(Press-News.org) Buck Institute researchers have discovered and are developing a novel, non-invasive biomarker test that can be used to measure and track performance of senolytics: a class of drugs that selectively eliminate senescent cells. The discovery is expected to play a major role in efforts to develop treatments that would battle a myriad of chronic age-related conditions that range from arthritis to lung disease to Alzheimer's disease and glaucoma. This biomarker is a unique signaling lipid metabolite, normally exclusively intracellular, but is released when senescent cells are forced to die. This metabolite is detectible in blood and urine, making non-invasive testing possible. With a growing list of senolytic drugs in development, detecting this metabolite via a companion test could verify performance of senolytic candidates.
"The list of age-related diseases definitively linked to cellular senescence keeps growing, as does the number of biotech companies racing to develop drugs to eliminate senescent cells," said Buck professor Judith Campisi, PhD, senior scientist on the study. "While the field has never been more promising, the lack of a simple biomarker to measure and track efficacy of these treatments has been a hindrance to progress. We are excited to bring this new biomarker to the field and look forward to it being used in the clinic."
Understanding senescence and identifying lipids as a new and potent component of the SASP
During cellular senescence, stressed or damaged cells permanently stop dividing, a putative mechanism to safeguard against cancer. Senescent cells are not dead - they spew out a stew of bioactive molecules that promote wound healing and chronic inflammation, the latter playing a major role in many age-related diseases as the cells accumulate over time. This bioactive stew is known as the SASP (senescence-associated secretory phenotype); its composition, and deleterious effects have been well-studied.
This work, performed in human cell culture and mice, shows that senescent cells also synthesize a large array of oxylipins, bioactive metabolites derived from the oxygenation of polyunsaturated fatty acids. "Lipid components of the SASP have been vastly understudied," says lead scientist Christopher Wiley, PhD, a former assistant research professor at the Buck, now at the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston. "The biosynthesis of these signaling lipids promotes segments of the SASP and reinforces the permanent growth arrest of senescent cells. This work provides a new way of understanding and studying senescence-driven pathology," he said. Oxylipins are implicated in many inflammatory conditions including cardiovascular disease and pain response. Many commonly used drugs, such as aspirin and ibuprofen, act by preventing oxylipin synthesis.
The biomarker is exclusive to senescent cells and may be of interest in cancer research
Wiley says senescent cells change their fatty acid metabolism and they do it in such a way that free polyunsaturated fatty acids accumulate inside the arrested cells where they are used to manufacture oxylipins. Researchers identified one of these fatty acids, 15-deoxy-delta-12, 14-prostaglandin J2 (dihomo-15d-PGJ2), as unique to senescent cells; it accumulates inside senescent cells and is released when the cells die. In this study, mice were given chemotherapy which induces widespread senescence, followed by a senolytic drug. The biomarker was only detected in the blood and urine of mice treated with both chemotherapy and the senolytic, but not with either on its own, confirming specificity for senolysis.
Researchers also showed that dihomo-15d-PGJ2 had a functional role in senescence. Inhibiting its synthesis allowed a subset of cells to escape senescence and continue dividing, and had a less inflammatory SASP profile. Addition of dihomo-15d-PGJ2 to non-senescent cell drove them into senescence by activating RAS, a cancer-promoting gene that is also known to cause senescence.
"We hope that identifying and including these bioactive lipids as part of the SASP will encourage researchers working in a broad range of fields to take a new look at cellular senescence," said Campisi. "The fact that one of these lipids ends up being a simple non-invasive biomarker for tracking the efficacy of treatments is a huge plus for those of us working to stem the ravages of age-related disease."
INFORMATION:
Citation: Oxylipin biosynthesis reinforces cellular senescence and allows detection of senolysis
DOI: 10.1016/j.cmet.2021.03.008
Other Buck Institute collaborators include Rishi Sharma, Sonnet S. Davis, Jose Alberto Lopez-Dominguez, Kylie P. Mitchell, Samantha Wiley, Fatourma Alimirah, Dong Eun Kim, Therese Payne, Andrew Rosko, Eliezer Aimontche, Sharvari M. Deshpande, Francesco Neri, and Chisaka Kuehnemann. Other co-authors include Marco Demaria, European Research Institute for the Biology of Aging, Groningen, Netherlands and Arvind Ramananathan, Institute for Stem Cell Science and Regenerative Medicine, Bengaluru, Karnataka, India.
Acknowledgments
This work was supported by grants from the National Institutes of Health (AG051729, AG057353, AG0172442, U2C-DK119886, T32-AG000266) and the Science and Engineering Research Board of India.
About the Buck Institute for Research on Aging
At the Buck, we aim to end the threat of age-related diseases for this and future generations. We bring 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. Our goal is to increase human health span, or the healthy years of life. Located just north of San Francisco, we are 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. Our success will ultimately change healthcare. Learn more at: https://buckinstitute.org
Gasoline, the primary transportation fuel, contains hydrocarbons with 5-11 carbons (C5-11) and is almost derived from petroleum at present.
Gasoline can also be produced from non-petroleum syngas. Nonetheless, achieving high conversions of syngas to C5-11 with excellent selectivity and stability remains a challenge.
