ROCHESTER, Minn. — A series of Mayo Clinic studies is helping reshape scientists' understanding of senescent, or "zombie," cells — aging cells that no longer divide but remain metabolically active and release inflammatory molecules that contribute to age-related diseases.

Published across Nature journals, the studies authored by scientists within the Robert and Arlene Kogod Center on Aging move the field beyond recognizing that senescent cells contribute to aging. Together, they provide new tools to identify these cells, uncover mechanisms that drive inflammation and explore strategies to reduce their effects in preclinical models. In collaboration with researchers across the U.S., they are part of an ambitious project to map senescent cells across different tissues. The project is called the Cellular Senescence Network (SenNet) Consortium and is funded by the National Institutes of Health Common Fund. Its primary objective is to compile comprehensive atlases of senescent cells within the human body over a lifetime.  

"This body of work is moving the aging field forward to precisely identify, understand and target the specific senescent cells that contribute to age-related dysfunction, which is the necessary groundwork to develop new therapies that support healthy aging," says Marissa Schafer, Ph.D., a Mayo Clinic researcher whose laboratory led several of the studies.

Exploring new therapeutic strategies

Several studies evaluated approaches designed to reduce the burden or harmful effects of senescent cells in preclinical models.

The research examined interventions, including senolytic drugs, a naturally occurring compound found in tomatoes, and genetic approaches that selectively target senescent cells. In aged mice, these strategies reduced measures of inflammation and improved outcomes associated with aging, including physical frailty, brain inflammation and cognitive performance.

Another study identified IL-23R as a potential blood biomarker that could one day help researchers assess biological aging and monitor responses to future therapies.

Although additional research is needed before these findings can be translated to patient care, the studies provide a stronger scientific foundation for developing more targeted interventions for age-related diseases.

Dr. Schafer is the senior author of the following papers:

• "IL-23R is a senescence-linked circulating and tissue biomarker of aging"
• "Spatial mapping and senolytic targeting of senescent and disease-associated microglia in aged mouse brain white matter"

Revealing why senescent cells drive inflammation

Additional studies uncovered previously unknown mechanisms that help explain why senescent cells produce persistent inflammation.

Researchers found that dysfunctional mitochondria — the structures that generate energy inside cells — contribute to inflammation through multiple pathways. One mechanism involves mitochondrial DNA and RNA activating immune signaling. Another shows that mitochondrial metabolism changes how inflammatory genes are activated through epigenetic regulation.

Together, these discoveries identify potential therapeutic targets that could reduce harmful inflammation without necessarily eliminating senescent cells.

João Passos, Ph.D., is the senior author of the following papers:

• "Distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues"
• "Mitochondrial metabolism and epigenetic crosstalk drive SASP"
• "Mitochondrial RNA cytosolic leakage drives the SASP"

A growing body of research

Taken together, these studies advance the field from demonstrating that senescent cells contribute to aging toward understanding which senescent cells matter most, how they drive disease and how they may be targeted more precisely.

Rather than focusing solely on eliminating senescent cells, the research supports a more nuanced approach that aims to identify the biological pathways responsible for harmful inflammation and develop therapies that selectively interrupt those processes.

Darren Baker, Ph.D., a Mayo Clinic researcher, is the senior author of the paper, "Senotypes define the diverse landscape of senescent cells."

The research is part of a larger effort at Mayo Clinic called the Precure Research initiative, which is focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.

Review the studies for a complete list of authors, disclosures and funding.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

• Julie Ferris-Tillman, Mayo Clinic Communications, newsbureau@mayo.edu

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ROCHESTER, Minn. — Researchers have uncovered a previously unknown mechanism that helps aging cells drive the chronic inflammation linked to many age-related diseases. The findings reveal how dysfunctional mitochondria — the cell's energy-producing structures — work with the cell's epigenetic machinery to switch on inflammatory genes, opening the door to a new therapeutic approach for promoting healthier aging.

The study, published in Nature, builds upon years of research showing that senescent, or "zombie," cells accumulate with age. While these cells no longer divide, they remain metabolically active and release a cocktail of inflammatory molecules known as the senescence-associated secretory phenotype, or SASP.

This persistent inflammation is thought to contribute to frailty, cardiovascular disease, cancer, neurodegeneration and other disorders of aging.

"For years, the field has focused on getting rid of senescent cells," says João Passos, Ph.D., a Mayo Clinic researcher and senior author of the study conducted in collaboration with Sanford Burnham Prebys Medical Discovery Institute. "Our strategy has been different. Instead of killing the cells, we asked whether we could switch off the inflammation that makes them harmful."

Previous work from the Passos laboratory demonstrated that damaged mitochondria leak mitochondrial DNA and RNA into the cell, activating immune pathways that trigger inflammation. The new study identifies a second, independent pathway that is equally essential.

"We found that inflammatory signaling alone isn't enough," says Helene Martini, Pharm.D., Ph.D., a Mayo Clinic researcher and first author of the study. "The cells also need a metabolic signal from mitochondria that changes how inflammatory genes are turned on."

