What do “epigenetic clocks” actually measure? These lab tests have become popular tools for studying biological aging, or how the body’s cellular function changes at a faster or slower rate than expected. However, the underlying biology behind each of these measurements has remained largely unknown until now.

A recent USC Leonard Davis School of Gerontology-led study published in npj Aging shows the variability in what five of the most widely used epigenetic clocks are actually measuring. The research team also developed new gene-expression based clocks to complement existing epigenetic clocks, which show even stronger predictive power for age-related disease and mortality.

Biology versus the calendar

Scientists have long known that people age at different rates biologically. Someone who is 70 years old on paper may have the health of a much younger person, while another 70-year-old may be much more frail than their same-age peers.

To measure that difference, researchers use epigenetic clocks to estimate biological age. These tools measure a chemical change called DNA methylation, which doesn’t change the genetic code itself but affects which genes are turned “off” or “on.” These chemical changes on top of the base DNA are collectively called the epigenome.

Examining the epigenome can predict health problems and even the risk of death better than chronological age alone. But until now, scientists did not know exactly what was happening inside cells that made the epigenetic clocks such powerful tools.

“Aging isn’t just about the number of candles on your birthday cake — it’s also about what’s happening inside your cells,” said lead author T. Em Arpawong, research associate professor of gerontology at the USC Leonard Davis School. “We found that different clocks capture different aspects of the biology of aging and developed new transcriptomic aging gene scores that complement existing clocks and, in some cases, better predict age-related disease and mortality.”

Surprising differences

In the study, Arpawong and the team studied blood samples from 3,227 participants in the Health and Retirement Study in the U.S. They compared DNA methylation patterns with gene expression, or how often genes are transcribed from DNA into RNA and used to make proteins. All of the transcription taking place within a cell at a given time is referred to as the transcriptome.

The researchers examined combined epigenetic and transcriptomic measurements to compare gene expression and identify the biological pathways highlighted by each of five epigenetic clocks.

They found that each aging clock was associated with different biological processes, from energy balance and cellular growth to immune cell activation and inflammatory signaling. Even though the clocks emphasized different biological pathways, they shared several common themes, including changes in the immune system, metabolism and cell communication — all well-known features of aging.

A new tool for prediction

The researchers further used the analysis to create new tools called transcriptomic aging gene scores (TAGS). The combined approach provided an even clearer picture of a person’s biological health; in several cases, TAGS predicted health outcomes such as frailty, walking speed, heart disease, diabetes, lung disease and death better than the epigenetic clocks alone.

The findings could help researchers choose the best aging clock for different studies. For example, one clock may be better for studying treatments that target the immune system, while another may be better for testing therapies that improve metabolism or slow the decline in physiological resilience.

The work also helps explain the biology behind tools that are becoming increasingly common in aging research. By linking DNA methylation changes with gene expression activity, senior author Eileen Crimmins said the study has further illuminated the “black box” of biological aging clocks, bringing scientists one step closer to using these measures to better predict disease, track healthy aging and one day guide medical care.

“By uncovering the molecular programs behind these biomarkers, our findings improve their interpretability and help guide their use in geroscience, epidemiology, and future clinical applications,” she said.

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About the study: Arpawong and Crimmins’ co-authors included Harshanna Badhesha, Jung Ki Kim, Christopher Beam, Kimberly Siegmund of USC; Steve Cole of UCLA; Eric T. Klopack of Indiana University; and Bharat Thyagarajan of the University of Minnesota. The study was supported by the National Institute on Aging (P30 AG017265).

Once or twice a week, chronic pain researcher Jason Kutch rises at dawn and heads to a Los Angeles-area surf break to catch some waves.

Kutch studies the effect of surfing on brain activity — but during those early morning surf sessions, he’s completely focused on keeping his balance in the crashing water.

“You have to coexist with this extremely powerful force that demands all of your attention,” says Kutch, a professor in the USC Division of Biokinesiology and Physical Therapy.

Kutch and Peter Westwick, professor of the practice of thematic option and history at the USC Dornsife College of Letters, Arts and Sciences, are both experts in the science and technology of surfing. Kutch is studying whether surfing can positively shift brain activity and relieve chronic pain. Westwick, also a surfer, explored the tension between the sport’s natural and engineered elements as co-author of The World in the Curl: An Unconventional History of Surfing.

