Senescent cells undergo an irreversible and permanent arrest of cell division and are hallmarks of both the aging process and multiple chronic diseases. Senescent cells — and more importantly the factors they secrete, known collectively as the senescence-associated secretory phenotype (SASP) — are widely accepted as drivers of aging and multiple age-related diseases.
A new study publishing on January 16 in the open-access journal PLOS Biology from Drs. Nathan Basisty, Judith Campisi, Birgit Schilling (Buck Institute for Research on Aging) and colleagues extensively profiles the SASP in human cells. They show that a core secreted protein “signature” of senescent cells is enriched with aging biomarkers found in human plasma.
The study utilizes a comprehensive and unbiased technique called mass spectrometry combined with bioinformatics to develop secreted protein signatures of senescent cells. The researchers’ results show that the SASP is about ten-fold more complex than is currently appreciated, allowing them to propose new signatures of senescent cells — both ‘core’ signatures shared across all senescent cells and signatures that identify specific subsets of senescent cells.
Mouse studies have demonstrated that the targeted removal of senescent cells has beneficial effects on cardiac, vascular, metabolic, neurological, renal, pulmonary and musculoskeletal functions. Therefore, the selective elimination of senescent cells or inhibition of the SASP that they secrete are promising therapeutic approaches to treat age-related diseases in humans. Development of drugs that eliminate senescent cells, known as senolytics, or drugs that inhibit the SASP, known as senomorphics, requires molecular markers to assess the abundance of senescent cells. However, there are currently no simple reliable secreted biomarkers to measure the senescent cell burden in humans.
“We hope that these biomarker signatures will help us measure the burden of senescent cells in human biofluids, such as plasma, to aid the translation of senescence-targeted therapies into the clinic,” says Dr Basisty. “We believe that the proteins secreted by senescent cells will also be important biomarkers for aging, neurodegenerative diseases, and other diseases marked by the presence of senescent cells.”
Along with this study, the researchers launched the SASP Atlas, a curated database of proteins secreted by senescent cells. This resource can be used by others in the research community to identify proteins originating from senescent cells in their own research.
A protein called Sestrin might be responsible for many of the benefits of a good workout
Whether it be a brisk walk around the park or high intensity training at the gym, exercise does a body good. But what if you could harness the benefits of a good workout without ever moving a muscle?
Michigan Medicine researchers studying a class of naturally occurring protein called Sestrin have found that it can mimic many of exercise’s effects in flies and mice. The findings could eventually help scientists combat muscle wasting due to aging and other causes.
“Researchers have previously observed that Sestrin accumulates in muscle following exercise,” said Myungjin Kim, Ph.D., a research assistant professor in the Department of Molecular & Integrative Physiology. Kim, working with professor Jun Hee Lee, Ph.D. and a team of researchers wanted to know more about the protein’s apparent link to exercise. Their first step was to encourage a bunch of flies to work out.
Taking advantage of Drosophila flies’ normal instinct to climb up and out of a test tube, their collaborators Robert Wessells, Ph.D. and Alyson Sujkowski of Wayne State University in Detroit developed a type of fly treadmill. Using it, the team trained the flies for three weeks and compared the running and flying ability of normal flies with that of flies bred to lack the ability to make Sestrin.
“Flies can usually run around four to six hours at this point and the normal flies’ abilities improved over that period,” says Lee. “The flies without Sestrin did not improve with exercise.”
What’s more, when they overexpressed Sestrin in the muscles of normal flies, essentially maxing out their Sestrin levels, they found those flies had abilities above and beyond the trained flies, even without exercise. In fact, flies with overexpressed Sestrin didn’t develop more endurance when exercised.
The beneficial effects of Sestrin include more than just improved endurance. Mice without Sestrin lacked the improved aerobic capacity, improved respiration and fat burning typically associated with exercise.
“We propose that Sestrin can coordinate these biological activities by turning on or off different metabolic pathways,” says Lee. “This kind of combined effect is important for producing exercise’s effects.”
Lee also helped another collaborator, Pura Muñoz-Cánoves, Ph.D., of Pompeu Fabra University in Spain, to demonstrate that muscle-specific Sestrin can also help prevent atrophy in a muscle that’s immobilized, such as the type that occurs when a limb is in a cast for a long period of time. “This independent study again highlights that Sestrin alone is sufficient to produce many benefits of physical movement and exercise,” says Lee.
Could Sestrin supplements be on the horizon? Not quite, says Lee. “Sestrins are not small molecules, but we are working to find small molecule modulators of Sestrin.”
Additionally, adds Kim, scientists still don’t know how exercise produces Sestrin in the body. “This is very critical for future study and could lead to a treatment for people who cannot exercise.”
