Unlocking longevity: Boosting lifespans with gut stress signaling
UNC Charlotte researcher Patricija van Oosten-Hawle, an assistant professor of biological sciences, is investigating how a particular reaction in the human gut is triggering a process that could help prolong tissue health and extend lifespan.
“The gastrointestinal tract is a major signaling system within humans, and it plays an important role in our overall health,” said van Oosten-Hawle. She recently received a $1.9 million grant from the National Institute on Aging to better understand the beneficial role of enteroendocrine (gut) cells.
“Under mild stress, certain signals are sent from the gut to other tissues that influences the health of other cell types and tissues, such as muscles,” van Oosten-Hawle explained. “These ‘stress’ signals being secreted by the gut are recognized by cells in the muscle. That process, in turn, triggers muscle cells to upregulate components for cellular protein quality control to maintain protein homeostasis in the muscle, which affects the entire organism.”
Protein homeostasis, or proteostasis, is a type of equilibrium that maintains cellular function and health. When we age, this equilibrium collapses in multiple organs. Proteins misfold or aggregate leading to cellular toxicity and decay, which is often linked with age-associated degenerative diseases. Examples include sarcopenia or muscle atrophy; metabolic disorders, including diabetes; or dementia in the form of Alzheimer’s or Huntington’s diseases.
“As we age, our muscle mass decreases. Stronger muscles will enable us to age more gracefully,” said van Oosten-Hawle. “My research aims to extend people’s quality of life, so we stay healthier longer.”
Signals produced by the nervous system, such as hormones and neuropeptides, have been studied extensively for their role in maintaining cell health unlike gut stress-induced signaling.
As a postdoctoral researcher, van Oosten-Hawle discovered how the signaling molecules within the gut respond to modulating the chaperone protein Hsp90 to keep cells fully functional.
“We induce mild stress in the gut by changing the expression of this chaperone protein and study the resulting effects in other tissues. The mild stress induced in the gut triggers damage control responses that boost proteostasis. Surprisingly, we found that these responses are not only activated within gut cells but that a type of stress response could be activated remotely in muscle cells by signals from the gut. In effect, this is like the gut serving as a preliminary alert system, notifying muscle cells of imminent threats so they can heighten their defenses beforehand. If we can learn how this can be modulated genetically or chemically, then it could lead to medical interventions that result in maintaining cellular health for longer as we age,” noted van Oosten-Hawle.
Using microscopic organisms for research
In the lab, van Oosten-Hawle and her team use the soil nematode Caenorhabditis elegans as a model system to study aging. C. elegans is a free-living, non-parasitic worm found around the world; adult nematodes are about 1 mm in length or the size of a comma, and genetic experiments can be done via a dissecting microscope.
According to the Whitehead Institute, C. elegans is complex enough to model other common aspects of animal biology, including muscle function, reproduction, digestion, wound healing and aging. Also, the organism shares many genes with humans and can even be used to model human disease.
“In fact, we are using C. elegans models of Alzheimer’s and Huntington’s disease in the lab. The worm’s body is transparent, so researchers can easily observe and capture images of changes occurring inside of its body down to a cellular or even sub-cellular level,” said van Oosten-Hawle. “Most C. elegans live about 30 days and their cell structure and biological processes are highly conserved, which makes it ideal for us to study cellular protein homeostasis and observe the collapse of homeostasis, which is an indicator to the start of aging.”
Providing students with hands-on research opportunities is a hallmark of the UNC Charlotte experience, and van Oosten-Hawle currently has several undergraduate students and four graduate students assisting with experiments.
“Science should be a fun and creative process. It is important to me that students in the lab have the liberty to explore diverse creative solutions and allow their potential and personalities to flourish while doing experiments,” said van Oosten-Hawle.
“While we use C. elegans for our main research questions, we really draw from various fields such as genomics, cell biology, bioinformatics and proteome research,” van Oosten-Hawle said. “We are collaborating with colleagues from Europe and around the world and researchers closer to home at UNC Chapel Hill and UNC Charlotte.”
Being part of international proteostasis groups around the world and having organized proteostasis conferences in the United Kingdom (UK Chaperone Meetings, 2018 and 2020) and the FASEB Catalyst conference in 2021, van Oosten-Hawle is a member of the recently formed Charlotte Group of Proteostasis Research. Each member works on a different aspect of proteostasis to understand how it is maintained in the cell.
Biological sciences faculty members in the group include Kausik Chakrabarti, Richard Chi, Kristen Funk, Valery Grdzelishvili and Andrew Truman, along with Adam Reitzel who is the co-director of CIPHER, the Center for Computational Intelligence to Predict Health and Environmental Risks.
“Bioinformatics is immensely important to make sense of all the data we have in proteostasis research,” van Oosten-Hawle observed. “Within the Charlotte group, we are writing grants and collaborating with one another. It is an exciting time to be at Charlotte and to be part of this diverse group where we discuss ideas and make new discoveries together.”
Prior to joining UNC Charlotte last fall, van Oosten-Hawle conducted research at the University of Leeds and Northwestern University, after earning a doctorate in molecular biology and biochemistry at the VU University Amsterdam in the Netherlands. Her team has published extensively with a recent paper in PloS Biology that discusses the importance of the intestine for aging. In 2019, she received the Ferruccio Ritossa Early Career Award from Cell Stress Society International for her discovery of transcellular chaperone signaling using C. elegans as a model system and was inducted as a Fellow of Cell Stress Society international in 2020.
Researcher Patricija van Oosten-Hawle, second right, with members of her lab: senior Evie Starr, lab assistant Mayuresh Shastri, Ph.D. students Akhil Souparnika and Valeria Uvarova, master’s degree student Katie Kessler and Loren Cocciolone, a Ph.D. student.