The researchers discovered that senescent cells increase production of acetyl-CoA, a molecule generated through mitochondrial metabolism. Acetyl-CoA enables epigenetic modifications — chemical changes that regulate whether genes are switched on or off without altering the DNA sequence itself. These modifications make inflammatory genes more accessible, allowing them to be robustly expressed.

In other words, mitochondrial DNA and RNA provide the inflammatory alarm, while mitochondrial metabolism grants the molecular "permission" needed to fully activate inflammatory genes.

"This is a completely new pathway," says Dr. Martini. "We found that dysfunctional mitochondria can promote inflammation by controlling epigenetic switches that turn inflammatory genes on."

The team also identified a promising therapeutic target: a mitochondrial citrate transporter known as SLC25A1. Blocking this transporter reduced the supply of acetyl-CoA, limiting activation of inflammatory genes even though the initial immune signals remained present. Together, these findings reveal a previously unrecognized control point that could be exploited to promote healthier aging.

The research is part of a larger effort at Mayo Clinic called the Precure Research initiative, which is focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.

Review the study for a complete list of authors, disclosures and funding.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

• Julie Ferris-Tillman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu

The post Scientists identify new mitochondrial pathway linked to harmful inflammation in aging appeared first on Mayo Clinic News Network.

Mayo Clinic researchers are uncovering the earliest shifts in disease biology — long before symptoms appear — revealing how disease takes root and opening new possibilities to change its course. 

By the time a disease is diagnosed, it may have been developing silently for years. Along the way, the body leaves clues: proteins shift, metabolism changes, immune responses evolve, and environmental exposures leave measurable traces. Until recently, many of these early signals were impossible to detect.

Mayo Clinic researchers are now charting that hidden period between health and disease — a new frontier in medicine that could transform how conditions such as Alzheimer's disease, heart failure, pulmonary fibrosis, chronic liver disease and chronic kidney disease are identified and intercepted before symptoms emerge.

The new Mayo Clinic initiative, called Precure Research, brings together biospecimens, advanced biological data, environmental health research, longitudinal clinical data, wearable technologies and artificial intelligence (AI) to better understand how disease begins, predict risk earlier and create new opportunities for prevention.  

"Precure Research marks the beginning of the next era of scientific discovery and its translation into patient care."

Dr. Konstantinos Lazaridis

A glimpse of what's possible 

The initiative is already generating discoveries. Mayo Clinic scientists have identified inherited risks for cancer and cardiovascular disease in nearly 2,000 people — many of whom had no previous indication they were at risk. Other studies have shown that certain precancerous changes can be detected years before cancer develops. AI can help clinicians identify signs of pancreatic cancer years before diagnosis, while subtle biological changes linked to Alzheimer's disease begin decades before memory loss. Mayo Clinic researchers are using AI, genetics and wearable technologies to reveal inherited heart disease before heart failure.

"Precure Research marks the beginning of the next era of scientific discovery and its translation into patient care," says Konstantinos Lazaridis, M.D., the Carlson and Nelson Endowed Executive Director of Mayo Clinic's Center for Individualized Medicine and director of Precure Research. "We are building the analytical and clinical tools needed to investigate questions that medicine has long recognized but has not been able to fully answer in ways that directly benefit patients."

The invisible years before diagnosis 

The initiative combines data from genes, proteins, metabolites, clinical records, wearable devices and environmental exposures to create a comprehensive view of how health changes and disease develops over time.

Underlying Precure Research is a new Mayo Clinic research ecosystem designed to study health and disease at an unprecedented scale. The initiative aims to build Mayo Clinic's largest integrated collection of biospecimens and scientific and health data to accelerate disease prediction and prevention.

Biological samples become data, and data becomes insight into the mechanisms of disease. Those insights drive the discovery of new biomarkers and therapies while informing smarter clinical trials.

AI helps researchers power that transformation, analyzing billions of data points simultaneously to reveal patterns that would otherwise remain invisible.

"Genomics showed us the blueprint, the underlying architecture of human biology," Dr. Lazaridis says. "Now we're watching that structure in motion — shifting, adapting, unfolding over time, shaped by the world around us and inside us, ultimately influencing the unique lives we each live." 

A lifetime of exposures

Disease is shaped by more than genetics alone. Across a lifetime, environmental and lifestyle exposures leave biological changes that accumulate over time. Scientists call this the exposome: the sum of those exposures and their effects on human biology.

These influences range from air, water and diet to pollutants, heavy metals, pesticides, physical activity, sleep, stress, noise and light.

"The air we breathe, the food we eat and the places we live leave a biological imprint," Dr. Lazaridis says. "Understanding those accumulated influences is essential to understanding why disease develops in one person and not another."

Researchers can now measure many of these exposures directly in blood and other biospecimens. Early efforts focus on heavy metals, pesticides and microplastics, linking those findings with geographic data to better understand how the places people live may influence their long-term health.

The exposome also captures protective influences, including nutrients and bioactive compounds that may support resilience and regulate inflammation, aging and metabolism.

A new vision for medicine 

The initial focus of Precure Research includes diseases of the brain, heart, kidneys, liver, and lungs, and their intersection with biological pathways such as inflammation, oxidative stress, aging and metabolic dysfunction.

Its long-term aim is to extend healthspan — the number of years people live in good health, free from chronic disease and disability — by addressing the drivers of chronic disease.

