The longest-living mammals on Earth, bowhead whales, can live more than 200 years.
In their lab on the University’s River Campus, a research team led by professors of Biology and Medicine Vera Gorbunova, PhD, and Andrei Seluanov, PhD, is studying cells in biopsied tissue from these giants of the ocean to uncover their secret to longevity. Their research into the mechanisms of longevity and genome stability goes back nearly 20 years and aims to solve one of the biggest mysteries of biology: aging.
The goal: Slow aging, slow disease.
“Aging is a risk factor for many diseases that are afflicting mankind. So, if we could slow down aging, we also would slow cancer, dementia, cardiovascular disease, and other conditions that increase with old age,” says Gorbunova, who is the Doris Johns Cherry Professor and co-director of the Rochester Aging Research Center.
“If we succeed to slow aging or improve the process of aging, then we will be able to delay many diseases,” Seluanov adds.
Their lab is part of the Vital Discovery pillar of the UR Aging Institute (URAI). In this area, basic and clinical researchers work to study longevity and the causes and conditions of aging—from basic science to translational studies to health care policy.
“We are building a strong research infrastructure that will translate scientific discovery into clinical care,” says URAI Director Annie Medina-Walpole, MD. “We’ll ask how and why we age and what factors determine longevity, life span and health span, and what interventions can be used to promote health, well-being, and vitality. This is how we’ll expertly care for the growing population of older patients in our region. And, finally, can we slow down the aging process itself, which can be viewed as the ultimate preventive medicine?”
At the Bench
In addition to bowhead whales, which are efficient at genome maintenance and DNA repair, Gorbunova and Seluanov study a variety of long-lived animals such as naked mole rats, beavers, squirrels, and bats. They, too, live long and have evolved unique molecular mechanisms of longevity and disease resistance. Bats, for example, have a unique immune system that is resistant to inflammation, a big driver of age-related diseases.
The lab is a pioneer in comparative studies on aging, focusing on short- and long-lived animals. Its studies of Eastern gray squirrels (average lifespan: 24 years) and naked mole rats (32) have found additional pathways to putting the brakes on aging. For example, they’ve identified an important gene for longevity in the naked mole rat that, when transferred to mice, increases their longevity as well. Cancer incidence typically increases with age, but these long-lived animals naturally resist it. Studying the mechanisms of that resistance has led to new insights that will soon be tested on humans at Wilmot Cancer Institute.
“The process of discovery is really amazing,” Seluanov says. “That’s what is fun. But in addition, we can apply that discovery to improve human health and help people. What can be better than that?”
When molecular biologist Dirk Bohmann, PhD, and his research team were recruited to URMC from the European Molecular Laboratory in 2001, he was using fruit fly genetics to understand how cells defend themselves against effects of environmental stressors such as toxins or radiation.
“It was clear that the ability of an organism to fend off these challenges wanes with age, contributing to the loss of resilience and fitness, thereby increasing the probability of disease and death. But it was unclear at a cell and molecule level why this happens,” says Bohmann.
At the time, the University hosted the Nathan Shock Center of Excellence in Basic Biology of Aging with a grant from the National Institute on Aging (NIA). Bohmann received a small pilot grant from the center to apply his work to aging. High-level publications and funding from the NIA followed, transforming his group into a leading aging research lab. Team members have gone on to become eminent researchers in their own rights.
The fact that long life is a trait that can run in families suggests—and a lot of research confirms—that aging is not simply the result of a randomly determined, inexorable grindstone, but is influenced by genetics. This can explain the differences seen in older adults as they age.
Hundreds of genes that influence aging have been identified in studies on a small earthworm known as caenorhabditis elegans. Many of these genes exist in humans, yet whether or how they will influence aging in humans is poorly understood. Studying how these genes function in model organisms, such as in earthworms, fruit flies, or rodents, provides insight into how to promote healthy aging in humans. The laboratory of Andrew Samuelson, PhD, associate professor of Biomedical Genetics, is using the worm to explore the fundamental mechanisms by which aging genes act, and how they may dictate lifespan, health span, and the onset of specific age-associated illnesses such as Alzheimer’s disease.
From the Bench to the Bedside
Because of the Institute, collaborations that bring basic research into the clinical setting are multiplying. Gorbunova and Seluanov, for example, are working with clinical scientists at Wilmot Cancer Institute to treat older patients suffering from the side effects of chemotherapy.
And Wilmot works closely with URAI.
