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A new model for mechanical stress describes how growing organisms on a stiffer substrate can paradoxically worsen certain health outcomes while increasing lifespan, according to a USC Leonard Davis study.

“The study of mechanical stress is important because many tissues become stiffer with age, and several age-associated diseases – like cancer – are associated with increased tissue stiffness,” said Assistant Professor Ryo Sanabria, the senior author of the study. “The best clinical example is that tumors are often initially identified by feeling a lump or mass, as solid-state tumors are characterized by a significant increase in stiffness compared to healthy tissue. Growth of cells in these stiffer environments can have profoundly different impact on organismal health and physiology.”

Mechanical stress refers to any type of physical stress, such as tension, torsion, bending, twisting, or exposure to stiffer environments, said co-first author of the study Maria Oorloff ’24.

Oorloff, who recently completed her bachelor of science in human development and aging at the USC Leonard Davis School within the USC Gerontology Enriching Medicine, Science, Technology, Engineering and Mathematics (GEMSTEM) to Enhance Diversity in Aging program, was co-first author with Adam Hruby, biology of aging PhD student.

“This project was extremely rewarding and an opportunity for me to expand my knowledge on the work that goes into a project in a basic science lab. Going into it, I had no expectations and I found that a lot of our findings were impactful in how C. elegans move and function,” Oorloff said. “I hope this research one day can help scientists understand cancer cell growth and survival, leading towards the betterment of drugs for treatment.”

The researchers sought the simplest method to apply mechanical stress for the microscopic nematode worm model organism C. elegans. They grew animals on a surface created to be four times stiffer than the standard substrate and compared their physiology to animals grown in standard growth conditions.

Several health metrics were lower for animals grown on stiffer substrate, including reduced reproduction and muscle function. However, the animals grown in the stiffer environment with more mechanical stress also had longer lifespans.

This surprising increase in longevity may be due to an increase in stress resilience and altered function of several cellular components, including the mitochondria and the actin cytoskeleton. The actin cytoskeleton is the network of proteins bound together in filaments that determine a cell’s shape and enables cellular movement and division.

“I initially thought that lifetime exposure to increased substrate stiffness would lead to an overactivation of stress response pathways, taxing the animal and leading to a shorter lifespan,” Hruby said. “We instead found a slight increase in lifespan which were dependent on changes to the actin cytoskeleton, which is consistent with previous research showing mechanical stress can cause alterations in actin filaments.”

While growth on stiffer substrates isn’t readily translatable to humans as an anti-aging intervention, the study does still have significant clinical potential, Sanabria said.

“Importantly, many of the changes that we see in C. elegans exposed to stiffer substrates – including increased survival, increased stress resilience, and changes to mitochondrial and cytoskeletal structure – are very similar to those found in cancer cells. Thus, it is entirely possible that we could potentially adapt our mechanical stress models for drug screening purposes,” they said. “If we could identify candidate drugs that reverse the phenotypes found in C. elegans exposed to mechanical stress, it is possible that these drugs can similarly inhibit cancer cell growth and survival.”

About the study

Growth on stiffer substrates impacts animal health and longevity in Celegans” appeared online in PLOS ONE on September 12, 2024. Along with Sanabria, Oorloff and Hruby, authors included Maxim Averbukh, Athena Alcala, Naibedya Dutta, Toni Castro Torres, Darius Moaddeli, Matthew Vega, Juri Kim, Andrew Bong, Aeowynn J. Coakley, Daniel Hicks, Jing Wang, Tiffany Wang, Sally Hoang, and Gilberto Garcia of the USC Leonard Davis School and Cray Minor and Kevin M. Tharp of the Sanford Burnham Prebys Medical Discovery Institute.

Hruby, Averbukh, and Garcia are supported by T32AG052374; Oorloff, Torres, and Vega are supported by 1R25AG076400 from the National Institute on Aging; Tiffany Wang is supported by the California Institute for Regenerative Medicine COMPASS Award EDUC5-13853; and Sanabria is supported by R00AG065200 from the National Institute on Aging, Larry L. Hillblom Foundation Grant 2022-A-010-SUP, and the Glenn Foundation for Medical Research and AFAR Grant for Junior Faculty Award. Some strains were provided by the CGC, which is funded by the NIH Office of Research Infrastructure Programs (P40 OD010440). Some gene analysis was performed using Wormbase, which is funded on a U41 grant HG002223.

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