Precure Research is part of Mayo Clinic's Bold. Forward. strategy to Cure, Connect and Transform healthcare — helping define a future where disease is identified earlier, understood more completely and intercepted before it takes hold.

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Mayo Clinic physicians are working hard to change how clinicians and patients think about aging. A new publication in Mayo Clinic Proceedings outlines a new framework for "healthspan" — the years of life spent in good health, with preserved function, cognition and independence. The paper, coauthored by Christina Chen, M.D., a Mayo Clinic physician in internal medicine and geriatrics, and Sara Bonnes, M.D., argues that living longer is not necessarily the same as living well and explores how a greater focus on healthspan could reshape medical care. Here, Dr. Chen discusses the research and its implications for patients and clinicians.

What is 'healthspan,' and how is it different from lifespan or longevity?

Patients often say, 'I want to live to be 100,' and that is a meaningful goal. But living longer may not be the same as living well.

Healthspan is about how well you live during those years — your ability to function independently, think clearly, and maintain a good quality of life. It shifts the focus from simply adding years to making sure those years are meaningful.

Why does this distinction matter now?

Doctors have been very successful at extending lifespan, but less effective at preserving the quality of those added years.

What we are seeing in clinical practice is that many people are living longer with chronic disease, reduced mobility, cognitive impairment and increasing dependence. That gap between years lived and years lived well is growing, and it is something clinicians see every day.

What are clinicians missing in today’s approach to care?

When we equate living longer with living better, care can become too focused on disease alone. We may not pay enough attention to one’s functional abilities, cognitive health, the ability to remain independent at home — the things patients value most.

Traditional measures like lab values or survival rates do not tell us whether someone can manage their daily activities, stay socially connected or continue living safely and independently. That is a critical gap in how we define success in medicine.

How can healthspan be measured in clinical practice?

Healthspan becomes actionable when we start measuring additional domains like physical function, cognitive health and independence in a consistent way.

We already have practical tools to do this — things like gait speed, grip strength, balance assessments, cognitive screening and patient-reported outcomes. These are validated measures that can be incorporated into routine care and give us a much clearer picture of how patients are actually doing.

When we also prioritize measuring these domains alongside thoughtful preventive care, we can track them over time and use them to guide clinical decisions in a way that aligns with what patients care about most.

How could a focus on healthspan change patient care?

A healthspan-focused approach shifts the goal of care toward helping patients stay independent, mobile and clear-minded for as long as possible.

It also changes how we talk to patients. Instead of focusing only on treating disease, we can frame care around how to preserve function, cognition and overall well-being so they are able to live well with dignity. That shift helps patients better understand the purpose behind recommendations and can improve engagement in their care.

What should patients and clinicians be thinking about differently?

We can start by changing the conversation, it begins with the words we use. Instead of asking only how to extend life, we can ask how to help patients live well, what are their goals and how can we help them reach those goals.

That includes preserving the ability to perform everyday activities, maintain social connections and continue living independently. Small changes in how we talk about care can help patients see that the goal is not just longevity, but living with quality, dignity and purpose.

What are the next steps for this research?

Our goal is to make healthspan something we can measure and track in everyday clinical practice. If we can do that, we can better align care with outcomes that truly impact patients' lives.

The next steps include developing standardized metrics, integrating them across specialties and designing care models that prioritize function, independence and long-term quality of life.

Review the study for a complete list of authors, disclosures and funding.

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In a laboratory at Mayo Clinic, a machine that looks strikingly similar to a desktop printer is quietly reshaping the future of dermatology. Instead of ink, it dispenses living human cells. Instead of paper, it builds tissue — layer by layer — replicating one of the body's most complex organs: skin.

For Saranya Wyles, M.D., Ph.D., a dermatologist and researcher at Mayo Clinic, the journey into 3D bioprinting began not with an ambitious plan to reinvent tissue engineering, but with a practical problem. Her team needed a better way to test new therapies.

"We were trying to find a preclinical model to develop an FDA application," Dr. Wyles explains. Traditional approaches rely heavily on animal testing, but skin biology varies widely across species. Even commonly used preclinical models fall short when it comes to mimicking human skin conditions such as eczema.

At the same time, alternatives such as donated human skin samples — often surgical waste — can only survive for a few days in the lab. That limitation makes it difficult to study chronic diseases or long-term treatment effects.

Faced with these constraints, Dr. Wyles and her team asked a bold question: What if they could build human skin from scratch?

From printer to patient-specific model

The answer took shape through 3D bioprinting, an emerging technology that uses "bioinks" — mixtures of living cells and supportive materials — to construct tissues.

The concept sounds deceptively simple. Much like a standard printer uses different color cartridges, a bioprinter uses different cell types. In the case of skin, that includes fibroblasts, keratinocytes and melanocytes — the essential building blocks of the dermis and epidermis layers of the skin.

But translating that concept into living tissue proved anything but simple. Early attempts produced structures that looked nothing like real skin. "It was like a cartoon version," Dr. Wyles recalls. "Not even close."

What followed was nearly a year of intensive troubleshooting, bringing together clinicians, biomedical engineers and tissue engineers in a collaborative effort. The challenge wasn't just printing cells — it was keeping them alive, functional and organized.

