Pinning down the locations and molecular markers of aging cells with experimental systems and cell imaging techniques will pave the way for anti-aging solutions.(Dr_Microbe | iStock)
Getting a handle on what leads to cellular senescence — an irreversible state where cells no longer proliferate — may provide scientists with a means to craft a blueprint of human aging. On the one hand, researchers have recognized the biological relevance of cellular senescence in age-related disease conditions like kidney dysfunction, neurodegeneration, and accumulated lung scarring (pulmonary fibrosis). On the other hand, cellular senescence plays roles in tissue repair processes during wound healing and in the prevention of tissue cancer formation. So, researchers want to figure out how to properly characterize these cells to combat age-related diseases.
Roy and colleagues from the National Institutes of Health in Maryland published a commentary in Cell where they identified five research areas to help scientists and clinicians harness research efforts on cellular senescence for enhanced aging and age-related disease therapeutics. These areas include identifying and characterizing senescent cells by their location in the body, their physical characteristics, and the molecules they contain (biomarkers). They also propose that identifying proper experimental model systems and validating what we know about senescence is fundamental to developing relevant therapeutics.
Advancing these research areas may help to answer questions like whether senescence mechanisms vary between body cell types, to what extent do senescent cells differ, and whether a universal senescence mechanism exists. The answers to these questions may help develop age-related disease therapeutics, including senolytics (molecules that induce senescent cell death) and senostatics (agents that slow senescence progression).
Fundamental to characterizing senescent cells, Roy and colleagues posit, is the generation of an atlas that describes differences in senescent cells and their spatial distribution throughout the body. To do so, they propose using artificial intelligence and computational approaches to sift through and make sense of large amounts of genetic, protein, metabolic byproduct, and spatial data. A senescent cell atlas would allow scientists to improve their understanding of aging processes and track senescence-related changes to see whether applied aging therapeutics work.
We also need to establish “gold standard” biomarkers of senescence to facilitate a better definition of senescence based on molecular signatures. To establish a “gold standard” set of senescent cell-identifying biomarkers, researchers can look at byproducts of metabolism (metabolites), cell surface and intracellular molecules, and senescence associated secretory proteins (SASPs) — age-induced inflammation-producing proteins released by cells. For example, we know that senescent cells consume and produce energy and perform the function of proliferation-competent cells but release SASPs. So, finding SASP protein markers to characterize senescent cells throughout the body will help in identifying senescent cells.
Tracking and identifying senescent cells through imaging techniques has been difficult for aging researchers since we haven’t sufficiently characterized them. Improved cell labeling techniques for visualization will be key to advance our abilities in tracking and analyzing senescent cells in whole bodies through non-invasive imaging like computer tomography — a scan that uses X-ray technology to see inside the body without making incisions.
Questions remain about whether experimental animal senescence recapitulates human senescence. Figuring out what experimental models mimic human aging will help advance our understanding of senescence. Computational modeling based on mathematical formulas may also contribute to research efforts once scientists generate a comprehensive atlas of tissue-resident senescent cells.
All of this new information regarding senescent cells, such as their locations and molecular characteristics, will need to be put to the test and validated. To do so, researchers may induce, eliminate, or modulate factors driving senescence in the context of health and disease. Applying validation techniques will be important to demonstrate the usefulness of senolytic approaches in an experimental model system.
“It is our view that the time is right to begin to address causes and consequences of cellular senescence along with exploring approaches to identify, track, trace, and perturb senescent cells in relevant experimental model systems,” stated Roy and colleagues in their commentary. “It is our sincere hope that in addition to helping NIH prioritize research activities that are likely to propel this field forward in the next 5–10 years, these discussions will broadly help the community of researchers working in the area of cellular senescence.”
These are gargantuan challenges, but they are necessary for transforming the aging research field for the development of therapeutic options to slow and combat aging and age-related diseases. When scientists improve our characterization of senescent cells and senescence itself, we will have a better understanding of why we age and whether we can do anything to slow or stop it.