New research from The Buck Institute has big implications for chronic diseases of aging.
The new research from The Buck Institute for Research on Aging, published today in Cell Reports, provides insights into how the immune system functions and opens up possibilities for new immunotherapeutics and a new biomarker of aging.
Longevity.Technology: The Buck Institute is a Californian-based non-profit corporation with a mission to extend the healthy years of life. A glance at their past and present associates reads like a Longevity Who’s Who and their research is just as exciting.
Today’s news about immunotherapy – biological therapy that activates or suppresses the immune system – not only augurs development of new treatments, but reveals a new aging biomarker that could be used in innovating new drugs and personalised medical therapies.
The paper, entitled Mechanical Stiffness Controls Dendritic Cell Metabolism and Function, 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.
“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
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; 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 and tracking the tension could provide a biomarker of aging and make it easier to test new drugs.
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 recognised globally as the epicentre of aging research.
“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
To understand how stiffness from the environment impacts immune cells, researchers analysed cultured dendritic cells (DCs) from mouse bone marrow and spleen at different degrees of physiological stiffness. Researchers then analysed DCs from humans.
The human DCs and mouse DCs both showed enhanced markers of activity under higher tension. Researchers identified the Hippo-signalling 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.
Key findings from this research
- 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.
- High stiffness grown DCs showed increased activation and flux in major glucose metabolic pathways.
- In models of autoimmune diabetes and tumour 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.
About the Buck Institute for Research on Aging
The Buck, 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 recognised 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