Each cell type has its own needs, from nutrients to mechanical conditions. "It's like roommates," Dr. Wyles says. "They all want different things."

The team had to design new culture systems, optimize materials and even fine-tune the physical "stretch" of the printed tissue to mimic natural skin. These details matter. Skin's elasticity affects everything from wound healing to itch and aging. Gradually, iteration by iteration, the model improved.

Building skin, layer by layer

Today, the process resembles a carefully choreographed construction project. First, the printer lays down the dermis — the deeper layer of skin — using fibroblasts embedded in a collagen scaffold. After several days of maturation, the epidermis is printed on top, forming the outer protective layer.

The result is a structured tissue that mirrors key features of human skin, including stratified layers and pigment-producing cells. Crucially, the model uses entirely human-derived components, including a plant-based recombinant collagen that avoids the variability and immune risks associated with animal-derived materials.

The printed tissue can survive for weeks — far longer than traditional skin explants — allowing researchers to study disease progression and treatment responses over time. And because it's printed, it can be replicated with remarkable consistency.

"No two preclinical models are exactly the same," Dr. Wyles notes. "But we can print hundreds of nearly identical samples."

Improving how therapies are tested

The implications of this technology extend far beyond the lab bench. Preclinical testing has long been a cornerstone of drug development, yet it remains an imperfect predictor of how therapies will perform in humans — nearly 90% of drugs that succeed in preclinical testing ultimately fail in clinical trials.

Bioprinted human skin models offer a promising alternative — one that is not only more biologically relevant, but also faster, more scalable and more ethical.

"From both an ethical and a financial standpoint, the difference is enormous," Dr. Wyles says.

Regulators are beginning to take notice. The Food and Drug Administration has already engaged with the Mayo Clinic team on the technology, reviewing data demonstrating that the printed skin can replicate both the structure and function of human tissue.

That includes side-by-side comparisons of patient skin and lab-grown models, showing similar cellular architecture and biological responses. As a result, the model has been recognized as a promising alternative in certain preclinical contexts — potentially reducing the need for large animal studies.

Toward personalized and precision dermatology

Beyond its applications in preclinical research, the technology opens the door to a more personalized approach to medicine. Researchers are now developing ways to create patient-specific "maps" of skin by analyzing biopsies at a molecular level. These maps capture everything from cell distribution to markers of aging, such as cellular senescence.

Using this information, the team can program the bioprinter to recreate an individual's skin in the lab.

"We can essentially print your skin based on your own biological blueprint," Dr. Wyles says.

That capability could transform how treatments are developed and tested — allowing scientists to evaluate therapies on models that reflect specific patients, populations or conditions. It also has implications for studying aging, pigmentation and diseases such as atopic dermatitis, which can vary widely across individuals and skin types.

Expanding complexity

The current models represent a significant advance, but they are only the beginning. Human skin is a highly complex organ, responsible not just for protection, but also for sensation, temperature regulation and immune function. To more fully replicate that complexity, the Mayo team is working to add new features to their printed tissues.

Future versions may include blood vessels, immune cells and nerve structures — elements that would enable even more realistic modeling of disease and drug response. Researchers also are developing pigmented models to better represent diverse skin tones, addressing a long-standing gap in dermatologic research.

"Skin of color is an area where we need better models," Dr. Wyles says.

From innovation to impact

As interest in the technology grows, so does demand. Pharmaceutical and cosmetic companies are already exploring collaborations, drawn by the potential to accelerate product development while reducing reliance on animal testing.

To meet that demand, Mayo Clinic is working to scale the technology through collaborations and licensing, while continuing to refine the science.

At the same time, Dr. Wyles is mindful of the broader mission.

"We want to democratize this," she says. "The goal is to make it accessible so more people can use it, test more therapies and ultimately get treatments to patients faster."

A new frontier in regenerative medicine

The potential applications extend well beyond drug testing. Bioprinted skin could one day be used in regenerative medicine — for example, creating grafts for burn victims or patients with chronic wounds. It may also serve as a platform for studying aging and developing interventions to improve skin health over time.

For now, the focus remains on refining the models and expanding their capabilities.

"We're really just at the beginning of what this platform can do," Dr. Wyles says.

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ROCHESTER, Minn. — Mayo Clinic researchers have uncovered how aging "zombie cells" trigger harmful inflammation that accelerates a severe and increasingly common form of fatty liver disease called metabolic dysfunction-associated steatohepatitis (MASH). As obesity rates rise worldwide, MASH is projected to increase and is already one of the leading causes of liver transplantation. 

"Liver scarring and inflammation are hallmarks of MASH. If left untreated, it can progress to liver cancer. This is why it's so important to understand the mechanisms driving the disease so that we can prevent it or develop more effective treatments," says Stella Victorelli, Ph.D., who is the lead author of the study published in Nature Communications.  

Dr. Victorelli and colleagues, who study aged or senescent "zombie" cells, identified a mechanism by which these cells drive liver scarring and inflammation. They found that small molecules called mitochondrial RNA, typically found within the cell's energy-producing mitochondria, can leak into the main part of the cell, where they mistakenly activate antiviral sensors called RIG-I and MDA5 — normally triggered when a virus infects a cell. In this case, the danger signal comes from the cell's own mitochondria, prompting a wave of inflammation that can damage nearby healthy tissue. 

