Researchers, clinicians and community leaders gathered at the USC Leonard Davis School of Gerontology on Feb. 27 for the inaugural USC Asian Health and Longevity Symposium, a groundbreaking daylong event focused on the factors shaping health and well-being for Asian and Asian-American communities.

The first-of-its-kind symposium highlighted how biology, culture, migration histories and social environments influence health across the lifespan. In Southern California, home to one of the nation’s largest and most diverse Asian populations, speakers said those patterns present both urgent health challenges and important opportunities for research, clinical care and community partnership.

Steven Shapiro, USC senior vice president for health affairs, said the symposium reflected a broader shift toward more personalized medicine.

“We’re at an incredible time in our human history to make progress on understanding the mechanisms of disease,” Shapiro said. “All of our diseases are just a constellation of our genes and our environment, so why not think about populations, such as Asians, individually as a road to this personalized care?”

Pinchas Cohen, dean of the USC Leonard Davis School and USC Distinguished Professor of Gerontology, Medicine and Biological Sciences, said the event represented years of planning and collaboration.

“This event has been an effort that’s been in motion for over two years and represents the culmination of a tremendous amount of work by many people, but it’s been a labor of love,” Cohen said.

Biodemography Research Paints a Nuanced Picture

Keynote speaker Eileen Crimmins, USC University Professor and AARP Chair in Gerontology, opened the scientific program with a broad look at health and longevity in Asian countries and among Asian Americans in the United States.

“The longest-lived people in the world are Asian,” Crimmins said, pointing to Hong Kong, Japan and South Korea. She noted that the U.S. now ranks 48th in the world in average lifespan, while Singapore, Japan and South Korea also lead on healthspan, or the years spent free of chronic disease or disability.

“It’s not just mortality, it’s also morbidity that’s better in these countries,” she said.

Crimmins said people of Asian descent in the U.S. appear to retain some of that advantage, with an average lifespan of 85 years compared with 78 years for white Americans. Asian Americans also have rates of heart disease and cancer about half those of white Americans, even though they show a higher prevalence of diabetes, including at a normal weight.

Using 22 biomarker measurements, Crimmins and her team have found that people of Asian descent appear to show slower epigenetic and transcriptomic aging, longer telomeres, fewer senescent cells and lower chronic inflammation. But she cautioned against reading those findings as a complete explanation.

“Across these measures of biology, this is a population that looks healthier than the majority population in many ways, but biology is not the whole story,” Crimmins said.

Brain Health in Asian Communities

As the symposium moved from population patterns to specific diseases, brain health emerged as a major focus.

Arthur Toga, director of the USC Mark and Mary Stevens Neuroimaging and Informatics Institute, described how advances in imaging and data science are changing the study of neurological disease. He said precision medicine depends on research that includes diverse participants.

“If you look at the faces of the people around you, we’re all humans — we all have eyes, noses, mouths — but we’re all different,” Toga said. “The same is true in the brain.”

Helena Chui, professor and chair of neurology at the Keck School of Medicine of USC and director of the Alzheimer’s Disease Research Center, discussed Alzheimer’s disease in Asian populations and the mix of genetic and lifestyle factors that shape risk. She noted that APOE4, the most studied Alzheimer’s risk gene, is less common in Asians but appears to carry a stronger risk when present.

“25 percent of the people in this room have one copy of APOE4, and 5% have two copies,” Chui said.

While genetic risk cannot be changed, Chui said several lifestyle factors can be addressed across the lifespan.

“The most important thing in early life is education; cultures that emphasize education are making a really good investment for the future,” she said. “And in mid-life, that’s when we really start to affect the curve for later life. There are many things we can do.”

She also pointed to physical activity, including Tai Chi, as one protective measure.

Understanding Metabolic Health Beyond BMI

Another major theme was the need to rethink how clinicians assess metabolic risk.

Anne Peters, professor of clinical medicine at the Keck School of Medicine of USC, drew on decades of treating diabetes patients around the world.

“I’ve traveled the world teaching about diabetes and learning from other people, and I’ve learned there is no one type of diabetes but a thousand,” Peters said. “I treat everyone from an individualized perspective, but if I know this population has these features, I’m more likely to treat them appropriately.”

Kurt Hong, clinical professor of medicine and gerontology, focused on the limits of body mass index as a measure of risk. BMI, he said, was designed as a population screening tool and does not reveal how fat is distributed in the body.

“BMI only uses height and weight. It doesn’t tell us anything about one’s risk based on body composition,” Hong said.

That matters, he added, because Asian individuals often carry more visceral fat — stored around the organs — at lower BMI levels. “If we rely only on BMI, we may miss people who are at real risk,” he said.

Steven Shapiro, USC Senior Vice President for Health Affairs

Dean Pinchas Cohen welcomes attendees to the first-ever USC Asian Health and Longevity Symposium

University Professor Eileen Crimmins

Sook-Lei Liew, associate professor in the USC Chan Division of Occupational Science and Occupational Health

Helena Chui, professor and chair of neurology at the Keck School of Medicine of USC and director of the Alzheimer’s Disease Research Center

Vivian Mo, chief medical officer for USC Care Medical Group and director of the Women’s Cardiovascular Center at USC, and USC Trustee Dominic Ng, CEO of East West Bank

Arthur Toga, director of the USC Mark and Mary Stevens Neuroimaging and Informatics Institute

Yang Chai, University Professor and dean of the Herman Ostrow School of Dentistry

Distinguished Professor and USC Leonard Davis School Dean Pinchas Cohen

Associate Professor Jennifer Tsui, director for cancer care delivery research and implementation science at the USC Norris Comprehensive Cancer Center

Keck School Associate Professor of Clinical Medicine Gino In

Lihua Liu, associate professor of population and public health sciences at the Keck School of Medicine of USC and director of the USC Cancer Surveillance Program

Traditional Chinese Medicine provider Hua-Bing Wen

Associate Professor of Clinical Medicine Parveen Garg

Hiroshi Kumagai, adjunct research associate professor of gerontology

USC Leonard Davis Board of Councilors member Mei-Lee Ney receives a custom lab coat from Dean Pinchas Cohen in recognition of the Ney Center for Healthspan Science

USC Leonard Davis Board of Councilors member Mei-Lee Ney and Dean Pinchas Cohen

PhD candidate Mengzhao Yan with USC Leonard Davis Board of Councilors member Shari Thorell and Bob Thorell

Following the symposium, attendees enjoyed a reception in the Andrus Center courtyard

Yang Chai, dean of the Herman Ostrow School of Dentistry of USC, and Pinchas Cohen, dean of the Leonard Davis School of Gerontology

Asian Cohort Data Sheds Light on Powerful Proteins

Cohen described emerging research on mitochondrial microproteins, small molecules produced from the separate, smaller genome within cells’ mitochondria versus the larger genome in the cell nucleus. These tiny proteins appear to play big roles in metabolism, muscle function and aging. One of the many such molecules discovered in the Cohen laboratory, MOTS-c, appears to help regulate metabolism and protect muscle tissue and has enormous clinical potential, he said.

“These microproteins can have powerful effects on metabolism and disease,” Cohen said. He predicts that MOTS-c, which has cleared a Phase 1 trial for patient safety, could become an important treatment for diabetes, obesity, sarcopenia (loss of muscle mass), and more. “These discoveries open entirely new directions in biology and aging research, with the potential to develop therapies that mimic the benefits of exercise.”

In addition, MOTS-c treatment may also one day be recommended for carriers of a gene variant that is much more common in Asian populations. The gene produces a mutant form of the protein that is biologically inactive and is linked to a huge increase in Type 2 diabetes risk for men who carry the gene and are sedentary, Cohen explained.