Yet both scholars believe that waves’ appeal and healing potential can’t be fully captured by data. Their experiences as surfers inform their insights into how this elemental force of nature shapes culture and health.

Communion with nature

In ancient Hawaii, where surfing emerged perhaps 1,500 years ago, the activity was woven into every aspect of cultural life, from courtship rituals to religious festivals, Westwick says.

The Hawaiian language reflects a belief in riding waves as a philosophical pursuit. “Nalu, the Hawaiian word for surf, can also mean to search for truth,” he says. “Additionally, nalu refers to the amniotic fluid that covers babies. Hawaiians were born surfing.”

Waves connect us not just to the watery environment of our mother’s wombs, but to Mother Nature — even as surfboards, wetsuits and even some features of the coastline are products of human engineering.

“Part of the attraction for surfers is that we are literally immersed in the natural world,” says Westwick, who surfs near his home in Santa Barbara. “We sit on our boards looking out to sea with our backs literally and figuratively turned on modern industrial civilization.”

‘Riding nature’s energy bands’

Though the marine environment offers a soothing counterpoint to the stresses of modern life, waves are unpredictable and, at times, destructive.

“Most ocean waves are a conversion of the wind energy of very distant storms,” Westwick says. “These disturbances on the ocean surface can travel thousands of miles and eventually reach a coastline. Close to shore, the ocean gets shallower, causing the waves to rise up, topple over and break.”

Surfing offers a direct experience of these powerful and capricious forces.

“If you catch a wave on your surfboard, this energy of distant storms has now been transferred to you,” he says. “You’re riding nature’s energy bands.”

Flight and flow

For Kutch, that energy transfer provides a singular thrill. “There’s something about shooting down that unbroken wave while standing on the board, and it can’t be described by any other term than ‘flying,’” he says.

Kutch notes that staying afloat is a delicate balancing act, both physically and mentally.

“Surfing is a repeated, goal-directed task in a highly sensory-rich environment that fluctuates moment to moment,” Kutch says. “That engages mechanisms in the brain in a special way.”

Kutch has identified a marker of brain activity called peak alpha frequency that may shift favorably after a surfing session and could be a factor in chronic pain relief. This scientific phenomenon highlights a poetic symmetry: ocean waves influence our brain waves.

Grappling with the ocean’s flow can also encourage a mental state known as “flow”: deep focus and total absorption in an activity. Artists, athletes and others have described flow as akin to being carried along by a water current.

In surfing, the concept is both literal and metaphoric: “A flow state can positively redirect your attention away from pain, anxiety and depression,” says Kutch, who credits surfing with resolving his own chronic pain. “I think there’s some magic in that space.”

 

Some of medicine’s smallest patients can present its biggest imaging challenges. An infant’s heart can be as small as a walnut, beating rapidly inside a body that will change dramatically as the child grows. Yet much of the equipment used in MRI comes in standard sizes better suited to adult bodies, and customized versions can cost thousands of dollars and take months or even years to manufacture.

USC researchers have developed a potential solution: flexible MRI sensors that can be customized to individual patients and 3D-printed in less than 10 minutes for about $30. In testing, the sensors produced roughly four times greater image contrast than standard commercial versions.

“By making customized MRI equipment faster and more affordable to produce, we have the potential to bring better imaging to patients who have traditionally had fewer options, especially infants and children,” said Yasser Khan, assistant professor of electrical and computer engineering and biomedical engineering at the USC Viterbi School of Engineering, whose lab at the USC Michelson Center for Convergent Bioscience designs and 3D-prints the customized coils.

Paired with specialized MRI technology at the USC Michelson Center, the sensors can also help capture anatomy in motion, including something as small and fast-moving as a beating heart.

“We’re bringing a level of precision and customization to MRI that isn’t available today,” he said.

A better fit for growing bodies

MRIs use powerful magnets and radio waves to generate signals from inside the body, which a computer then turns into detailed images. Devices called coils act like antennas to pick up those signals, and the closer they fit to the area being scanned, the clearer the image can be.

That makes fit especially important for small patients. A coil designed for an adult may leave gaps when placed around an infant or child, making it harder to capture a strong signal. And because children grow rapidly, equipment that fits at one stage may not fit as well a few years or even months later.