When the researchers blocked the sensors, inflammation dropped sharply. The study also found that proteins BAX and BAK, which help open pores in the mitochondrial membrane, enable mitochondrial RNA to escape. In a preclinical MASH model, inhibiting BAX and BAK prevented RNA from escaping and was associated with less inflammation and healthier liver tissue. 

What are 'zombie' cells?

As we age, some cells enter senescence — a state in which they stop dividing but continue releasing inflammatory and tissue‑damaging molecules. When people are young, the immune system typically eliminates these senescent, or "zombie," cells. With age, however, they can persist and contribute to a range of age‑related health problems and diseases. 

While some research focuses on removing these cells, this team investigated how to quiet their harmful signals.  

"With age, we accumulate 'zombie' cells, which can lead to more disease," says João Passos, Ph.D., senior author of the study. "Our idea is that if we can quiet these cells earlier, we can prevent runaway inflammation and the development of many age‑related conditions, including liver disease. Understanding the mechanisms that drive disease allows us to target and delay those processes — potentially benefiting more than one condition." 

Dr. Passos and colleagues also are developing new technology to spatially map senescent cells throughout the body during aging. 

This research was conducted in partnership between the Robert and Arlene Kogod Center on Aging and the Center for Cell Signaling in Gastroenterology (C-SiG) at Mayo Clinic. 

The research is part of a larger effort at Mayo Clinic called the Precure initiative, which is focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions. 

Review the study for a complete list of authors, disclosures and funding.   

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About Mayo Clinic  
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.  

Media contact: 

• Kelley Luckstein, Mayo Clinic Communications, newsbureau@mayo.edu

The post ‘Zombie’ cells spark inflammation in severe fatty liver disease, Mayo Clinic researchers find  appeared first on Mayo Clinic News Network.

ROCHESTER, Minn. — Mayo Clinic researchers have developed a new tool that can estimate a person's risk of developing memory and thinking problems associated with Alzheimer's disease years before symptoms appear. The research, published in The Lancet Neurology, builds on decades of data from the Mayo Clinic Study of Aging — one of the world's most comprehensive population-based studies of brain health.

The study found that women have a higher lifetime risk than men of developing dementia and mild cognitive impairment (MCI), a transitional stage between healthy aging and dementia that often affects quality of life but still allows people to live independently. Men and women with the common genetic variant, APOE ε4, also have higher lifetime risk.

Predicting Alzheimer's disease

Alzheimer's disease is marked by two key proteins in the brain: amyloid, which forms plaques, and tau, which forms tangles. Drugs recently approved by the Food and Drug Administration remove amyloid from the brain and can slow the rate of disease progression for people with MCI or mild dementia.

"What's exciting now is that we're looking even earlier — before symptoms begin — to see if we can predict who might be at greatest risk of developing cognitive problems in the future," says Clifford Jack, Jr., M.D., radiologist and lead author of the study.

The new prediction model combined several factors, including age, sex, genetic risk as associated with APOE genotype and brain amyloid levels detected on PET scans. Using the data, researchers can calculate an individual's likelihood of developing MCI or dementia within 10 years or over the predicted lifetime. Of all the predictors evaluated, the brain amyloid levels detected on PET scans was the predictor with the largest effect for lifetime risk of both MCI and dementia.

"This kind of risk estimate could eventually help people and their doctors decide when to begin therapy or make lifestyle changes that may delay the onset of symptoms. It's similar to how cholesterol levels help predict heart attack risk," says Ronald Petersen, M.D., Ph.D., neurologist and director of the Mayo Clinic Study of Aging, who is a co-author of the study.

The research stands apart because it draws from the Mayo Clinic Study of Aging, a long-running effort in Olmsted County, Minnesota, that tracks thousands of residents over time. The analysis for this study included data from 5,858 participants. Unlike most studies, Mayo researchers are able to continue following participants even after they stop actively taking part, using medical record data — ensuring nearly complete information about who develops cognitive decline or dementia.

"This gives us a uniquely accurate picture of how Alzheimer's unfolds in the community," says Terry Therneau, Ph.D., who led the statistical analysis and is the senior author of the study. "We found that the incident rate of dementia was two times greater among the people who dropped out of the study than those who continued to participate."

The study elevates the significance of MCI, which is the stage targeted by current Alzheimer's drugs that slow but do not stop progression.

While the new tool is currently a research instrument, it represents a major step toward more personalized care. Future versions may incorporate blood-based biomarkers, which could make testing more accessible.

The work was supported by the National Institute on Aging, the GHR Foundation, Gates Ventures and the Alexander Family Foundation.

The research is part of a larger effort at Mayo Clinic called the Precure initiative focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.

"Ultimately, our goal is to give people more time — time to plan, to act and to live well before memory problems take hold," says Dr. Petersen.

Review the study for a complete list of authors, disclosures and funding.

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About Mayo Clinic 
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news. 