Hiroshi Kumagai, adjunct research associate professor of gerontology, discussed how muscle biology contributes to healthy aging and described how physical activity can reduce levels of another mitochondrial microprotein, PUTZ, linked to negative metabolic health outcomes. Similarly to MOTS-c, a variant of the gene found more commonly in East Asian individuals codes for a form of the protein linked to significant increases in sarcopenia.

One day, a medicine containing a neutralizing antibody for the disadvantageous protein could help, especially for individuals with the genetic variant or for those with frailty or mobility issues, Kumagai said. For now, the recommendation is clear.

“Skeletal muscle is not just for movement – it also functions as an endocrine organ that plays key roles in metabolism and longevity,” Kumagai said. “Physical activity can dramatically reduce risk. … Start exercising today, not tomorrow.”

Tailoring Treatment for Oral and Systemic Health

The symposium also highlighted the connection between oral health and broader health outcomes.

Yang Chai, dean of the Herman Ostrow School of Dentistry of USC, said the mouth can provide important clues about systemic disease.

“Oral health is deeply connected to systemic health, with aging biology, chronic disease management, and precision therapeutics,” Chai said. “The mouth is both a mirror and a mediator of systemic disease.”

That discussion included the risks associated with medications used to treat osteoporosis. Parish Sedghizadeh, professor of clinical dentistry, said bisphosphonate-related osteonecrosis of the jaw is a serious complication that can arise when treatment standards do not account for population differences.

“This treatment is one-size-fits-all, and that’s where the problem arises,” Sedghizadeh said.

Uttam Sinha, professor at the Keck School and director of the USC Head and Neck Center, noted that head and neck cancers are especially prevalent in Asia, particularly Southeast Asia, and said prevention must be part of the response.

“Over the last two to three decades, incidence and mortality have risen,” Sinha said. “We have to do something different than the way we practice today.”

Cancer Disparities and Community Translation

Lihua Liu, associate professor of population and public health sciences at the Keck School and director of the USC Cancer Surveillance Program, led a discussion on cancer in Asian populations.

Wendy Setiawan, professor of population and public health sciences at the Keck School and co-leader of the USC Cancer Epidemiology Program, said that even within Los Angeles County, cancer risks vary widely across Asian ethnic groups.

“We cannot lump all Asians together as one group,” Setiawan said. “We have to look at specific ethnicities to identify high-risk groups and provide targeted prevention strategies.”

Gino In, associate professor of clinical medicine, described how precision oncology has sometimes advanced only after researchers studied tumors in Asian populations.

“The tide is turning in the war on cancer, and targeted therapy and precision medicine is going to be the key to this,” In said. “Our differences and our diversity should not be seen as something that divides us, because in scientific cancer research, our differences and our diversity can actually push progress, can push breakthroughs, and can save lives.”

Jennifer Tsui, inaugural director for cancer care delivery research and implementation science at the USC Norris Comprehensive Cancer Center, described working with the county’s Federally Qualified Health Centers (FQHCs) to provide staff training and community education encouraging patients to receive cervical cancer screenings. She said science only matters if it reaches the people it is meant to help.

“We’ve talked about amazing science all day, but the question is how successful is that if it never makes it to the people affected?” Tsui said.

Holistic Wellness Shaped by Both Eastern and Western Ideas

Conventional Western medicine and traditional Asian health practices can be complementary to one another versus conflicting, said Vivian Mo, chief medical officer for USC Care Medical Group and director of the Women’s Cardiovascular Center at USC. She spoke about her experience with patients using Traditional Chinese Medicine alongside mainstream care, noting that trust and communication are critical.

“It’s honestly a mutual education; I’ve learned a lot from my patients,” Mo said.

USC Trustee and CEO of East West Bank Dominic Ng said many Eastern health traditions emphasize prevention and wellness rather than waiting until illness develops.

“People are paying a lot more attention to wellness; people want to live well and stay healthy while they extend the longevity of life,” Ng said.

Hua-Bing Wen, who practices acupuncture and herbal medicine in West Los Angeles, said Traditional Chinese Medicine offers a holistic framework for aging that focuses on preserving function and resilience.

“Anything we do in Chinese medicine is based on patterns. We come up with that pattern by gathering all the information together,” Wen said. “Along with a physical exam, this information can also include imaging tests, bloodwork, and other results.”

Sean Curran, professor of gerontology and vice dean of the USC Leonard Davis School, said research from his lab points to intriguing overlaps between traditional approaches and geroscience. His team found that tea and compounds derived from oolong tea extended lifespan in C. elegans and appeared to reduce tau aggregation in models of Alzheimer’s disease.

“We don’t know the exact mechanism yet,” Curran said, “but with the possibility that we can pharmacologically treat this with something that was just found in tea, we start to move away from the anecdotal idea of tea being healthy for you to identifying the molecule that might be leading to increased health.”

Supporting Continued Investigation

As the symposium concluded, Cohen reflected on an “amazing day” and the breadth of ideas shared throughout the symposium. He also recognized USC Leonard Davis School Board of Councilors member Mei-Lee Ney for her support of aging research and scholarship.

In 2018, Ney gave the largest donation in the USC Leonard Davis School’s history to establish the Ney Center for Healthspan Science. Cohen, who directs the Ney Center presented Ney with a personalized Ney Center lab coat and described her as a valuable member of the research team.

“This day wouldn’t be complete without recognizing those who help us do this important work,” Cohen said. “I’m proud to call Mei-Lee a friend and colleague.”

Several attendees shared their appreciation and enthusiasm for the event and the wider initiative on health and longevity in Asian populations.

“What I found especially interesting was how the event showed both the ways Asian populations are connected to broader population health issues and the ways they have unique health and aging experiences that deserve focused attention,” said USC Leonard Davis PhD in Gerontology candidate Mengzhao Yan. “To me, having our school lead this initiative focused on Asian health and aging is important because it demonstrates a commitment to recognizing and addressing the specific experiences of underexamined communities, while also creating knowledge that can improve health for the whole population.”

Photos: USC/Kristopher Head; Beth Newcomb

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A new study led by researchers at the USC Leonard Davis School of Gerontology suggests that the benefits of the Mediterranean diet may be driven, in part, by tiny proteins hidden within our mitochondria, opening a new window into how diet shapes aging and disease risk.

The study, led by USC Leonard Davis Instructional Associate Professor of Gerontology Roberto Vicinanza, found that people who closely follow a Mediterranean-style diet have higher levels of two mitochondrial microproteins, humanin and SHMOOSE – both of which have been linked to protection against cardiovascular disease and neurodegeneration.

“These microproteins may act as molecular messengers that translate what we eat into how our cells function and age,” Vicinanza said. “It’s a new biological pathway that helps explain why the Mediterranean diet is so powerful.”

Diet, Mitochondria and Aging

The Mediterranean diet, which is rich in olive oil, fish, legumes, fruits and vegetables, has long been associated with lower risk of heart disease, diabetes and cognitive decline. But the mechanisms behind these benefits are still being uncovered.

In the new study, researchers analyzed blood samples from older adults with varying levels of adherence to the diet. Those with the highest adherence showed significantly elevated levels of humanin and SHMOOSE, along with lower markers of oxidative stress, a key driver of aging and chronic disease.

The team also found that specific foods appeared to matter. Olive oil, fish and legumes were associated with higher humanin levels, while olive oil and lower intake of refined carbohydrates were linked to higher SHMOOSE.