Khan compares the challenge to choosing the right camera lens.

“If you use a large lens to image something very small, you’re not going to get the clearest picture,” Khan said. “But if you can tailor the lens, in this case the MRI coil, to the individual patient, you can capture a much better image.”

The researchers wanted to make a coil that could closely follow the contours of the body rather than leave space between the sensor and the skin. That required rethinking both the material and the way MRI coils are manufactured.

After about three years of experimentation, Khan’s team developed a process for 3D printing conductive silver ink onto a thermoplastic elastomer, a soft, stretchable material with properties similar to human skin. The material can stretch roughly 5% to 10%, allowing the coil to bend and move with the body.

The team tested different flexible materials, plastics and formulations of printable metal before arriving at the combination of silver ink and thermoplastic elastomer. The researchers also had to develop the electronics needed to connect the unconventional coils to an MRI system.

Because the coils begin as digital designs, their dimensions can be changed quickly. A researcher can adjust the size or shape on a computer and print a new coil rather than wait for a specialized part to be manufactured.

“For a growing child, that could mean creating different coils as the body changes,” Khan said. “The goal is to give children access to imaging equipment designed for their bodies, so doctors can get the clearest picture possible as they grow.”

Built and tested under one roof

The technology grew out of the kind of interdisciplinary collaboration the USC Michelson Center was designed to foster, bringing engineers, imaging scientists and clinicians together to tackle complex challenges and accelerate scientific discovery.

In this case, two labs brought complementary expertise to the same problem. 

The Khan Lab specializes in flexible and wearable electronics, including devices that can bend, stretch and conform to the body. 

The Dynamic Imaging Science Center (DISC), led by Krishna Shrinivas Nayak, professor of electrical and computer engineering and biomedical engineering at USC Viterbi, develops advanced MRI technologies, including methods for capturing the body as it moves.

The DISC Lab is also home to what researchers describe as the only MRI system of its kind in the world, allowing USC scientists to test new technologies and push the boundaries of imaging the body in motion.

Clinical collaborators help connect those capabilities to the needs of patients. John Wood, director of cardiovascular MRI at Children’s Hospital Los Angeles and professor of pediatrics and radiology at the Keck School of Medicine of USC, works with Nayak on some of the most difficult challenges in pediatric imaging, including real-time imaging of the fetal heart. His experience imaging children’s hearts helps inform where new, more adaptable technologies could have the greatest impact.

“We need environments where different ideas can collide,” Khan said. “This project wouldn’t have happened without access to the MRI and conversations with cardiologists, radiologists and imaging scientists. When you bring that expertise together, you can solve problems none of us could solve alone.”

Women live longer than men in nearly every country in the world, yet they experience higher rates of disability, dementia and many other age-related conditions. Scientists have long noted these differences, but they still do not fully understand why they occur — or how that knowledge can be used to improve healthy aging. Understanding these differences could lead to more effective ways to prevent disease, maintain independence and extend healthy life for everyone.

A new $7.5 million, five-year grant from the National Institutes of Health will establish the USC Geroscience Specialized Center of Research Excellence on Sex Differences in Aging (GeroSCORE) to address that challenge.

The award establishes USC’s first NIH Specialized Center of Research Excellence (SCORE) and positions the USC Leonard Davis School of Gerontology as a national leader in advancing research on sex differences in aging.

Funded by the National Institute on Aging in partnership with the NIH Office of Research on Women’s Health, GeroSCORE brings together experts in aging biology, neuroscience, psychology, epidemiology, demography, sociology and data science to understand how biological sex interacts with genetics, hormones, behavior, and social and physical environments to shape aging across the lifespan.

“This center represents exactly the kind of bold, interdisciplinary science needed to address the most important challenges in aging,” said Pinchas Cohen, dean of the USC Leonard Davis School. “For decades, USC has helped shape the field of geroscience. GeroSCORE builds on that foundation by bringing together outstanding scientists to answer fundamental questions about aging while creating new opportunities for collaboration, innovation and scientific leadership.”

Building the future of aging research

Although research on sex differences has expanded rapidly in recent years, progress has been slowed by fragmented approaches and a lack of common methods and resources across disciplines.

GeroSCORE was created to help change that.