Media contact:

• Tia Ford, Mayo Clinic Communications, newsbureau@mayo.edu

The post Mayo Clinic scientists create tool to predict Alzheimer’s risk years before symptoms begin appeared first on Mayo Clinic News Network.

ROCHESTER, Minn. — When it comes to treating disease, one promising avenue is addressing the presence of senescent cells. These cells — also known as "zombie cells" — stop dividing but don't die off as cells typically do. They turn up in numerous diseases, including cancer and Alzheimer's disease, and in the process of aging. While potential treatments aim to remove or repair the cells, one hurdle has been finding a way to identify them among healthy cells in living tissue. 

In the journal Aging Cell, Mayo Clinic researchers report finding a new technique to tag senescent cells. The team used molecules known as "aptamers" — small segments of synthetic DNA that fold into three-dimensional shapes. Aptamers have the ability to attach themselves to proteins on the surfaces of cells. In mouse cells, the team found several rare aptamers, identified from among more than 100 trillion random DNA sequences, that can latch onto specific cell surface proteins and flag senescent cells.

"This approach established the principle that aptamers are a technology that can be used to distinguish senescent cells from healthy ones," says biochemist and molecular biologist Jim Maher, III, Ph.D., a principal investigator of the study. "Though this study is a first step, the results suggest the approach could eventually apply to human cells."

From a quirky idea to collaboration  

The project began with the quirky idea of a Mayo Clinic graduate student who had a chance conversation with a classmate.

Keenan Pearson, Ph.D. — who recently received his degree from Mayo Clinic Graduate School of Biomedical Sciences — was working under the mentorship of Dr. Maher, studying how aptamers might address neurodegenerative diseases or brain cancer.

A few floors away, Sarah Jachim, Ph.D., — who was also then conducting her graduate research — was working in the lab of researcher Nathan LeBrasseur, Ph.D., Director, Mayo Clinic Robert and Arlene Kogod Center on Aging, who studies senescent cells and aging.

At a scientific event, the two happened to chat about their graduate thesis projects. Dr. Pearson thought aptamer technology might be able to identify senescent cells. "I thought the idea was a good one, but I didn't know about the process of preparing senescent cells to test them, and that was Sarah's expertise," says Dr. Pearson, who became lead author of the publication.  

They pitched the idea to their mentors and to researcher Darren Baker, Ph.D., who investigates therapies to treat senescent cells. At first, Dr. Maher acknowledges, the students' idea seemed "crazy" but worth pursuing. The three mentors were excited about the plan. "We frankly loved that it was the students' idea and a real synergy of two research areas," says Dr. Maher.

The students obtained compelling results sooner than they expected and quickly recruited other student participants from the labs. Then-graduate students Brandon Wilbanks, Ph.D., Luis Prieto, Ph.D., and M.D.-Ph.D. student Caroline Doherty, each contributed additional approaches, including special microscopy techniques and more varied tissue samples. "It became encouraging to expend more effort," Dr. Jachim says, "because we could tell it was a project that was going to succeed."

Identifying attributes of senescent cells

 The study has provided new information about senescent cells beyond a way to tag them. "To date, there aren't universal markers that characterize senescent cells," says Dr. Maher. "Our study was set up to be open-ended about the target surface molecules on senescent cells. The beauty of this approach is that we let the aptamers choose the molecules to bind to."

The study found several aptamers latched onto a variant of a specific molecule on the surface of mouse cells, a protein called fibronectin. The role of this variant fibronectin in senescence is not yet understood. The finding means that aptamers may be a tool to further define unique characteristics of senescent cells.

Additional studies will be necessary to find aptamers that can identify senescent cells in humans. Aptamers with the ability to latch onto senescent cells could potentially deliver a therapy directly to those cells. Dr. Pearson notes aptamer technology is less expensive and more versatile than conventional antibodies, proteins that are typically used to differentiate cells from one another.

"This project demonstrated a novel concept," says Dr. Maher. "Future studies may extend the approach to applications related to senescent cells in human disease."

See the study for a complete list of authors, disclosures and funding.

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

• Julie Ferris-Tillman, Ph.D., Mayo Clinic Communications, newsbureau@mayo.edu 

The post A new tool to find hidden ‘zombie cells’ appeared first on Mayo Clinic News Network.

ROCHESTER, Minn. — The immune system is meant to protect the body from infection and disease. But with age, it can become less capable of doing so. However, Mayo Clinic researchers have found that some older people maintain "immune youth" – a new term coined by Mayo researchers to explain a young immune system in someone over age 60.

"We are studying why some individuals have a 'fountain of youth' in their immune systems. We want to learn from them," says Cornelia Weyand, M.D., Ph.D., a Mayo Clinic rheumatologist and clinician-scientist. She is a lead author on a perspective paper published in Nature Aging.

Dr. Weyand's research team discovered this cellular fountain of youth in more than 100 older patients who came to Mayo Clinic to receive treatment for an autoimmune disease that affects the arteries, including the aorta, called giant cell arteritis. Dr. Weyand and colleagues found in the diseased tissue of these patients specialized immune cells, called stem-like T cells. These immune cells behave like young stem cells that usually regenerate and aid healing and growth; but in this case, they were spreading the disease. This team of researchers also discovered autoimmune stem cells in humans previously.