“These findings suggest that specific components of the Mediterranean diet may directly influence mitochondrial biology,” said USC Leonard Davis School Dean and USC Distinguished Professor Pinchas Cohen, the study’s senior author. “Humanin and SHMOOSE could serve as biomarkers for adherence to the Mediterranean diet and have clinical significance.”

A New Role for Mitochondrial Microproteins

The study builds on more than two decades of research led by Cohen, a pioneer in the discovery of mitochondria-derived peptides.

Unlike traditional proteins encoded in nuclear DNA, these microproteins are produced from small open reading frames in the separate mitochondrial genome, regions once thought to be nonfunctional.

Among the most well-studied is humanin, which was first identified by Cohen and colleagues in 2003. It has since been linked to improved insulin sensitivity, cardiovascular protection, longevity and preservation of cognitive function.

More recently, Cohen’s lab discovered SHMOOSE (Small Human Mitochondrial ORF Over SErine tRNA), a microprotein tied to brain health. A genetic variant of SHMOOSE has been associated with increased Alzheimer’s disease risk, while the normal form appears to protect neurons from amyloid-related damage.

“These peptides are emerging as key regulators of aging biology,” Cohen said. “They connect mitochondrial function to diseases like Alzheimer’s and heart disease and now, potentially, to nutrition.”

Linking Diet to Cardioprotection

Another notable finding from the study is a potential interaction between humanin and Nox2, an enzyme that produces harmful reactive oxygen species.

Higher humanin levels were associated with lower Nox2 activity, suggesting that the peptide may help reduce oxidative stress and protect the cardiovascular system.

The researchers propose that the Mediterranean diet may work through a dual mechanism: directly lowering oxidative stress while also boosting mitochondrial microproteins that further suppress damaging pathways.

“This could represent a new cardioprotective mechanism of the Mediterranean diet,” Vicinanza said.

From the Lab to Global Advocacy

Instructional Associate Professor of Gerontology Roberto Vicinanza addresses a UN meeting regarding the science and health benefits of the Mediterranean diet.

Beyond the lab, Vicinanza has also been active in promoting the Mediterranean diet on a global stage, linking his scientific work to a broader international effort to advance it as a model for health, culture, and sustainability. He has worked with the Municipality of Pollica in Italy, a UNESCO Mediterranean Diet emblematic community, to support the establishment of the International Day of the Mediterranean Diet at the United Nations. The observance will be held annually on November 16 and is aimed at raising awareness of the diet’s health, cultural, and environmental benefits worldwide. That broader mission aligns with the study’s findings, he said.

“We’re connecting centuries-old dietary traditions with cutting-edge molecular biology,” Vicinanza said. “It supports the idea that healthy eating patterns with little to no ultra-processed foods reflect how humans have eaten over long periods and may create conditions to which mitochondria—ancient cellular organelles—are likely adapted.”

Toward Precision Nutrition and Healthy Aging

While the study was relatively small and observational, the findings point to a new frontier in “precision nutrition,” where biomarkers like mitochondrial microproteins could help tailor diets to optimize health and longevity.

Future research will explore whether dietary interventions can directly increase levels of humanin, SHMOOSE and related peptides and whether those changes translate into reduced disease risk.

“Our goal is to move from observing associations to understanding causality,” Vicinanza said. “If we can harness these pathways, we may be able to design nutritional strategies that promote healthy aging at the molecular level.”

—

About the Study

The study, “Mediterranean diet adherence is associated with mitochondrial microproteins Humanin and SHMOOSE; potential role of the Humanin–Nox2 interaction in cardioprotection,” was published March 9, 2026 in Frontiers in Nutrition. Coauthors included Junxiang Wan and Kelvin Yen of the USC Leonard Davis School and Vittoria Cammisotto, Francesco Violi and Pasquale Pignatelli of Sapienza University of Rome.

The work was funded by the USC Daryl and Irwin Simon Nutrition for Alzheimer’s Disease Prevention Research Fund (to Vicinanza), the Hanson-Thorell Family Research Award (to Vicinanza), National Institutes of Health grant P30AG094848 (to Cohen) and PRIN 2022 grant 000031_23_PP_PIGNATELLI_PRIN_2022-B53D23021240006 (to Pignatelli).

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He would know. Nearly 25 years ago, Cohen — a professor at UCLA at the time — led a study on a growth hormone called insulin-like growth factor (IGF) that unintentionally revealed the existence of a small peptide called humanin. But this tiny protein wasn’t coded for in the DNA within the cell’s nucleus; it arose from the separate, smaller genome within the mitochondria, organelles known primarily for their function as energy-producing “powerhouses” of cells.  

Humanin’s source in the mitochondrial genome, 16S rRNA, wasn’t initially thought to be a region that could code for proteins at all. The notion that it could code for humanin and similar “microproteins” was initially met with a great deal of skepticism from others in the scientific community, recalls Cohen, who joined the USC Leonard Davis School in 2012. It took many years of subsequent research from Cohen and colleagues for the wider field to accept that 16S, as well as other similar regions of nuclear and mitochondrial DNA, could produce tiny proteins with huge roles in metabolism, aging and age-related diseases.

“People now recognize that there are these things called small open reading frames, and that they can express small proteins, or microproteins. This opens up the human genome, originally thought to contain only 20,000 genes, and increases it by at least two orders of magnitude,” Cohen explains. “And in the mitochondrial DNA, where we primarily work, there used to be thought to exist only 13 protein-coding genes that are all involved in the mitochondrial biology. Now, we think there are approximately 700 of them.”

What started as an inadvertent finding has, after weathering years of skepticism and sparking the interest of more and more researchers, started a new era in biology and drug discovery, he says. 

“The discovery of microproteins that we made 25 years ago and have built upon now was a real, unique body of work that represents a new chapter in biology,” Cohen says. “It really changes how we look at genetics and transcriptomics and proteomics. It completely reshuffles the deck, if you will.”

Mitochondria’s Multifaceted Role

Mitochondria aren’t simply energy factories for our cells; they also have important roles in metabolism, cell death, communication between cells and more. Their small, circular genome and their complex abilities reflect their evolutionary origin — before they were mitochondria, they were bacteria that were engulfed by larger cells to form a symbiotic relationship, which happened 1.5 billion years ago. This significantly upgraded ancient organisms’ ability to extract energy from food sources, allowing a more complex system to exist.

“Because mitochondria used to be bacteria themselves, they appear to retain some ability to sense their environment and communicate information to other mitochondria,” Cohen says.

Mitochondria’s communication skills are of particular interest to Changhan David Lee, associate professor of gerontology at the USC Leonard Davis School. Originally trained as a microbiologist and bacterial geneticist, he became more interested in the mitochondrial genome as he completed his PhD in genetic, molecular and cell biology at USC. In 2012, he joined Cohen’s group and began searching for new, small genes in the mitochondrial DNA that expanded the observations made in the Cohen lab. Lee was particularly excited about this concept as he was investigating new genes in bacterial genomes during his undergraduate training. 

“At the time, mitochondria were still largely thought about as ‘just making energy,’ but it didn’t really make sense that that was the only thing that mitochondria would have evolved to have become,” Lee says. “I knew there was something more to it. And then I found Hassy’s research, and it just clicked. So, I joined his lab, and we set off to find some new genes.”

One of the genes they discovered coded for a protein called MOTS-c. Found during a screening for peptide activity in response to metabolic changes, the microprotein was first described in 2015 for its role as an “exercise mimetic,” restoring insulin sensitivity and counteracting diet-induced and age-dependent insulin resistance. Subsequent studies of MOTS-c led by Cohen, Lee and colleagues have greatly expanded the microprotein’s job description, uncovering its role as both sender and receiver in intracellular communication during cellular stress and its protective effect against the muscle loss that often accompanies obesity and aging, as well as highlighting how the hormone is expressed in the brain to help regulate metabolism. 