More than 60 percent of people with cancer are ages 65 and over, and a third are older than 75. Even though those numbers are expected to rise as the population ages, older adults are severely underrepresented in clinical trials, says Supriya Mohile, MD the Philip and Marilyn Wehrheim Professor of Medicine and director of Geriatric Oncology Research at Wilmot. Most cancer trial participants are in their fifties and early sixties. Resulting treatments are designed for younger adults who don’t have many of the challenges that come with older age, such as with memory, mobility, and multiple medications.
Still, the field of geriatric oncology has grown dramatically since Mohile’s training in the early 2000s, particularly in the last decade as clinicians and researchers try to understand the risks and benefits of treating cancer in older people, she says.
Like much of the work done in the URAI, the geriatric oncology clinic at Wilmot, founded by Mohile and led by Allison Magnuson, DO (’02, Flw ’13, Flw ’14, MS ’20), associate professor of Medicine, combines research with patient care. SOCARE—Specialized Oncology Care and Research in Elders—is recognized in the U.S. and abroad for providing the most comprehensive, evidence-based care for patients age 70 and older. With a team of six geriatric oncologists, it’s the largest clinical group of its kind in the country.
The opportunity to do translational research while working with patients is a big draw for fellows and residents, and the program is growing from within as a result. Magnuson did fellowships in oncology and geriatrics at Rochester. Now director of SOCARE, she is researching ways to reduce cancer-related cognitive dysfunction, or “chemo brain,” in older patients, who are at greater risk.
Magnuson’s latest research breaks new ground. She received a $2.5 million award from the NIA to study how oncologists can better deliver care to cancer patients who have pre-existing dementia or Alzheimer’s disease. About 7 percent of older cancer patients are in this situation, and current data provide no guidance on whether cancer treatments are safe for these individuals, how to assess the patient’s ability to reason and understand information, and how to have difficult three-way conversations between doctor, patient, and the patient’s representative when complex treatment decisions must be made. Magnuson plans to adapt and test an existing geriatric assessment tool for use in these cases.
Vice Chair for Basic and Translational Science Laura Calvi, MD, holds an NIA-supported $2.3 million grant focused on the mechanisms by which the bone marrow ages. This is significant because abnormal mature cells in the bone marrow can cause inflammation and bone loss, and can support the development of leukemia and other blood cancers. Calvi, who holds professorships in the departments of Medicine; Pathology and Laboratory Medicine; Pharmacology and Physiology; and the Cancer Institute, is working with the Center for Musculoskeletal Research to understand how phagocytosis of dead and dying cells affects bone aging.
Kah Poh Loh, MBBCh (Flw ’18, Flw ’19), a hematologist, oncologist, and geriatrician, develops ways for older cancer patients to use digital technology, such as mobile apps, for behavioral and supportive care interventions. Before launching an app-based trial, for example, she consults with older patients on user-friendly design—from font size to information flow. Loh and two other Wilmot Cancer Institute researchers, Michelle Janelsins-Benton (MS ‘05, PhD ‘08, MPH ’13), associate professor of Surgery, Radiation Oncology, and Neuroscience, and Paula Vertino, PhD, professor of Biomedical Genetics and of Pathology and Laboratory Medicine, were awarded the inaugural UR Aging Institute pilot grant this past year.
“In every step of the design, they’re partnering with patients. It’s not ‘no,’ it’s ‘how,’” Mohile says. They’re doing really interesting work, and they’re rising stars nationally.”
Eight to 10 geriatrics professionals and students come from around the world every year for SOCARE’s visiting scholars program. After they return home to start clinics and research of their own, they replicate what they’ve learned with ongoing guidance from Wilmot colleagues.
Alzheimer’s Disease, Dementia, and Dementia Care
A new T32 training grant from the NIA will support six PhD students each year who are studying Alzheimer’s disease and aging, says Kerry O’Banion, MD, PhD (Flw ’91), vice chair and professor in the Department of Neuroscience. O’Banion and Gorbunova are co-principal investigators on the five-year, $1.44 million grant.
Participants will study the basic biology of aging and neuroinflammation, attend weekly seminars, and shadow staff in the Department of Psychiatry’s Memory Care Clinic.
“The unique aspect is that PhD students seldom get to see the translational or clinical side that their research in, for example, mice might impact,” O’Banion explains. “You could call it a more holistic view of the challenge.”
The grant confirms Rochester’s strengths in Alzheimer’s disease research, he adds. “It’s recognition that this is a place for training the next generation of investigators in this area.”
