NIH SenNet Consortium Unveils First Comprehensive Atlas of Senescent Cells, Introducing 'Senotypes' Framework
核心洞察
The NIH-funded Cellular Senescence Network (SenNet) published the first comprehensive atlas of senescent cells across human tissues, including brain, lungs, and lymph nodes.
Researchers introduced "senotypes," a new classification system grouping senescent cells by tissue location and surrounding conditions, enabling more targeted therapeutic approaches.
Mayo Clinic studies identified IL-23R (搜索) as a potential blood biomarker for biological aging and demonstrated that senolytic interventions reduced inflammation and improved cognitive performance in aged mice.
A research consortium funded by the National Institutes of Health has established a transformative new framework for understanding cellular senescence, publishing the first comprehensive atlas of senescent cells across the human body. The work, presented in a compendium of papers in the June 11 issue of Cell and across Nature journals, represents a foundational step toward developing targeted therapies for age-related diseases (搜索).
The Cellular Senescence Network (SenNet) program, launched by the NIH Common Fund in 2021, has grown into a large collaborative effort led by the National Institute on Aging (NIA) and the National Cancer Institute (NCI). Its primary objective is to compile comprehensive atlases of senescent cells within the human body over a lifetime.
Introducing 'Senotypes': A New Classification System
Central to the consortium's work is the concept of "senotypes," a novel classification system that groups senescent cells based on where they are found in the body and the conditions surrounding them. This framework recognizes that cells can differ widely depending on tissue type, health status, and environment.
"By mapping where different senotypes are found and what makes them unique, we aim to build a more complete picture of senescent cells across the body," said Nicole Kleinstreuer, Ph.D., NIH Deputy Director for Program Coordination, Planning, and Strategic Initiatives, who leads the NIH Common Fund. "This knowledge could help researchers move toward more targeted therapies that focus on harmful cells while preserving beneficial ones."
In healthy tissues, senescent cells support wound healing and serve as a defense mechanism by preventing tumor growth. They are normally cleared by the immune system, but as immune function declines with age, these cells accumulate and release harmful signals that contribute to chronic disease and other age-related conditions.
Mapping Senescence Across the Body
The SenNet atlas charts senescent cells in tissues from areas including the brain prefrontal cortex, lungs, and lymph nodes. The consortium also developed new computational tools to identify unique biological features of senescent cells, leading to the discovery of blood-based markers that can predict kidney disease (搜索), frailty, and the future risk of diabetes (搜索) in human aging studies.
The research showcases novel single-cell, spatial omics, and AI-based methods designed to overcome the challenge of identifying and analyzing rare senescent cells within complex human tissues.
Mayo Clinic Contributions: Biomarkers and Mechanisms
A series of Mayo Clinic studies, authored by scientists within the Robert and Arlene Kogod Center on Aging, further advances the field. One study identified IL-23R (搜索) as a senescence-linked circulating and tissue biomarker of aging, which could one day help researchers assess biological aging and monitor responses to future therapies.
"This body of work is moving the aging field forward to precisely identify, understand and target the specific senescent cells that contribute to age-related dysfunction, which is the necessary groundwork to develop new therapies that support healthy aging," said Marissa Schafer, Ph.D., a Mayo Clinic researcher whose laboratory led several of the studies.
Uncovering the Drivers of Inflammation
Additional Mayo Clinic studies uncovered previously unknown mechanisms explaining why senescent cells produce persistent inflammation. Researchers found that dysfunctional mitochondria contribute to inflammation through multiple pathways: mitochondrial DNA and RNA activate immune signaling, and mitochondrial metabolism changes how inflammatory genes are activated through epigenetic regulation.
João Passos, Ph.D., senior author on several papers, led work demonstrating distinct senotypes in p16- and p21-positive cells across human and mouse aging tissues, as well as studies on mitochondrial metabolism and epigenetic crosstalk driving the senescence-associated secretory phenotype (SASP).
Therapeutic Implications
The research points to potential future applications including identification and early testing of senolytics, a class of experimental drugs designed to selectively eliminate senescent cells. In preclinical models, interventions including senolytic drugs, a naturally occurring compound found in tomatoes, and genetic approaches that selectively target senescent cells reduced measures of inflammation and improved outcomes associated with aging, including physical frailty, brain inflammation, and cognitive performance in aged mice.
Rather than focusing solely on eliminating senescent cells, the research supports a more nuanced approach that aims to identify the biological pathways responsible for harmful inflammation and develop therapies that selectively interrupt those processes.
Darren Baker, Ph.D., a Mayo Clinic researcher, is the senior author of the paper "Senotypes define the diverse landscape of senescent cells." The research is part of a larger effort at Mayo Clinic called the Precure Research initiative, focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease.
Although additional research is needed before these findings can be translated to patient care, the studies provide a stronger scientific foundation for developing more targeted interventions for age-related diseases (搜索).