In 2021, Research Assistant Professor of Gerontology Hiroshi Kumagai discovered a naturally occurring mutation found in 8% of Japanese individuals that predisposes them to Type 2 diabetes. Kumagai also recently discovered a key mechanism for the action of MOTS-c by unraveling the molecule CK2, with which MOTS-c interacts in muscle.

USC Leonard Davis School research has also shed light on how MOTS-c plays a role in immune system regulation. In mice that had been genetically engineered to develop autoimmune diabetes, a model of Type 1 diabetes in humans, treatment with injections of MOTS-c protected pancreatic cells from being attacked by immune cells and prevented the onset of the disease, per a 2021 study. And new research from Lee’s lab posits that MOTS-c is the first mitochondria-encoded peptide found to be a host-defense peptide, a protein that directly combats bacteria and regulates immune function.

“This shines a bit more of an evolutionary light on what the mitochondria, from its humble bacterial origin, may have had to do during evolution to work out a symbiotic relationship with a bigger cell and protect itself,” Lee says.

Mitochondrial Genetics and Aging 

Research Associate Professor of Gerontology Kelvin Yen has long been interested in aging, conducting research on caloric restriction and longevity in mice as an undergraduate at the University of California, Berkeley, and studying the role of insulin and IGF signaling in extending the lifespan of worms as a PhD student at Mount Sinai School of Medicine. In 2010, as a postdoctoral researcher at the University of Massachusetts, Yen attended a talk given by Cohen on novel mitochondrial peptides and their role in aging and was immediately intrigued.

“It was super cool and very exciting,” Yen recalls. “I’d never heard of these microproteins before in my life, much less a mitochondria-specific microprotein.” Yen reached out to Cohen following the talk to ask about postdoctoral opportunities; he relocated to Los Angeles and joined the Cohen lab in 2011. 

Since then, interest in mitochondrial microproteins has expanded rapidly, not only as USC Leonard Davis researchers identified more proteins but also as mass spectrometry technology improved, enabling more thorough confirmation of the new peptides, Yen explains. And as the body of research has grown, it has further highlighted the connections among mitochondrial biology, aging and age-related diseases.

In a 2016 study, the Cohen group uncovered the genes for six new mitochondrial microproteins, which were dubbed small humanin-like peptides (SHLP, pronounced “schlep”) 1 through 6, and described their possible protective roles versus age-related diseases, including cancer. Of the six, SHLP 2 has been particularly interesting, with the initial study suggesting that it has insulin-sensitizing, anti-diabetic effects.  

Subsequent research published in 2024 showed how a variant of the SHLP 2 gene with a single-nucleotide polymorphism (SNP, or “snip”) — a difference in just one “letter” of the protein’s genetic code — increased both its expression and stability and cut the risk of Parkinson’s disease by 50%. The paper, first-authored by Adjunct Research Professor of Gerontology Su-Jeong Kim, noted that the variant was found in 1% of people of European descent.

Similarly, the mitochondrial microprotein MENTSH, recently characterized by Yen, appears to have a SNP variant associated with an increased risk of diabetes. The variant is more commonly found in people of Native American descent, Yen says.

Mitochondrial genetics offers unique insight into aging across various populations due to its location outside the nucleus of the cell, Cohen says. “With every other gene in the body, there are two copies; every person is an admixture of their two parents,” he says. “But mitochondrial DNA only comes from our mother; we only get one copy, and there is no admixture. This allows us to use mitochondrial DNA to trace our maternal ancestry.”

In addition, while mitochondrial DNA is passed directly from mother to child, it also undergoes evolution at 10 times the rate of nuclear DNA. As a result, “there’s a lot of diversity within the mitochondrial DNA that’s directly linked to maternal ethnicity,” Cohen explains. 

Cross-Disciplinary Strength

As USC Leonard Davis researchers have characterized more microproteins, they have also been able to leverage the school’s leadership in biodemography, the incorporation of biological data into large population studies. With the genetic information that’s included in studies such as the Health and Retirement Study in the U.S., scientists can get a clearer picture of how mitochondrial DNA relates to health in humans, says USC University Professor and AARP Chair in Gerontology Eileen Crimmins, a pioneer in biodemography.

“Because we have built these large data sets with representative samples of individuals from different backgrounds, we can look up various genetic markers and we can see how they relate to health outcomes in real populations, with all the other competing things that affect their health,” Crimmins says. She and colleague Em Arpawong, research associate professor of gerontology and director of the Gerontology Bioinformatics Core, have invoked multiple data sources and data types, from genetic code to gene expression levels, to collaborate in unraveling how the mitochondrial genome works together with the nuclear genome to affect aging-related processes. They are co-authors on many USC Leonard Davis mitochondrial microprotein studies, designing analyses that take results from the lab bench and put them into real-life context. Brendan Miller, a 2022 USC PhD in neuroscience graduate, says the interdisciplinary nature of the Leonard Davis School was the “perfect environment” for his work. His fascination with mitochondria having their own genome and his interest in Alzheimer’s led him to the school and Cohen’s lab, and having Crimmins as a co-mentor helped him obtain his skills in statistical methods, population genomics and big-data analyses.

“As a result, we’ve been able to go into these large population databases and find different mitochondrial genes and variants of these genes and immediately bring them down into an experiment that we can test,” Miller says. “That was the biggest standout of USC: having multiple experienced investigators from different backgrounds working on the same question.”

Miller, now a postdoctoral scientist at the Salk Institute, was first author of a 2022 Cohen lab study that identified the mitochondrial peptide SHMOOSE. He used the techniques he learned at USC to identify a mutated version of the protein that increased Alzheimer’s disease risk and brain atrophy. Nearly a quarter of persons of European descent appear to have the mutation, which is associated with a 30% increase in Alzheimer’s risk. 

“Ultimately, the goal for SHMOOSE would be to find ways to increase its sensitivity or stability, and pinpoint the exact mechanism that it is involved in,” Miller says, explaining that the peptide’s significant association with Alzheimer’s risk could make it an important drug candidate. 

Microproteins in general are exciting potential treatments for age-related disease by nature of their size, he adds. 

“Peptides offer a significant advantage in drug development because they’re specific as protein binders,” Miller explains. “There’s often many off-target effects from using larger drug templates. But for peptides, they are smaller and tend to be more specific.”

The tiny peptides produced from the mitochondrial genome appear to have big impacts on obesity, diabetes, frailty, Alzheimer’s and more, according to research from the Cohen lab. Additional recently discovered peptides also show promise against cancer, heart disease and eye disease.

Looking to the Future

Since Cohen arrived at the USC Leonard Davis School in 2012, he and his team have discovered and published research on a dozen mitochondrial microproteins, with many more in the pipeline, he says. The tools and techniques he and colleagues have developed continue to advance the field and propel discoveries toward translation.

“We know that these peptides have important roles in Alzheimer’s disease, Parkinson’s disease, cancer, obesity, diabetes, heart disease and probably multiple other issues related to health and aging. And we’ve created a pathway for discovery, characterization, IP protection, preclinical development and potential commercialization,” Cohen says. 

He notes that an analog of MOTS-c has reached human clinical trials in a company he co-founded, with a Phase 1 study suggesting that MOTS-c treatment indeed has beneficial effects similar to what was seen in animal data. “It is overall a very exciting field with a lot of potential,” he says. “Naturally, it needs substantial investment to move to the next step, but the scientific foundation and rationale are only getting stronger and more compelling.”