More than 400,000 adults over age 65 in New York have dementia, and nearly 600,000 family caregivers provide 835 million hours of unpaid care every year, according to the Alzheimer’s Association. URMC has tapped into this need with a host of programs devoted more broadly to dementia and dementia care, as well as geriatric mental health and well-being. In these clinics and centers, translational research and patient care go hand in hand:
- The Memory Care Program focuses on neurodegenerative conditions that affect adults and the aging nervous system, such as Alzheimer’s disease and other forms of dementia. Patients receive diagnosis, treatment, and ongoing care. It opened 30 years ago and is the only program of its kind in upstate New York that is part of a psychiatry department. The University of Rochester also has the only geriatric psychiatry fellowship program in upstate New York.
“We have many clinical trials going at once and are a major site for testing of new treatments for Alzheimer’s disease, including monoclonal antibodies,” says Elizabeth (E.J.) Santos, MD (BA ’94, Flw ’06, MPH ’13), associate professor of Psychiatry, Neurology, and Medicine, and clinical chief of the Division of Geriatric Mental Health and Memory Care. “Our expertise in caring for patients with dementia is recognized nationally and internationally.”
- AD-CARE—The Alzheimer’s Disease, Care, Research, and Education program is led by Anton Porsteinsson, MD (Res ’93), the William B. and Sheila Konar Professor of Psychiatry. The lab participates in international studies in Alzheimer’s disease prevention, cognitive impairment, diagnostic tools, and behavioral disturbances. AD-CARE is co-located with the Memory Care Program, allowing access to world-class clinical care and opportunities to participate in cutting-edge research.
- The Rochester Roybal Center for Social Ties & Aging Research, also known as Roc STAR Center, is one of 135 Roybal Centers funded by NIA. The Roybal Center program focuses on the translation of discoveries from basic behavioral and social research into effective interventions to improve the lives of older people and assist institutions in adapting to the aging of our society. The Roc STAR Center, supported by a $3.6 million grant, is the only Roybal Center focused on the loneliness and social isolation of caregivers of a family member with dementia.
Research has shown that loneliness increases risk for chronic disease and mortality as much as smoking, obesity, and a sedentary lifestyle. Despite this, there are few scientifically developed interventions to improve social connectedness. “Our work aims to fill this critical gap,” says Kathi Heffner, PhD, co-director of the center and the Marie Curran Wilson and Joseph Chamberlain Wilson Professor of Nursing, professor of Medicine and Psychiatry, associate chief of Research for the Division of Geriatrics & Aging, and a member of the URAI’s executive committee.
Through pilot fund research grants, the Roc STAR Center is building a person-centered portfolio of interventions that community organizations and long-term care facilities can offer struggling caregivers. For example, the center is collaborating with the Geriatric Workforce Enhancement Program education series to develop Connections Planning, an online training module for long-term care providers and staff to treat and prevent loneliness and isolation in older adults.
Loneliness among older adults happens, but it is not the norm, says co-director Kimberly Van Orden, PhD (Flw ’10). “In fact, most older adults experience increased psychological well-being and satisfaction with relationships as they age. Social connectedness is actually an aging-related strength that can be capitalized upon to promote well-being.”
- NEW Brain Aging Center—The Network for Emotional Well-Being and Brain Aging opened in 2021 with a $2.5 million NIA grant. It is a collaboration among five partners, including URAI and colleagues at Duke, UC Santa Cruz, Johns Hopkins, and Stanford universities. Researchers are studying how an aging brain affects emotional well-being in older adults, and how emotional well-being affects brain function and cognitive aging.
- HOPE Lab—The Helping Older People Engage Lab conducts randomized clinical trials to discover ways to increase social connectedness and improve well-being through older age.
- HARP—The Healthy Aging Research Program is a multidisciplinary clinical and behavioral research collaborative to promote healthy aging. HARP partners with the Roybal Center, HOPE Lab, and the Elaine C. Hubbard Center for Nursing Research on Aging, as well as community organizations serving older adults, to help investigators design and implement clinical research studies with older adults.
- The Stress and Aging Research Lab conducts basic clinical research on the ways in which stress and emotional well-being impact older adults’ immune systems and health outcomes, as well as randomized clinical trials of stress interventions to promote healthy aging.
Solving Real-World Problems
In the URAI’s Vital Discovery pillar, scientists are working closely with clinicians to bring their research into the living laboratory of health care.
A First in Aging Trials
The Gorbunova and Seluanov Lab is working with clinicians in Wilmot Cancer Institute on one of the first U.S. aging trials to come from basic research. In a recent mice trial, they administered a seaweed compound that activates a gene that can reverse aging. It rejuvenates the way DNA is packaged in the cell, carrying an extra dose of a gene that reorganizes mutated DNA strands into a normal configuration. Treated mice showed signs of improved fitness; they ran faster on the treadmill, and their tails became more flexible.
