New Buck Institute Research is Big News for Longevity

This article was published in Longevity.Technology on January 12, 2021

“Heart disease, cancer and lower lung disease are among the top causes of death in the US. Computer algorithms from our study show that all of these conditions are strongly modulated by genes or protein interactions that are induced by tension in the immune system.”

Dan Winer, MD, Associate Professor, Buck Institute for Research on Aging

New research from the Buck Institute, published today in Cell Reports, provides new insights into how the immune system functions. This opens up possibilities for new immunotherapeutics and a new biomarker of aging. The paper, entitled Mechanical Stiffness Controls Dendritic Cell Metabolism and Function, Chakraborty et al, describes how mechanical force primes and likely controls immunology during acute and chronic disease because it readies the immune system in the face of danger. The findings suggest that stiffness in tissues in the body likely drive immune responses in many chronic diseases and impact the innate immune system by increasing its metabolism. 

The association between tissue stiffness and aging is well known. For example, as people age their lungs and the blood vessels in their lungs become stiffer. Some people’s lungs double in stiffness as they age. This research suggests that tissue stiffness may initiate an inflammatory loop that leads to chronic inflammation which accelerates biological aging and drives many age-related diseases, and the genes that are activated via cellular tension are potential targets for immunotherapeutics. Techniques currently exist that enable the mapping of tension in specific tissues and organs. Tracking the tension could provide a biomarker of aging and make it easier to test new drugs.  

Buck Institute for Research on Aging (source Margaretta Colangelo)

“The immune system is carefully tuned to respond to environmental cues, which impact downstream immunological function and metabolism.”

Chakraborty et al, Cell Reports, January 12, 2021

The research was conducted by researchers at the Buck Institute in collaboration with Stanford University, the University Health Network at the University of Toronto, and the University of Alberta. Buck Associate Professor Dan Winer, MD, and his team, led by Mainak Chakraborty, MSc, Research Assistant at the University Health Network in Toronto and Sue Tsai, a former post-doctoral fellow in the lab, now an Assistant Professor at the University of Alberta. The Buck Institute is recognized globally as the epicenter of aging research. 

To understand how stiffness from the environment impacts immune cells, researchers analyzed cultured dendritic cells (DCs) from mouse bone marrow and spleen at different degrees of physiological stiffness. Researchers then analyzed DCs from humans. The human DCs and mouse DCs both showed enhanced markers of activity under higher tension. Researchers identified the Hippo-signaling molecule, TAZ, as an important factor impacting DC metabolism and function under tension in the innate immune response. Dr. Winer noted that this seems to be a critical pathway for sensing environmental force in both arms of the immune system and hopes that this research leads to the development of new force-targeting immunotherapies that would allow the immune system to function normally across the many conditions that lead to changes in tissue stiffness.   

Pancreas samples from mice receiving injections of immune cells cultured on higher tension. The blue dots correspond to immune cells attacking the islets that make insulin. (Image source the Buck Institute for Research on Aging)

Key findings from this research

• Environmental stiffness promotes DC inflammatory function
• Tension primes DC metabolism, even without pattern recognition receptor input
• TAZ bridges mechanosensory signals to DC metabolism and function
• Tension directs phenotypes of human monocyte-derived DCs
• High stiffness grown DCs showed increased activation and flux in major glucose metabolic pathways
• DCs grown at physiological resting stiffness showed reduced proliferation, activation and cytokine production compared to cells grown under high stiffness which mimicked fibro-inflammatory disease
• In models of autoimmune diabetes and tumor immunotherapy, the cellular tension primed the DCs to elicit a response from the adaptive immune system, which kicks in specifically and secondarily following infection or injury

Adopting new culturing techniques

As a final note, Dr. Winer urged researchers to consider changing the way they culture immune cells. For decades, most scientists have been using plastic plates to grow their cells. These plastic plates exert tension thousands of times higher than what a cell feels in the body. Immune cells anchor themselves in the dish that they are grown in, so the type of plate used in research affects the cells. Dr. Winer and his team grow immune cells on soft silicone gels which have been treated to closely mimic the physiology inside the body. Dr. Winer encourages researchers to use new culturing techniques, such as soft silicone gels, instead of plastic, to mimic the physiology inside the body. 

Buck Institute for Research on Aging (source Margaretta Colangelo)

About the Buck Institute

The Buck Institute aims to end the threat of age-related diseases for this and future generations. The Buck brings together the most capable and passionate scientists from a broad range of disciplines to study mechanisms of aging and to identify therapeutics that slow down aging. The goal is to increase human health span, or the healthy years of life. Located just north of San Francisco, The Buck is globally recognized as the pioneer and leader in efforts to target aging, the number one risk factor for serious diseases including Alzheimer’s, Parkinson’s, cancer, macular degeneration, heart disease, and diabetes. The Buck wants to help people live better longer. Learn more at: https://buckinstitute.org

Citation: Mechanical Stiffness Controls Dendritic Cell Metabolism and Function

DOI: 10.1016/j.celrep.2020.108609

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Copyright © 2021 Margaretta Colangelo. All Rights Reserved.

This article was written by Margaretta Colangelo. Margaretta is a leading AI analyst based in San Francisco. She serves on the advisory board of the AI Precision Health Institute at the University of Hawaiʻi Cancer Center. 

Twitter @realmargaretta