Another part of growing the school’s strength in mitochondrial research has been recruiting and educating researchers who are excited about mitochondria and their roles in aging. Ana Silverstein and Melanie Flores, 2024 PhD in molecular biology graduates and postdoctoral researchers in the Cohen lab, both say they didn’t know much about mitochondria when starting their PhD program but broadly knew they wanted to study the immune system and cancer, respectively. Both note that learning about Cohen’s research during a presentation for molecular biology PhD students immediately sparked their interest.

“I saw immense overlap in my research interests in immunity and inflammation, and exploring questions related to mitochondrial function and the field of aging seemed like this exciting and nebulous expedition that I became eager to be a part of,” Silverstein says. “I jumped into longevity research and never looked back.”

Both researchers are already contributing to the rapidly growing body of mitochondrial microprotein research. Silverstein is working to characterize a peptide that’s a potential regulator of obesity and inflammation, while Flores is investigating a peptide that appears to be involved in regulating tumor growth and survival and could have potential implications for cancer therapeutics.

After more than two decades, the initial skepticism surrounding the discovery of mitochondrial microproteins has morphed into infectious excitement about this uncharted territory in biology — and the USC Leonard Davis School is blazing the trail.

“We’ve established multiple investigators within the school who are part of this process working on various different microproteins, all of which are important and relevant in aging, and have created the infrastructure to continue to use these tools to identify additional high-value mitochondrial microproteins that can be translated into potential interventions in diseases of aging,” Cohen says. “A lot of the people that I’ve trained have chosen this to be their field of study. And we’ve created a real force here, with many collaborations within USC and other collaborators in Los Angeles, around the country and around the world.”

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In a study of centenarians conducted in collaboration with scientists at Albert Einstein College of Medicine, the variant, affecting a mitochondrial microprotein called humanin, was found to be more prevalent in individuals who reached the age of 100 in spite of having the APOE4 allele which predisposes people to Alzheimer’s disease and earlier death.

In a series of analyses, the researchers found that the presence of the variant (termed P3S-humanin) in APOE4 carriers seemed to preserve cognitive function. The P3S variant is thought to be extremely rare in the general population and is found primarily in people of Ashkenazi Jewish descent. Subjects were enrolled in the Einstein Longevity Genes Project, a study of more than 500 healthy centenarians, near-centenarians and their children.

“This new study sheds light on resilience genes that help people live longer and partially explains why some people at high risk for developing Alzheimer’s disease are spared,” said senior author Pinchas Cohen, distinguished professor of gerontology and biological sciences and dean of the USC Leonard Davis School. “It also opens a new direction for exploring therapies based on mitochondrial microproteins.”

The findings appeared online on March 23, 2024, in the journal Aging Cell.

“This work shows the incredible utility of studying centenarians to discover new targets for healthy longevity,” said  co-author Nir Barzilai, director of the Institute for Aging Research at Einstein.

In addition to demonstrating the direct binding and stabilizing effects of the P3S-humanin on the harmful APOE4 protein, the investigators showed that giving the P3S microprotein to mice engineered to express human APOE4, (and develop an Alzheimer’s-like condition), reduced the build-up of amyloid-beta in their brains. This build-up is a key feature of Alzheimer’s disease.

Mitochondrial microproteins and aging

Cohen has long studied how different mitochondrial small genes might influence aging. His team pioneered the emerging field of microproteins and has already described ten of them, including one, named MOTS-c,  that has progressed to clinical trials for reducing obesity.

Earlier this year, his lab identified a microprotein that offers protection against Parkinson’s disease (named SHLP2) and in 2022 they described a new microprotein that is also involved in Alzheimer’s (named SHMOOSE).  This latest finding builds upon the team’s prior mitochondrial research and represents an advance at the intersection of longevity science, precision health, and microprotein discovery.

In the current study, first author Brendan Miller, a former Cohen Lab doctoral student and current postdoctoral scientist at the Salk Institute, led a series of experiments that identified P3S, a rare humanin variant that was most prevalent among centenarians of Ashkenazi decent. They found that approximately 12% of these centenarians had this variant, which changes the third amino acid from proline to serine. In contrast, the frequency of humanin P3S was less than 0.2% in other populations of European and non-European descent.

APOE4 and Alzheimer’s Risk

Individuals who carry the APOE4 version of the APOE gene usually face poorer health outcomes compared to those with the common version (APOE3) and have significantly higher risk of Alzheimer’s disease as well as shorter lifespans. However, APOE4 carriers, who also inherited the P3S variant were largely protected from these poor outcomes. Among APOE4-carrying centenarians, those with humanin P3S outperformed those without the humanin variant in a test of cognitive function, suggesting that the variant mitigated the increased risk posed by the APOE4 gene.

The team further studied the effects of humanin P3S by administering the protein to mice genetically engineered for Alzheimer’s with a humanized APOE4 gene. Treatment with humanin P3S resulted in a marked reduction of amyloid-beta in the brains of the mice. Treatment with the standard version of humanin resulted in some decrease of amyloid-beta but was outperformed by humanin P3S. Further in vitro and computer analysis indicated that humanin P3S’s slight structural differences allowed it to bind more effectively to APOE4, resulting in increased uptake and destruction of amyloid-beta.

“This humanin P3S, when made by mitochondria, actually binds the protein product of APOE4 very tightly. This seems to help clear away harmful amyloid-beta, which builds up in the brains of people with Alzheimer’s,” said Miller. “Our experiments showed that this protein variant could be a reason why some people with the risk-gene avoid Alzheimer’s and maintain good brain health into old age.”

New insights and directions

The study illustrates a new way of understanding how people with the APOE4 gene may resist common age-related diseases like Alzheimer’s, and the findings also emphasize the need for further research into how interactions between mitochondrial and nuclear DNA influence aging. The researchers say that ultimately, this discovery opens more therapeutic avenues for individuals at risk for age-associated diseases, such as Alzheimer’s disease.

“Going forward, since humanin P3S is a microprotein, it could serve as a template for drug design,” said Cohen. “Microproteins are much smaller than typical proteins, providing advantages for drug development. Additionally, since we understand where humanin P3S binds to the protein product of APOE4, designing small molecules could be a viable strategy.”

Along with Miller and Cohen, coauthors included Su-Jeong Kim, Kevin Cao, Hemal H. Mehta, Neehar Thumaty, Hiroshi Kumagai, Tomomitsu Iida, Cassandra McGill, Christian J. Pike, and Kelvin Yen of the USC Leonard Davis School; Kamila Nurmakova and Zachary A. Levine of Yale University; Patrick M. Sullivan of Duke University Medical Center; Nilüfer Ertekin-Taner of the Mayo Clinic Department of Neuroscience; and Gil Atzmon and Nir Barzilai of the Albert Einstein College of Medicine.

This work was supported by National Institutes of Health/National Institute on Aging grant AG057912 and the Yale Center for Research Computing to Levine, NIH RF1AG058068 to Pike; NIH/NIA T32AG00037 to Miller; and NIH/NIA grants R01AG061834, R01AG068405, R01AG069698, P01AG034906, and P30AG068345 to Cohen.

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The variant, located in a mitochondrial microprotein dubbed SHLP2, was found to be highly protective against Parkinson’s disease; individuals with this mutation are half as likely to develop the disease as those who do not carry it. The variant form of the protein is relatively rare and is found primarily in people of European descent.

The findings appear January 3, 2024, in the journal Molecular Psychiatry.

