federation for Aging Research.

Others on the research team from Mayo Clinic are:

  • Joshua Farr, Ph.D.
  • Ming Xu, Ph.D.
  • Megan Weivoda, Ph.D.
  • David Monroe, Ph.D.
  • Daniel Fraser, Ph.D.
  • Jennifer Onken
  • Brittany Negley
  • Jad Sfeir, M.D.
  • Mikolaj Ogrodnik
  • Christine Hachfeld,
  • Nathan LeBrasseur, Ph.D.
  • Matthew Drake, M.D., Ph.D.
  • Robert Pignolo, M.D., Ph.D.
  • Tamar Pirtskhalava, Ph.D.
  • Tamara Tchkonia, Ph.D.
  • Merry Jo Oursler, Ph.D.

Mayo Clinic and Drs. Kirkland, Pirtskhalava and Tchkonia have a financial interest related to this research.

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Wed, Jun 21 8:00am · Cellular Senescence Research Highlighted at World Science Festival

Mayo Clinic’s aging research was among the featured topics at the 10th annual World Science Festival in New York earlier this month.

James Kirkland, M.D., Ph.D., director of the Robert and Arlene Kogod Center on Aging, shared details about cell senescence breakthroughs and next steps in the field during a 90-minute session called “Engineering Immortality?” The discussion also included research related to bioengineering, cell biology, medicine and ethics.

The World Science Festival is a five-day gathering that celebrates science and features programs that explore innovative ideas across fields. Sessions took place at locations throughout the city, including Times Square, parks, museums, galleries and performing art venues. Dr. Kirkland noted that one of the aims of the festival was to encourage young people to pursue the sciences and is optimistic about the future of aging researchers.

“Increasingly, younger people who are choosing careers and making the decision about where to invest their future are recognizing the excitement of understanding the fundamental aging processes and that by developing interventions that target them we may be able to have a substantial, or even transformative, impact on the health of an entire population,” says Dr. Kirkland.

Other participants in the “Engineering Immortality?” session included: Joseph Fins, M.D., a professor of medical ethics and chief of the division of medical ethics at Weill Cornell Medical College; Jamie Metzl, a senior fellow for technology and national security of the Atlantic Council, novelist, blogger, syndicated columnist, media commentator, and expert in international affairs and biotechnology policy; and Doris Taylor, Ph.D., director of regenerative medicine research and director of the center for cell and organ biotechnology at the Texas Heart Institute in Houston.

Mon, Mar 20 8:00am · Nathan LeBrasseur, Ph.D., receives Director’s Award

The Mayo Clinic Robert and Arlene Kogod Center on Aging is pleased to announce that Nathan LeBrasseur, Ph.D., has received the 2016 Director’s Award for his work as a researcher and program director of the Healthy Aging and Independent Living (HAIL) program.

The Director’s Award is presented to investigators who show achievement in the following areas:

  • Contribution to aging research and advocacy
  • Landmark papers and achievements on aging
  • Citizenship and education

Dr. LeBrasseur oversees multidisciplinary efforts to extend health span and promote autonomy in older adults. The HAIL program is designed to translate discoveries in the biology of aging from the laboratory bench to the clinical bedside. Ongoing work includes blood- and performance-based measures of health and function, pharmacological interventions targeting mechanisms of aging, and rapidly scaled and implemented means to promote autonomy and well being in older adults.

“Dr. LeBrasseur brings a unique and valuable perspective to the Center,” says James Kirkland, M.D., Ph.D., Director of the Center on Aging. “As the director of the Healthy Aging and Independent Living program, he has done an excellent job of bringing researchers together and setting up collaborations. He has published a number of important studies including breakthrough findings recently published in Nature Communications.”

In this study, Dr. LeBrasseur and others demonstrate a link between the biology of aging and idiopathic pulmonary fibrosis. Idiopathic pulmonary fibrosis occurs when lung tissue becomes damaged and scarred. The thickened, stiff tissue makes it difficult for the lungs to work properly, causing shortness of breath, fatigue, declining quality of life, and, ultimately, death. Life expectancy after diagnosis is between three to five years and there are currently no effective treatment options.