"We observed that these patients have very young immune systems despite being in their 60s and 70s. But the price they pay for that is autoimmunity," she says.

Autoimmunity is when the immune system mistakenly attacks healthy tissues and organs.

In addition, the researchers saw that the immune checkpoint inhibitors that regulate the immune system were not working properly.

Benefits of immune system aging

"Contrary to what one may think, there are benefits to having an immune system that ages in tandem with the body," says Jörg Goronzy, M.D., Ph.D., a Mayo Clinic researcher on aging who is a co-lead author of the paper. "We need to consider the price to pay for immune youthfulness. That price can be autoimmune disease."

Immune aging is a sophisticated adaptation mechanism that the immune system can use to prevent autoimmune disease, say the researchers.

They are in the process of developing new diagnostic tests that will help find patients and healthy individuals who carry high numbers of immune stem cells and may be predisposed to autoimmune disease later in life. The research is part of a larger effort at Mayo Clinic called the Precure initiative, focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.

Review the study for a complete list of authors, disclosures and funding. 

Additional resources:
Mayo Clinic advances research on mysterious blood vessel disease

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About Mayo Clinic
Mayo Clinic is a nonprofit organization committed to innovation in clinical practice, education and research, and providing compassion, expertise and answers to everyone who needs healing. Visit the Mayo Clinic News Network for additional Mayo Clinic news.

Media contact:

• Alison Satake, Mayo Clinic Communications, newsbureau@mayo.edu

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For Anthony Maita, 'Buddy' is not just any other dog.

"He's the best thing that's ever happened to me," says Anthony.

It's no wonder, considering Buddy was right by Anthony's side during one of the most challenging times of his life — when Anthony began having epileptic seizures.

Watch: When seizures don't stop: Anthony's battle against drug-resistant epilepsy

Journalists: Broadcast-quality video (2:38) is in the downloads at the end of this post. Please courtesy: "Mayo Clinic News Network." Read the script.

"I started having the seizures, noticeable seizures, and from there, it just started getting worse and worse," recalls Anthony.

It began after Anthony graduated from high school. He was making plans for his future and looking forward to attending college. That's when the seizures began.

Initially, the seizures were mild but quickly became more severe. "The experience (seizure) is like a loss of time, like a blank spot in your memory — like you're waking up without any recollection of what happened," says Anthony.

"The seizures were several times a week. His lips would be blue. His mouth would be blue," says Patricia Maita, Anthony's mother. "It so hard to see your child go through that and feel so helpless."

Doctors tried to manage Anthony's seizures with medication, but nothing worked. Eventually Anthony was diagnosed with drug-resistant epilepsy, or DRE.

In search of hope, Anthony's family turned to Mayo Clinic in Arizona.

"Up to a third of patients who develop epilepsy during their life will become resistant to medication," explains Jonathon J. Parker, M.D., Ph.D., a neurosurgeon at Mayo Clinic who specializes in treating the most serious and complex cases of epilepsy, including DRE.

"These patients have tried at least two medications, and they're still having seizures. At that point, we know the chances of seizure freedom unfortunately become very low, and that's when we start looking at other options," says Dr. Parker.

A battle for millions worldwide

Anthony is one of approximately 50 million people worldwide diagnosed with epilepsy. It is one of the most common neurological disorders globally. It is characterized by recurrent unprovoked seizures caused by abnormal electrical activity in the brain.

Of those diagnosed with epilepsy, approximately 30%, or 15 million people, are considered medication-resistant. Uncontrolled seizures often rob many people of their ability to live and function independently.

While it is rare, seizures can lead to sudden unexplained death in epilepsy, or SUDEP. "We know that more frequent seizures mean the patient is at higher risk of SUDEP, so that's why we are very aggressive about treating epilepsy with all the tools we have available," says Dr. Parker.

Current treatment options for patients with DRE include surgical procedures such as brain resection to remove a portion of the brain tissue responsible for generating seizures. A less invasive procedure involves laser ablation therapy that pinpoints and destroys abnormal brain tissue. While often effective, these surgical approaches carry the risk of possible side effects, such as memory impairment, motor deficits and speech difficulties. 

Neuromodulation is another surgical approach that uses electrical or magnetic stimulation to interrupt abnormal neural activity without removing brain tissue.

Unlocking new hope for patients

Now, a growing number of scientists across the globe are part of an innovative trend in research, investigating novel ways to treat DRE. It involves the use of regenerative medicine as a "reparative" approach to help the brain heal. 

Dr. Parker is the lead investigator of the first-in-human clinical trial at Mayo Clinic which studies the use of implanted specialized inhibitory brain cells as a potential reparative treatment for DRE. Dr. Parker's clinical trial is underway in Arizona.

Mayo Clinic in Arizona is one of 29 sites nationwide participating in the inhibitory brain cell implant clinical trial for patients with focal epilepsy, where seizures originate in a specific region of the brain. 

Anthony became Mayo Clinic's first patient to undergo the investigational brain cell implant. 

"We use a very minimally invasive technique where we inject the inhibitory cells through a pencil eraser-sized incision in the back of the head. Our hope is that, over time, these cells become part of the brain and help repair the neural circuitry, and reduce or prevent seizures without the side effects," says Dr. Parker. The cells are implanted in a one-time, single-dose procedure.