First discovered by Pinchas Cohen at the USC Leonard Davis School in 2016, SHLP2 is made within the cell’s mitochondria. Previous research from the Cohen Lab established that SHLP2 is associated with protection from aging-related diseases including cancer and that levels of the microprotein change in patients with Parkinson’s disease; they rise as the body attempts to counteract the pathology of Parkinson’s disease but often fail to mount additional production as the disease progresses.

This latest finding builds upon the USC team’s prior mitochondrial research and represents an advance at the intersection of longevity science, precision health, and microprotein discovery.

“This study advances our understanding of why people might get Parkinson’s and how we might develop new therapies for this devastating disease,” said Cohen, professor of gerontology, medicine and biological sciences and senior author of the study. “Also, because most research is done on well-established protein-coding genes in the nucleus, it underscores the relevance of exploring mitochondrial-derived microproteins as a new approach to the prevention and treatment of diseases of aging.”

For this study, first author Su-Jeong Kim, an adjunct research assistant professor of gerontology at the USC Leonard Davis School, led a series of experiments that leveraged the Lab-developed microprotein discovery pipeline that begins with a big data-driven analysis to identify variants involved in disease. Thousands of human study subjects from the Health & Retirement Study, Cardiovascular Health Study, and Framingham Heart Study were screened for the SHLP2 variant. By comparing genetic variants in the mitochondrial DNA in patients with Parkinson’s disease and in controls, researchers found a highly protective variant found in 1% of Europeans, that reduced risk of Parkinson’s disease by twofold, to 50% of average.

Next, they demonstrated that this naturally occurring variant results in a change to the amino acid sequence and protein structure of SHLP2. The mutation – a single nucleotide polymorphism (SNP), or a change to a single letter of the protein’s genetic code – is essentially a “gain-of-function” variant that is associated with higher expression of SHLP2 and also makes the microprotein more stable. According to their findings, the SHLP2 variant has high stability compared to the more common type and provides enhanced protection against mitochondrial dysfunction.

The research team was able to use targeted mass spectrometry techniques to identify the tiny peptide’s presence in neurons and found that SHLP2 specifically binds to an enzyme in mitochondria called mitochondrial complex 1. This enzyme is essential for life, and declines in its function have been linked not only to Parkinson’s disease but also to strokes and heart attacks.

The increased stability of the SHLP2 variant means that the microprotein binds to mitochondrial complex 1 more stably, prevents the decline of the enzyme’s activity, and thus reduces mitochondrial dysfunction. The benefits of the mutant form of SHLP2 were observed in both in vitro experiments in human tissue samples as well as in mouse models of Parkinson’s disease, according to the study.

“Our data highlights the biological effects of a particular gene variant and the potential molecular mechanisms by which this mutation may reduce the risk for Parkinson’s disease,” said Kim. “These findings may guide the development of therapies and provide a roadmap for understanding other mutations found in mitochondrial microproteins.”

Coauthors included Brendan Miller, Nicolas G. Hartel, Ricardo Ramirez II, Regina Gonzalez Braniff, Naphada Leelaprachakul, Amy Huang, Yuzhu Wang, Thalida Em Arpawong, Eileen M. Crimmins, Kelvin Yen, Giselle M. Petzinger, Michael W. Jakowec, and Nicholas A. Graham of USC; Penglong Wang and Chunyu Liu of the National Heart, Lung, and Blood Institute, National Institutes of Health; and Xianbang Sun and Daniel Levy of Boston University.

This work was supported by Department of Defense grant W81XWH2110625 to Kim and by NIH grants P01AG034906, R01AG068405 and P30AG068345 to Cohen. Pinchas Cohen is a consultant of CohBar Inc.

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The protein, called SHMOOSE, is a tiny “microprotein” encoded by a newly discovered gene within the cell’s energy-producing mitochondria. A mutation within this gene partially inactivates the SHMOOSE microprotein and is associated with a 30% higher risk for Alzheimer’s disease across four different cohorts. Nearly a quarter of people of European ancestry have the mutated version of the protein, according to the researchers.

The research appears Wednesday, September 21 in the journal Molecular Psychiatry.

The researchers say that both the substantial risk and high prevalence of this previously unidentified mutation differentiate it from other proteins involved in Alzheimer’s disease. Apart from APOE4 — the most potent known genetic risk factor for the disease — only a limited number of other gene mutations have been identified and these only mildly increased risk by less than 10%. Also, because the microprotein is approximately the size of the insulin peptide, it can be easily administered, which increases its therapeutic potential.

“This discovery opens exciting new directions for developing precision medicine-based therapies for Alzheimer’s disease, focusing on SHMOOSE as a target area,” said Pinchas Cohen, professor of gerontology, medicine and biological sciences and senior author of the study. “Administration of SHMOOSE analogs in individuals who carry the mutation and produce the mutant protein may prove to have benefit in neurodegenerative and other diseases of aging.”

Brendan Miller, ’22 PhD in neuroscience graduate and first author of the study, used big data techniques to identify genetic variations in mitochondrial DNA associated with disease risk. After analyses revealed a gene mutation increased Alzheimer’s disease risk, brain atrophy, and energy metabolism, Miller and his colleagues discovered that the mutated gene coded for the SHMOOSE microprotein and began studying its mutated and default forms. The researchers stated SHMOOSE is the first mitochondrial-DNA-encoded microprotein to have been detected using both antibodies and mass spectrometry.

The microprotein appears to modify energy signaling and metabolism in the central nervous system. It was found in mitochondria of neurons and its levels in cerebrospinal fluid correlated with biomarkers of Alzheimer’s disease. A variety of cell culture and animal experiments showed that SHMOOSE alters energy metabolism in the brain in part by inhabiting a crucial part of the mitochondria, the inner mitochondrial membrane.

An emerging field of study

Miller said the findings highlights the importance of the relatively new field of microproteins. For decades, scientists have studied biology mostly by considering a set of 20,000 large protein-coding genes. However, new technology has highlighted hundreds of thousands of potential genes that encode smaller microproteins.

“The field of microproteins is still so new,” Miller said. “We don’t yet know how many microprotein genes are even functional, and the cost to study a potential microprotein one-by-one from a list of thousands is just too expensive and inefficient. The approach my colleagues and I used to detect SHMOOSE shows the power of integrating big genetics data with molecular and biochemical techniques to discover functional microproteins.”

USC Leonard Davis researchers are leaders in the study of microproteins, especially those coded within the mitochondrial genome. In 2003, Cohen and his colleagues were one of the three research teams to independently discover the protein humanin, which appears to have protective health effects in Alzheimer’s, atherosclerosis and diabetes.  In the past few years, the Cohen Laboratory discovered several other mitochondrial microproteins, including, small humanin-like peptides, or SHLPs, and a microprotein called MOTS-c, an exercise-mimetic peptide that has entered clinical trials for obesity and fatty liver.

Additional coauthors include Su-Jeong Kim, Hemal H. Mehta, Kevin Cao, Hiroshi Kumagai, Neehar Thumaty, Naphada Leelaprachakul, Henry Jiao, Thalida E. Arpawong, Eileen Crimmins, Meral A. Tubi, Evan T. Hare, Meredith N. Braskie, Léa Décarie-Spain, Scott E. Kanoski, Lu Zhao, Arthur W. Toga, Junxiang Wan, and Kelvin Yen of USC; as well as Joan Vaughan, Jolene Diedrich, and Alan Saghatelian of the Salk Institute for Biological Studies; Nilüfer Ertekin-Taner of the Mayo Clinic; and Francine Grodstein and David A. Bennett of the Rush University Medical Center.