A research group led by Prof. LIU Zhongmin and Prof. ZHU Wenliang from the Dalian Institute of Chemical Physics (DICP) of the Chinese Academy of Sciences realized highly efficient and selective conversion of syngas to gasoline-range liquid hydrocarbons over a dual-bed catalyst.
The study was published in Chem Catalysis on April 2.
This dual-bed catalyst, (CZA +Al2O3)/N-ZSM-5(97), consists ...
Up to one in five employees at an academic medical institution are considering leaving their professions due to the strains of coping with the pandemic in their own lives, according to a new University of Utah Health study. Individuals who had caregiving responsibilities were among those most likely to contemplate leaving or reducing hours.
The findings suggest that retaining highly trained doctors, nurses, and scientists in the aftermath of the COVID-19 pandemic could be the next great health care challenge.
"It's sobering to learn that, during a time of economic recession, at least one-fifth of our workforce were considering leaving their jobs because of the severe levels of stress they were experiencing," says Angela Fagerlin, Ph.D., the study's senior author and professor ...
SAN FRANCISCO, CA (April 2, 2021) -- In recent years, advancements in DNA sequencing have exposed a large amount of hidden diversity in reef-building corals: species that appear identical to one another but are genetically distinct. Typically ignored as they are invisible to the naked eye, a team of researchers at the California Academy of Sciences and The University of Queensland, along with over a dozen international collaborators, is taking a more holistic approach to understand these hidden species by investigating overlooked ecological differences that have wide-ranging implications for the vulnerability and resilience of reef-building corals. The team hopes that their findings, ...
What The Study Did: This survey study examined the career development, productivity, childcare needs and likelihood of leaving the workforce among employees at an academic medical center during the COVID-19 pandemic.
Authors: Angela Fagerlin, Ph.D., of the University of Utah in Salt Lake City, is the corresponding author.
To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/
(doi:10.1001/jamanetworkopen.2021.3997)
Editor's Note: The article includes conflicts of interest and funding/support disclosures. Please see the article for additional information, including other authors, author contributions and affiliations, conflict of interest and financial disclosures, and funding ...
What The Study Did: Researchers compared rates of health maintenance organization (HMO) enrollment, by race and ethnicity, for children with commercial and public coverage with the use of national survey data.
Authors: Alon Peltz, M.D., M.B.A., M.H.S., of Harvard Medical School in Boston, is the corresponding author.
To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/
(doi:10.1001/jamanetworkopen.2021.4162)
Editor's Note: The article includes conflicts of interest and funding/support disclosures. Please see the article for additional ...
Extended surges in the South and West in the summer and early winter of 2020 resulted in regional increases in excess death rates, both from COVID-19 and from other causes, a 50-state analysis of excess death trends has found. Virginia Commonwealth University researchers' latest study notes that Black Americans had the highest excess death rates per capita of any racial or ethnic group in 2020.
The research, publishing Friday in the Journal of the American Medical Association, offers new data from the last 10 months of 2020 on how many Americans died during 2020 as a result of the effects of the pandemic -- beyond the number of COVID-19 deaths alone -- and which states and racial groups were hit hardest.
The rate of excess deaths -- or deaths above the number that ...
More than 60% of U.S. adults who vape are interested in quitting, according to a study published today in JAMA Network Open by MUSC Hollings Cancer Center researchers. And among those who vape to help them to quit smoking, some are successful while others continue smoking and using electronic cigarettes.
The study, which analyzed longitudinal survey data from more than 30,000 adults across the country, aimed to provide the most up-to-date estimate of how many Americans are interested in stopping their use of e-cigarettes or have made past attempts to quit.
According to the findings, former cigarette smokers had the highest intentions and interest in quitting. This is likely due to an increasing number of smokers using e-cigarettes to transition away from cigarettes, said the study's authors.
While ...
What The Study Did: This study updates an analysis of deaths in the United States in 2020, including deaths due to COVID-19 as well as all other causes.
Authors: Steven H. Woolf, M.D., M.P.H., of the Virginia Commonwealth University School of Medicine in Richmond, is the corresponding author.
To access the embargoed study: Visit our For The Media website at this link https://media.jamanetwork.com/
(doi:10.1001/jama.2021.5199)
Editor's Note: The article includes funding/support disclosures. Please see the article for additional information, including other ...
People who radicalize to extremist ideologies often are triggered by negative life events or exposure to propaganda, and those who escape from extreme groups frequently are aided by an individual or group that intervenes to help them reject the philosophy, according to a new RAND Corporation study.
Expanding access to mental health care, creating opportunities for exposure to diverse cultural groups and media literacy education all are important strategies that may aid the battle against extremism, according to researchers. However, harsh law enforcement actions often are unproductive in changing people's extremist beliefs.
The RAND study describes personal accounts based on interviews ...
ITHACA, NY, April 2, 2021 - A team of researchers from the Boyce Thompson Institute (BTI) has discovered a distinct group of bacteria that may help fungi and plants acquire soil nutrients. The findings could point the way to cost-effective and eco-friendly methods of enriching soil and improving crop yields, reducing farmers' reliance on conventional fertilizers.
Researchers know that arbuscular mycorrhizal (AM) fungi establish symbiotic relationships with the roots of 70% of all land plants. In this relationship, plants trade fatty acids for the fungi's nitrogen and phosphorus. However, AM fungi lack the ...
