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Cellular defense mechanisms shed light on life span research

A cartoon by USC undergraduate Megan Bernstein depicts the content of a paper on starvation response.

New research by a team at the USC 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 detailed a discovery made in the lab of Sean Curran, assistant professor of biogerontology at USC Davis. Curran’s lab looked at how proteins in human 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 finding that, in the presence of a starvation environment, cells initiate and regulate complex metabolic changes, sheds new light on the study of existing cellular mechanisms, as well as opening the door for the possibility of intracellular bioengineering.

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, or mito-SKN-1, as defined by the team.

“The regulation of life span is complex,” Curran said. “SKN-1/Nrf were discovered decades ago, but this work uncovers a novel role for this well-established player.

“This discovery changes how we think about how transcription factors are regulated,” he explained.

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

The researchers focused on the interaction of proteins PGAM-5 and MXL-3 with mitochondrial pools of SKN-1. Though 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, which highlighted key molecular and physiological genetic differences of special interest to scientists.

“This starvation response has a huge impact on nutrient pathways that regulate life span 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.”

The team also found a correlation to the SKN-1 effects in mice when the activated Nrf similarly induced a starvation response. The discovery has 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.

The publication of the research represents a scientific and personal milestone for Curran, who holds appointments at USC Davis 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 Nguyen (USC Davis); Jacqueline Lo (USC Dornsife); 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 and The Ellison Medical Foundation.

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