The study was supported by NIH grants P30AG10161, P30AG072975, R01AG15819, R01AG17917, U01AG61356, R01AG069698, RF1AG061834, R01AG068405, P30AG068345, P01AG055369, DK118402, F31 AG059356, and T32 AG00037; as well as The Quebec Research Funds Postdoctoral Fellowship. Intellectual property related to SHMOOSE has been filed by the University of Southern California.

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Measures of muscle health correlate with overall health in older populations. While a lack of exercise or poor diet can contribute to age-related muscle loss, genetic factors also likely play a role, according to the researchers.

The research, published this month in eLife, identifies specific genetic contributors associated with age-related muscle loss, a condition connected to a decline in quality of life, an increased risk of falls, and sarcopenia, the progressive loss of strength and performance that impacts up to half of older adults.

“While aging is universal, the genetic factors that contribute to differences among individuals as they age are unclear. We wanted to examine the role that genetic variations in a mitochondrial enzyme play in age-related changes to mobility and were able to uncover a new biomarker of age-related muscle health,” said Osvaldo Villa, a Biology of Aging PhD student at the USC Leonard Davis School of Gerontology.

Villa is a co-first author of the study alongside Nicole Stuhr, a current PhD student in the laboratory of USC Leonard Davis Professor Sean Curran, and Chia-An Yen, who recently earned her PhD under Curran’s mentorship.

For their study, the team screened the roundworm Caenorhabditis elegans (C. elegans) for genetic mutations that contribute to a build-up of oxidative stress, a process that can cause cell damage in muscle tissue. They found that mutations in a mitochondrial gene called ALH-6 were strongly associated with stress responses specifically in the muscle. Over time, worms with these mutations displayed premature decline in mobility; slower crawling and swimming.

Next, the team analyzed data from the U.S. Health and Retirement Study (HRS) to see if genetic variants in the human equivalent of this gene, called ALDH4A1, were also linked to age-related mobility changes. The HRS has enrolled more than 36,000 US adults aged 50 and over, and collected genetic and health information. By analyzing a subset of participants with genetic data and measures of strength, the researchers found that older adults with certain variations in the ALDH4A1 gene had slower walking speeds and reduced hand strength as they aged.

“These findings suggest that variations in the ALH-6 or ALDH4A1 gene can impact muscle aging in C. elegans and humans, and may help predict muscle health in people as they age,” said Stuhr.

The team cautions that many human genes likely interact with each other, as well as diet and other factors, to influence strength and mobility as people age. More studies are needed to understand all of the genes involved in these age-related changes.

The study adds to previous USC Leonard Davis School research related to mitochondrial proteins and muscle mass and provides a model to understand the complex role mitochondria play in organismal health over the lifespan.

It also introduces a new experimental platform for comparing biological data from humans with that of the C. elegans by leveraging collaboration with the Genomic Translation Across Species Core (GTASC) in the USC-Buck Nathan Shock Center of Excellence in the Basic Biology of Aging. The GTASC is co-led by USC Leonard Davis School Research Assistant Professor Thalida Em Arpawong and University Professor Eileen Crimmins, additional co-authors on this study.

“We are now planning to partner with other researchers to allow them to integrate their genetic research models with our human gene-wide association scanning approach, said senior author Curran, professor of gerontology, molecular and computational biology and associate dean of research at the USC Leonard Davis School. “Building on our work in this way could help with identifying new predictors of age-related changes in muscle health and other age-related conditions.”

This work was funded by the NIH R01 AG058610 and RF1 AG063947 to S.P.C., T32 AG052374 to O.V. and N.L.S. and T32 GM118289 to N.L.S. This study was supported in part by funding from The National Institute on Aging, through the USC-Buck Nathan Shock Center (P30 AG068345). The National Institute on Aging has supported the collection of both survey and genotype data for the Health and Retirement Study through co-operative agreement U01 AG009740.

Press release courtesy of eLife with additional reporting by the USC Leonard Davis Office of Communications. Top: microscopy image of C. elegans courtesy of the Curran Lab.

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Daryl and Irwin Simon, founders of the largest natural organic food company, have established a new research fund at the USC Leonard Davis School. The USC Daryl and Irwin Simon Nutrition for Alzheimer’s Disease Prevention Research Fund was created to explore the role diet can play in the prevention or delay of Alzheimer’s disease.

Previous research by USC Leonard Davis Professor Christian Pike found that a diet high in cholesterol, fat and sugar may be associated with a greater incidence of Alzheimer’s disease in people who carry the ApoE4 gene. In addition, USC Leonard Davis Professor Valter Longo is a leader in advancing research on dietary interventions to reduce risk factors for age-related diseases, including Alzheimer’s and related dementias. USC Leonard Davis Research Assistant Professor Kelvin Yen identified novel mitochondrial hormones, such as humanin, that respond to healthy diets and promote neuroprotection.

“We are thrilled to have early adopters and leaders in the health food industry support new research in this important area,” said Dean Pinchas Cohen. “It is appropriate that the couple that helped mainstream health food in major markets would help us advance the science of nutrition and disease prevention research at the USC Leonard Davis School.”

“My husband, Irwin, and I have dedicated nearly 30 years of our lives to educating people around the world on the importance of eating a healthier diet, particularly focusing on natural and organic foods and ingredients,” said Board of Councilors member and USC Leonard Davis School benefactor Daryl Simon. “We are now very proud and excited to work with the USC Leonard Davis School, which is world-renowned for its efforts to reduce the risk of Alzheimer’s disease, particularly for those who carry the ApoE4 gene.”

Alzheimer’s disease remains one of the costliest and deadliest diseases of aging. An estimated 5.4 million Americans currently have Alzheimer’s, which costs a staggering estimated $286 billion a year. Additionally, research collaborators at the USC Schaeffer Center for Health Policy and Economics predict that the number of people diagnosed with Alzheimer’s in the U.S. will more than double in the next 35 years, to 9.1 million, with total care costs in excess of $1.5 trillion.

USC Leonard Davis researchers will be able to submit grant proposals for funding from the research fund over several grant cycle competitions. These seed grants are designed to fund the collection of pilot data that can lead to larger, more established funding sources, such as National Institutes of Health grants. The first awardees are Research Assistant Professors Sebastian Brandhorst, Amy Christensen and Kelvin Yen, who teamed up for a joint project. 

Research Assistant Professor Sebastian Brandhorst

 

Research Assistant Professor Amy Christensen

 

Research Assistant Professor Kelvin Yen

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Assistant Professor Changhan David Lee

A new study has shown that treating type 1 diabetes-prone mice with the small protein MOTS-c prevented the immune system from destroying insulin-producing pancreatic cells, effectively preventing the onset of the autoimmune disease.

The small protein that first made headlines as an “exercise mimetic” increasingly appears to also have a big role in regulating the immune system, said Assistant Professor of Gerontology Changhan David Lee, co-corresponding author of the study.

Regulating the immune system

Type 1 diabetes, previously known as juvenile diabetes, is an autoimmune disease that accounts for 5 to 10% of diabetes cases. In patients with type 1 diabetes, the immune system attacks the islet regions of the pancreas, which are made up of hormone-producing cells. When immune cells mistakenly destroy healthy beta cells—the pancreatic cells that produce the sugar-regulating hormone insulin—the body loses the ability to make insulin, control blood sugar levels and properly use sugar for energy.

In mice that had been genetically engineered to develop autoimmune diabetes, treatment with injections of MOTS-c prevented the onset of the disease. The new study illustrates how treating mice with MOTS-c supports regulatory T-cells—the immune cells that recognize which cells are the body’s own—and thereby reduces the activation of “killer” T-cells that improperly attack healthy cells in the pancreatic islets.