“We know that women and men age differently; the challenge is understanding why,” said Professor Jennifer Ailshire, UPS Foundation Chair at USC Leonard Davis and one of the center’s directors. “By bringing together expertise that has traditionally been separated, GeroSCORE will help uncover how biology, environment and life experiences combine to shape aging.”

The center will conduct innovative research while also developing new tools, analytical methods and scientific resources that can be shared broadly. It will support pilot projects, train early-career investigators, convene national and international experts, and collaborate across the NIH SCORE network to accelerate discovery.

“The next generation of breakthroughs will come from connecting ideas across disciplines and creating better tools for researchers,” said Teal Eich, associate professor of gerontology and co-director of the center. “Our goal is not only to answer important scientific questions but also to build the frameworks that allow the entire field to move forward.”

The center’s research spans the full spectrum of aging science, from laboratory models to human participants to large population studies:

• Bérénice Benayoun, associate professor of gerontology, will lead a project to investigate how menopause influences brain aging using a novel animal model that more closely reflects the human menopausal transition.
• Teal Eich will combine neuroimaging, cognitive assessments, hormone measures and other biomarkers to examine how biological and neuroendocrine aging contribute to Alzheimer’s disease risk.
• Eric Klopack, adjunct assistant professor of gerontology and assistant professor of epidemiology and biostatistics at Indiana University, in collaboration with Ailshire and USC University Professor Eileen Crimmins, will use large population studies to investigate how genetic, environmental and social exposures interact to shape health and aging differently across the life course.

Together, these projects seek to identify the biological and environmental pathways that drive sex differences in aging and reveal new opportunities for prevention and intervention.

A national resource for discovery

Beyond its research program, GeroSCORE will serve as a national resource by developing shared tools, expanding scientific collaboration and training the next generation of researchers studying sex differences in aging.

“Scientific progress depends on more than individual discoveries,” said Crimmins, AARP Chair in Gerontology and GeroSCORE co-director. “It comes from building the methods, collaborations and scientific community that make discovery possible. Our vision is for GeroSCORE to become a national hub that helps shape the future of research on sex differences in aging while improving health and quality of life for generations to come.”

Several years ago, psychiatrist Jennifer Hong was brutally attacked by a patient. The attack deprived her brain of oxygen for almost a minute; the resulting physical and mental health effects were devastating, both professionally and personally.

Now in the last year of her child and adolescent psychiatry (CAP) fellowship at the Keck School of Medicine of USC, Hong credits the Lifestyle Redesign program at the USC Mrs. T.H. Chan Division of Occupational Science and Occupational Therapy with helping her get her life back on track.

“Because of this program, I have tons of optimism for the future,” Hong says. “Nothing has helped me with my anxiety and my depression and my life more than occupational therapy.”

Lifestyle Redesign is an innovative framework created at USC Chan to coach patients — mostly USC students — to develop daily routines that promote health and wellness.

The program takes a broader interpretation of occupational therapy beyond traditional associations with surgery recovery and workplace optimization.

“Lifestyle Redesign reflects the evolution of occupational therapy from a profession historically associated with rehabilitation to one that also plays a central role in prevention, health promotion and chronic disease management,” says Lindsey Shomer, associate professor of clinical occupational therapy and clinical manager of USC Chan’s OT faculty practice.

Kelly Liao, a USC Chan assistant professor of clinical occupational therapy, says that the way the program is designed expands opportunities for her and her colleagues to help patients like Hong manage their conditions.

“Through the program, we see patients improve their overall self-efficacy, get connected to resources and build up health-promoting habits and routines,” Liao says.

Creating new routines

 The Lifestyle Redesign program was developed through a controlled trial in the 1990s led by former USC Chan faculty member Florence Clark and her research team. The trial evaluated the ability of an OT-based program to prevent disease and improve the health outcomes of older adults through lifestyle changes.

“What makes the Lifestyle Redesign program unique is that we don’t simply teach strategies,” Shomer says. “We partner with clients to develop sustainable habits and routines that are meaningful to them.”

The program’s main office is in the Health Research Association building on the USC Health Sciences Campus. A dedicated team also sees patients at a second clinic within the USC Engemann Student Health Center on the USC University Park Campus. Many clinicians work on a hybrid schedule, offering both in-person and telehealth services.

