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Mitochondria

Starvation-Induced Cellular Defense Mechanisms Shed Light on Lifespan Research

By Featured, Lifespan Health, Mitochondria

New research by a team at the USC Leonard Davis School of Gerontology into how organisms respond to lack of nutrition could have a far-reaching impact on how we understand obesity and longevity and potentially fight chemotherapy-resistant cancer.

Published in Cell Metabolism, the paper details a discovery made in the lab of Sean Curran, assistant professor of biogerontology at the USC Leonard Davis School of Gerontology. Curran’s lab looked at how proteins in our bodies respond to starvation, in particular a protein known as SKN-1 that binds to DNA and affects how the starvation response is mediated. (Nrf is the mammalian equivalent of SKN-1.)

The Curran lab’s finding that, in the presence of a starvation environment, cells initiate and regulate complex metabolic changes, sheds fascinating new light into the study of existing cellular mechanisms as well as opening the door for exciting intracellular bioengineering possibilities.

Curran and his team also found that although a mitochondrial pool of SKN-1 has never previously been identified, it is indeed present, most likely in the outer membrane of the mitochondria — they term this discovery mito-SKN-1.

“The regulation of lifespan is complex. SKN-1/Nrf were discovered decades ago, but this work uncovers a novel role for this well established player,” Curran said. “This discovery changes how we think about how transcription factors are regulated.”

Using a roundworm known as C. elegans, Curran and his lab studied how complex organisms responded on a cellular level to being starved.

They focused on the interaction of proteins PGAM-5 and MXL-3 with mitochondrial pools of SKN-1. Although most starved C. elegans were able to recover and achieve fertile adulthood when reintroduced to food, specially mutated worms were unable to turn off the body’s starvation response even in nutrient-rich environments – highlighting key molecular and physiological genetic differences of special interest to scientists.

“This starvation response has a huge impact on nutrient pathways that regulate lifespan and survival,” Curran said. “Although the amount of SKN-1 did not seem to make a difference, it’s the activated form of SKN-1 that matters.”

His team also found a correlation to the SKN-1 effects in mice when their activated Nrf similarly induced a starvation response. The team’s discovery has enormous potential repercussions when extrapolated to Nrf-positive tumors, which tend to be resistant to chemotherapy.

“By exploiting this starvation response, we might be able to think of new treatments,” Curran said.

This publication represents both a scientific and personal milestone for Curran, who holds joint appointments at the USC Leonard Davis School and in molecular and computational biology at the USC Dornsife College of Letters, Arts and Sciences as well as in biochemistry and molecular biology at the Keck School of Medicine at USC.

“Combining genetic, cell and molecular biology, and biochemistry approaches, this the first major publication from the Curran lab,” he said. “I am really proud of it.”

Co-authors of this study were Jennifer Paek and Tammy N. Nguyen (USC Leonard Davis School of Gerontology); Jacqueline Y. Lo (Dana and David Dornsife College of Letters, Arts and Science); Sri Devi Narasimhan, Kira Glover-Cutter, Stacey Robida-Stubbs and T. Keith Blackwell (Joslin Diabetes Center, Harvard Stem Cell Institute and Harvard Medical School); and Takafumi Suzuki (Tohoku University School of Medicine, Japan).

The research was funded by the National Institutes of Health (grants number R01GM6289 and R00AG032308) and the Ellison Medical Foundation.

Welcome!

By Featured, Mitochondria

Pinchas Cohen, a prominent researcher and leader in the field of gerontology, begins his tenure as dean of the USC Leonard Davis School of Gerontology, effective July 16. He will also become the holder of the William and Sylvia Kugel Dean’s Chair in Gerontology as well as executive director of the Ethel Percy Andrus Gerontology Center.

Formerly vice chair for research at the UCLA School of Medicine, Cohen has overseen numerous teaching, training and research activities at UCLA and has been involved in programs related to diseases of aging, including cancer, Alzheimer’s disease and metabolic disorders.

Previously, he served as chief and professor of endocrinology at Mattel Children’s Hospital and associate director of the UCSD-UCLA Diabetes and Endocrinology Research Center.

Focusing his research on the emerging field of mitochondrial biology, Cohen and his team have worked to demonstrate the importance of mitochondrial peptides in aging and longevity. He is co-founder of CohBar, a biotechnology company developing mitochondrial peptides for the treatment of diabetes.

Cohen has received several awards for his work in the field of aging, including a National Institute of Aging EUREKA Award, the National Institutes of Health Director’s Transformative Research Award and the Glenn Award for Research in Biological Mechanisms of Aging.

He serves on the boards of several professional journals and societies, including the American Federation for Aging Research and the Growth Hormone Research Society.

A prolific author, Cohen has published more than 250 papers in top scientific journals and his work has been cited in the Los Angeles Times and the New York Times.

Cohen earned his MD degree with top honors from the Technion School of Medicine in Israel, and was a resident and fellow at Stanford University, after which he spent seven years at the University of Pennsylvania.

“I’m honored to be given this once-in-a-lifetime opportunity to lead the world’s oldest and largest school of gerontology,” Cohen said. “I look forward to joining forces with our amazing faculty, staff and students to continue and expand the USC Leonard Davis School’s mission: to improve the quality of life for older adults through research, service and education.”

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