“We are able to prevent the onset of type 1 diabetes in mouse models,” Lee said. “MOTS-c injections seem to tame the immune system and to tell them not to tackle their own cells.”

Conversely, in a subsequent analysis in humans, type 1 diabetes patients had significantly lower levels of MOTS-c circulating in their blood compared to non-diabetic patients, and a study of human cells from both diabetic and non-diabetic patients revealed that MOTS-c treatment reduced the activation of “killer” T-cells.

New targets for treatments

This potential immune-regulating role of MOTS-c highlights possible new targets for treatment of autoimmune diseases beyond type 1 diabetes, Lee explained.

“It’s been thought for the longest time that the immune system is exclusively encoded in the nuclear genome,” Lee said. “Now we’re bringing into play an immune regulator that’s encoded in the mitochondrial genome.”

MOTS-c is one of several more recently identified hormones that are encoded in the DNA of mitochondria, the “powerhouses” of cells that convert food into energy; most other hormones are encoded in DNA in the nucleus.

Lee and Professor Pinchas Cohen, dean of the USC Leonard Davis School, first described MOTS-c in 2015, along with its role in restoring insulin sensitivity and counteracting diet-induced and age-dependent insulin resistance – effects commonly associated with exercising. The team has also studied MOTS-c’s role in intracellular communication as well as how the hormone is expressed in the brain to help regulate metabolism.

“The mitochondrial genome encodes for previously unknown genes that yield small proteins with multiple physiological roles, including aging, exercise, metabolism, and immunity,” Lee said. “Further studies on the molecular mechanism of these mitochondrial-encoded peptides are ongoing and may provide novel therapeutic targets for autoimmune conditions, which increases as we age.”

About this study

“Mitochondrial-encoded MOTS-c prevents pancreatic islet destruction in autoimmune diabetes” first appeared online in Cell Reports on July 27, 2021. Lee’s coauthors include co-corresponding author Young Min Cho, first author Byung Soo Kong and Se Hee Min, all of the Seoul National University College of Medicine in South Korea.

This research was supported by the Basic Science Research program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education of Korea (2017R1A2B4007166 ) and by Seoul National University Hospital ( 0320160040 ) to Young Min Cho and NIH grants R01AG052258 and R01GM136837 to Lee.

Top: In mice that had been genetically engineered to develop autoimmune diabetes, “killer” T-cells (darker spots) infiltrate and destroy insulin-producing cells in the pancreas (left). Treatment with injections of MOTS-c reduced T-cell infiltration and prevented the onset of the disease (right).

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On the need for policy changes:

Associate Professor Julie Zissimopoulos

“I think one important policy change is solutions to support family caregivers in the workplace, compensation programs. But this isn’t going to be enough. Demographic trends suggest that family caregiving as the main source of care is likely not sustainable. People are having fewer children, and there are more Americans with dementia. So we really need an insurance system to cover long-term care. The current system does not function well. [Those] who take it up tend to only be those at high risk with very high healthcare costs. So we need to be a little innovative here, maybe consider a voluntary auto-enrollment in long-term care insurance with an opt-out much like what has worked well in the retirement savings market.”

“Medicare could also help; we had a new benefit of Part D that covers drug expenditures and protects against very high out-of-pocket spending for those beneficiaries with high drug expenditures. This was very successful. Medicare could do something similar for long-term care, but it will be very costly. So we will need to figure out who will pay, how we will finance this and, and who is going to bear the costs of this. Will it be the younger generation through taxes on, say, health insurance premiums? If so, how are we going to make sure that they don’t bear the full burden?”

Assistant Professor Marc Vermulst: the role of genetic mutations in human aging and disease

On the origins of Alzheimer’s and Parkinson’s disease:

Assistant Professor Marc Vermulst

“One of the things I’m really interested in is the occurrence of age-related diseases, for example Alzheimer’s and Parkinson’s disease. And one of the major questions is ‘why do people get these diseases?’ There are families that have a mutation that makes them more predisposed to getting these diseases, but that really only explains five to maybe 15% of all of the cases. The remaining 85 to 95%, we really have no clue why these people get these diseases. So what I’m trying to do is I’m trying to explain these remaining 85%.”

‘Because all of these diseases are caused by misfolded proteins, and transcription errors cause these misfolded proteins, I think that we have found a new mechanism that can cause these diseases. And if the mechanism is indeed correct, that means we can now do something about it. So it’s really about finding the origin of the disease itself in order to be able to design medicine for it.’

Associate Professor Hussein Yassine: Uncovering links between nutrition, genes, and risk for Alzheimer’s disease

On what can people do to reduce Alzheimer’s disease risk:

Dr. Hussein Yassine

“I think timing is key. I think if you know that you are at increased risk based on family history or APOE4 genotype, nutritional and lifestyle interventions during middle age will provide you likely the most benefit. Our research and others suggest that between the ages of 45 and 65, those at risk individuals should be on certain lifestyle modifications, whether it is at least one serving of fatty fish per week, or some good exercise regimen. We’re not talking about marathon running; maybe three times a week, 15 minutes per day is good enough. Lifestyle modifications, no smoking, reduced consumption of simple sugars to avoid complications of diabetes and obesity, increased intake of green leafy vegetables, which are enriched in polyphenols and antioxidants, good sleep, listening to music, certain forms of meditation, or, in some individuals, praying. And all of these factors have a positive effect on mitigating or decreasing the chances of getting Alzheimer’s.”

Professor John Tower: the roles of sex differences and mitochondria on aging

On sex-specific interventions:

Professor John Tower

“I think what I would expect is we’re going to see sex-specific interventions in aging and aging-related diseases, even diseases common to the male and the female, like Parkinson’s and Alzheimer’s, that having an intervention that’s tailored to the male or the female will be more efficacious.”

Research Associate Professor Donna Benton

Research Associate Professor Donna Benton: Family Caregiving Challenges During COVID-19

On how to better support dementia caregivers:

“The policies need to be there so that we get better diagnoses, that we have more physicians who are trained to recognize and help family members, that social services and physicians also know where to refer people to once they have a diagnosis of dementia and how to help the family because … the physician isn’t going to be there to help with support groups. They’re not going to become the support group person. They’re not going to help them navigate other social services. But if they make the right referral to, say, the Alzheimer’s Association or AARP or a California Caregiver Resource Center system, that actually helps start the process so that the caregiver will have somebody who they can call whenever they need to. … Over the course of many years, as the disease progresses, you’re going to need different training [and] different information.”

Professor Mara Mather

Professor Mara Mather: Slowing down the progression of Alzheimer’s disease

On the potential benefits of meditation:

“One study, which looked at a large sample of people who have practiced meditation for many years versus people who have not practiced meditation, found that when they just used a machine learning technique to guess at how old the brains were of each person, this algorithm guessed that on average, the meditators’ brains were 7.5 years younger than their actual age, compared to the control brains, which were non-meditators and didn’t show that effect. So it seems that meditation is associated with benefits for actual brain health, which is really interesting.”

Professor Christian Pike

Professor Christian Pike: Sex differences in Alzheimer’s disease

On the differences between men and women regarding Alzheimer’s disease:

“There are so many differences between men and women in Alzheimer’s disease. I mean, at the core of it, the disease is very much the same across all people. But then when you begin to break it down into the effects of different risk factors, you begin to see significant differences. … And in recent years there’s been a greater emphasis on sex differences in the more we look, the more differences between the male brain and the female brain that we find.”

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