USC students can schedule a free 20-minute conversation with one of the program’s therapists to learn more about occupational therapy and Lifestyle Redesign.

 Fighting through the fog

Hong says the resulting brain injury from her attack affected her attention, memory and executive functions the worst: She couldn’t remember the alphabet, was easily overwhelmed by tasks and couldn’t hear in crowded rooms. After seeing several therapists, she was diagnosed with attention-deficit/hyperactivity disorder (ADHD), depression, anxiety and PTSD.

When Hong moved to Los Angeles to begin the CAP fellowship at Keck School of Medicine, she struggled to take care of herself and manage the increased expectations of the program.

“I didn’t even notice I was not attending to my basic needs, such as showering or brushing my teeth on most days,” Hong says. Her inability to keep up her new daily demands culminated in forgetting to renew her medical license and being placed on temporary leave.

After CAP leadership referred her to the Lifestyle Redesign program, Hong says she instantly clicked with Liao, whom she described as “graceful, patient and supportive.”

“I immediately knew this was going to change every aspect of my life for the better, and I could not wait to continue,” Hong says.

First things first

To get Hong back on track, she and Liao first tackled Hong’s morning habits. After analyzing the environmental and sensory components of her routine, the pair discovered that Hong did not like being cold or wet in the morning. So, Liao helped Hong create practical workarounds, including placing a heater next to her bed and a cup at her bathroom sink to avoid scooping water into her mouth. This allowed her to optimize the first hours of her day.

“Before, I would be in bed for two hours literally every morning, dreading getting up,” Hong says. “Kelly completely transformed my morning routine, and we eventually worked on time management and awareness, prioritization, task initiation and completion, and incorporating environmental and externalizing scaffolding to help me cement my routines.”

One striking realization Hong had from working with Liao was how little she understood the ways ADHD affected many aspects of her everyday life and the lives of her patients — despite being a child psychiatrist.

“I wasn’t stupid, incompetent or careless for being the way I am,” Hong says. “I learned so much self-love and understanding for the way my brain functions. And that life does not need to always be this hard, all the time.”

 Trojan through and through

Liao, who describes herself as a “Trojan through and through,” was part of the bachelor’s-to-master’s program at USC Chan before earning her doctorate there. She says the Lifestyle Redesign program played a significant role in her decision to pursue her doctoral degree at USC.

“Mental health has always been a huge passion of mine, and after researching the Lifestyle Redesign program I found that it’s a perfect blend of holistic healthcare that looks at people’s behaviors, compared to traditional psychotherapy,” Liao says.

Because the program addresses chronic disease management, her colleagues in the program include clinicians who specialize in a variety of conditions, such as diabetes, hypertension and cancer.

Liao emphasizes that the aim of chronic disease management is not to “cure” the patient’s condition. “Clients become more confident once they know the strategies, tools and resources to use, so when challenges arise, they’re able to problem-solve and independently navigate those situations.”

Prioritizing health in college

It can be challenging to encourage college students to prioritize health and wellness at a time in life when many young people believe their body “can survive almost anything,” Liao says.

“We also know being in college means academics come first — sometimes self-care like sleeping and eating gets thrown to the side when midterms and finals are coming up.”

This was the case with Alex Zhi, a second-year graduate student at the USC Marshall School of Business. Zhi’s primary care physician referred him to the Lifestyle Redesign program for sleep issues.

After months of biweekly sessions with Liao, Zhi realized that because of occupational therapy, he could tackle issues in other areas of his life, including physical activity, nutrition and mental health.

“With Kelly’s help, I feel like I have so much support and so many resources,” Zhi says. “I feel like I literally transformed into another person: I went from someone who only eats Trader Joe’s frozen food and couldn’t get myself off the couch to someone who cooks constantly, gets enough protein and vegetables, and works out like five to six times a week.”

Zhi also found that the structure of occupational therapy sessions was more effective for him than the traditional therapy he’s experienced in the past.

“Taking very tangible steps, with someone who keeps me accountable and that I can brainstorm with, was more engaging and helped me achieve what I wanted faster,” Zhi says.

For Hong, who has now been in the program for nearly a year, the experience has been transformational.

“I learned that ADHD is actually my superpower,” Hong says. “With the proper scaffolding and skills learned through OT, I know this is just the beginning. There is absolutely nothing I cannot accomplish.”