"Honestly, it was pretty easy," says Anthony. "I had no trouble with it." Anthony was discharged from the hospital the next day.

Doctors say it is still too early to determine whether the brain cell implant was effective, but they are hopeful.

"Anthony has been doing great since the procedure," says Dr. Amy Z. Crepeau, a neurologist at Mayo Clinic. "We have a great deal of optimism in regard to the potential of this brain cell therapy. Developing a safe and effective, minimally invasive treatment that does not carry the possible negative side effects could be a game changer in treating patients with DRE and improving their quality of life."

Tabitha's life-long struggle to control seizures

Tabitha Wilson lives in fear, never knowing when or where the next seizure will strike.

The Florida resident was diagnosed with epilepsy at the age of 2. She was placed on medication that adequately managed her seizures — until the week before her high school graduation. 

"I was 17 years old sitting in history class when the seizure happened," recalls Tabitha. "They had to load me up in an ambulance in front of the whole school."

Tabitha tried new types of medications, but the seizures only got worse.

"I fell down a flight of stairs, burned myself while cooking. I've completely blacked out and don't know where I am or who you are," says Tabitha. She was eventually diagnosed with drug-resistant epilepsy.

Tabitha underwent three brain surgeries to treat her DRE. Still, the seizures continued.

"I'll have good days and bad days. Some days, I'll have two, three, four seizures, back-to-back," says Tabitha.

Her uncontrolled seizures have robbed Tabitha of the ability to live independently. "I can't drive. I can't cook. I can't go swimming alone. I can't take a bath, only a shower and if someone is home with me," says Tabitha.

Watch: Tabitha Wilson shares what it's like to live with drug-resistant epilepsy.

Tabitha turned to Mayo Clinic in Florida where she learned about a clinical trial also investigating the potential of regenerative medicine as a possible treatment for DRE.

Dr. Sanjeet S. Grewal, director of stereotactic and functional neurosurgery at Mayo Clinic, is leading a team of researchers studying the use of implanted stem cells in conjunction with deep brain stimulation for patients like Tabitha.

Deep brain stimulation is one of the most recent FDA-approved methods of neuromodulation therapy for epilepsy. Studies show that patients who undergo deep brain stimulation experience median seizure reduction up to 70% after five years. However, Dr. Grewal says it is uncommon for patients to become seizure-free. 

"Unfortunately, neuromodulation doesn't give us the seizure freedom we want, and that's why we are trying to combine deep brain stimulation with stem cell therapy to see if we can increase the efficacy of neuromodulation," he says. 

Tabitha became the first patient to undergo the investigational treatment. Dr. Grewal says she is also the first person in the world to undergo surgery for deep brain stimulation and receive stem cell therapy in the thalamus in her brain as a potential treatment for DRE. 

Watch: Dr. Sanjeet Grewal, neurosurgeon, explains how Mayo researchers are leading a new trend in research for treating patients with drug-resistant epilepsy.

The clinical trial involves the use of mesenchymal stem cells, a type of adult stem cell that has anti-inflammatory properties. MSCs may also support tissue repair and healing. Further scientific research is needed to confirm their therapeutic potential in the field of regenerative medicine.

The MSCs used in the clinical trial are derived from fat tissue and created at the Human Cell Therapy Laboratory at Mayo Clinic in Jacksonville, Florida under the leadership of Abba Zubair, M.D., Ph.D., a pioneer in cell therapy.

Dr. Zubair's research teams have developed a cost-effective method of producing MSCs for use in potential treatments for conditions such as stroke.

Dr. Zubair has also led innovative research, including sending stem cells to the International Space Station to investigate how microgravity impacts their growth.

"My mission is to discover ways to address problems that patients have been struggling with and find a solution for them.
I believe the future is bright. "

Dr. Abba Zubair, Pioneer in Cell therapy, Mayo Clinic in Florida

Dr. Zubair has several research projects scheduled to launch into space in 2025.

"MSCs are what we call multipotent, meaning they can differentiate into different cell types based on where they're placed. If they are placed near blood vessels, they can become blood vessel types. If they're placed by heart cells, they can become heart cell types," explains Dr. Grewal.

The hope is the MSCs eventually become neural or brain cell types and interact in the part of the brain where the seizures occur. "It's called paracrine signaling, where they're releasing signals to the brain tissue around them and interacting in a way to try to repair that tissue."

Since undergoing the procedure, there has been an improvement in Tabitha's seizure management. However, Dr. Grewal says it is too early to know whether this is due to the deep brain stimulation, stem cells or both. 

Drs. Grewal and Parker say there is still a long road ahead to determine whether these cell therapies are proven safe and effective for patients with DRE. But they agree each day brings them one step closer to a potential treatment or cure for patients like Tabitha and Anthony.

"We've thought about this for generations, we just didn't have these technologies to enable it. Now we do," says Dr. Grewal. "So, whether it's wound healing, neurodegeneration, epilepsy or stroke, there are so many different studies going on investigating the potential of regenerative or reparative therapies."

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• Laser ablation surgery helps treat young man’s epilepsy

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