Dr. LeBrasseur and his team, which included experts across specialties at Mayo Clinic, as well as Newcastle University Institute for Ageing and The Scripps Research Institute, studied the lung tissue (made available by the National Institutes of Health) of healthy individuals and of persons with mild, moderate and severe idiopathic pulmonary fibrosis.

Researchers found that the markers of cellular senescence, a process triggered by damage to cells and linked to aging, were higher in individuals with idiopathic pulmonary fibrosis and further increased with disease severity. Then, they demonstrated that factors secreted by senescent cells could drive inflammation, abnormal tissue remodeling, and fibrosis, which are hallmarks of the disease. In a mouse model of the human disease, Dr. LeBrasseur’s team showed that both suicide gene- and drug-mediated removal of the senescent cells from unhealthy mice improved clinically relevant measures of lung function and physical health, such as exercise capacity on a treadmill.

While further studies are needed, researchers hope that targeting senescent cells could be a viable treatment option for individuals who suffer from idiopathic pulmonary fibrosis.

Dr. LeBrasseur was also senior author on a study showing that poor diet and lack of exercise accelerate the accumulation of harmful senescent cells and the onset of age-related conditions in mice, published in Diabetes, as well as a study where his team developed a way to accurately measure a circulating factor, called GDF11, to better understand its potential impact on the aging process, published in Cell Metabolism. The latter study represents an effort to identify “frail” patients at risk for adverse health outcomes following medical procedures, such as surgery or chemotherapy. Dr. LeBrasseur and his team believe that their work can help clinicians leverage: the right treatment for the right patient at the right time; prehabilitation strategies to optimize presurgical resilience; or more robust transitional care plans for vulnerable older adults.

 

Jan 19, 2016 · Mayo Clinic and Others Call Aging into the Limelight

James Kirkland, M.D., Ph.D., Director of the Mayo Clinic Robert and Arlene Kogod Center on Aging

James Kirkland, M.D., Ph.D., Director of the Mayo Clinic Robert and Arlene Kogod Center on Aging

Aging: It’s a topic that impacts each and every one of us. It’s the single greatest risk factor for most chronic diseases, which account for the majority of morbidity and health care expenditures in developed nations. In a recently released book, “Aging: The Longevity Dividend,” experts in the field explore the topic and concurrent research in-depth and call for aging to be brought into the limelight.

Linda Partridge of the Max Planck Institute for Biology of Ageing synthesizes the opportunity at hand in a Nature review of the book. “Basic science and human demographic studies have delivered an unprecedented opportunity to tackle the comorbidities of later life,” says Partridge. “To translate these discoveries into drugs and changes in medical practice, and to reap the consequent economic benefits, will require some radical changes: breaking down disease siloes, training a new generation of physicians and scientists capable of working across disciplinary boundaries, and altering public attitudes and policy.”

This may seem like a tall order, but researchers at the Mayo Clinic Robert and Arlene Kogod Center on Aging, including James Kirkland, M.D., Ph.D., have devoted their livelihood to this very goal. Dr. Kirkland, Director of the Center on Aging, is an editor on “Aging: The Longevity Dividend” along with S. Jay Olshansky, Ph.D., of the University of Illinois at Chicago, and George M. Martin, M.D., of the University of Washington. In a chapter titled, “Translating the Science of Aging into Therapeutic Interventions,” Dr. Kirkland addresses challenges of developing new drugs to target aging.

“While the challenges may be many, we have a great appreciation for the enormity of the human, social and fiscal implications of increasing health span – the healthy, productive time in life – and improving the quality of life for older adults,” says Dr. Kirkland. “This book sets the stage for the next evolution in the field of aging.”

The Center on Aging brings together basic scientists and clinicians to focus on delaying the aging process as a whole, as opposed to tackling individual age-related diseases. Recent research from the Center supports the possibility that using specific drugs to target senescent cells – cells that contribute to frailty and disease associated with age – could eliminate or delay diseases associated with aging. To learn more about age-related research, visit Mayo Clinic’s News Network.

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