Now with Gorbunova, principal investigators Janelsins-Benton and Luke Peppone, PhD (BA ’99, MPH ’10), associate professor of Surgery, Orthopaedics, and Cancer, will use the same compound in a small trial with 32 older adult cancer patients who suffer from the side effects of chemotherapy. Funded by a pilot grant through the URAI, the trial will be one of the first bench-to-clinic trials to look at the fundamentals of aging. If the outcome is encouraging, they’ll test it with healthy participants.
“That’s where the URAI really helped. We weren’t connected to the clinical side before,” Seluanov says. “This type of coordination is really enhanced by having the Aging Institute.”
A regional collaboration also holds promise for research their lab and others do in the URAI. UR is partnering with the University at Buffalo and Roswell Park Comprehensive Cancer Center in early-phase drug development. The New York State-funded Empire Discovery Institute holds promise for translating URAI research efforts into therapeutically viable products that target longevity genes to extend lifespan and health span to a point where commercial partners can develop them into FDA-approved medicines.
Data Played Out in a Pandemic
Health services researcher Brian McGarry, PT (PhD ‘16), assistant professor of Medicine and Public Health Sciences, studies whether health care systems that serve older adults are really set up to meet their needs. McGarry joins a prominent group of collaborators in the Department of Public Health Sciences, Department of Psychiatry, and School of Nursing engaged in studying the impact of organizational factors and health care policies on outcomes for nursing-home care, acute home-health care, and long-term services and supports their recipients, including veterans, using the CMS, AHRQ, VA, and additional data sources.
With a new five-year grant from the National Institute on Aging, McGarry will study how older adults with cognitive decline navigate the enormous amount of consumer choice built into Medicare. In his previous work as a physical therapist, McGarry saw firsthand how hard it was for patients to figure out. Now he studies how public policies are put into practice, how they affect the cost and quality of care, and how these policies can help support older adults when they are making difficult health care and health coverage decisions.
He and other researchers in the Division of Geriatrics & Aging meet regularly with clinicians to vet aggregated administrative data, such as claims, to see if it tells an accurate story.
“Most of my colleagues are clinicians working with older adults. I get to sit side by side with them and work on research questions that are pertinent to their practice and their patient population,” he says. “It’s something the Aging Institute embodies—making that connection between the number cruncher/researcher and the clinicians who are living the stuff day to day.”
This collaboration also fuels McGarry’s research into the burden that COVID-19 imposed on nursing homes. In the early days of the pandemic, McGarry did rapid turnaround research for administrators and policy makers—for example, investigating the extent of staff shortages and the time it took to get COVID-19 test results. Now he is studying weekly data from facilities to see how testing might have been done differently to avoid the high number of nursing home deaths.
Besides dampening demand for nursing home care, which has long-term implications for the industry, the pandemic took the lives of more than 150,000 residents in the United States. McGarry says this fact alone fuels his work, so his colleagues can prepare for the next outbreak. “That’s important to me. What could be done better? And what, from a systematic standpoint, could make nursing homes safer for the staff who work there and the residents who live there?”
The answer to that question is the driving force behind high quality, age-friendly care at our regional hospitals and nursing homes. Kevin McCormick, MD, PhD (Res ’96, Flw ’98), professor of Clinical Medicine, is leading regional efforts in geriatrics as the medical director of Jones Memorial Hospital in Wellsville, N.Y.
UR Medicine Geriatrics Group (URMGG), led by Dallas Nelson, MD (Res ’03, Flw ’05), associate professor of Medicine, provides comprehensive care to some of our region’s most frail older adults in 12 skilled nursing facilities and 33 assisted and independent living facilities, while Santos, Adam Simning, MD, PhD, assistant professor, and others in the Department of Psychiatry’s Geriatric Mental Health and Memory Care Division provide telemental health services and supports to residents and staff of about 90 nursing facilities across the state of New York.
The COVID-19 pandemic provided unprecedented opportunities for crisis management and leadership within URMC, the Rochester community, and its surrounding regions; including the care of nursing home residents with COVID-19 infection, delivery of vaccines, boosters, and monoclonal antibody treatment; transition to telemedicine visits; and outbreak testing.
McGarry; McCormick; Nelson; and Ryan Gilmartin, MHA, URMGG senior program officer, along with many other UR Medicine faculty and advanced practice providers, rose to this incredible challenge and exhibited extraordinary commitment, leadership, and expertise to coordinate and improve our community’s response to the COVID-19 pandemic.