Jan. 07, 2021
The ability to delay and possibly prevent the onset of age-associated conditions and extend human health span is the focus of a rapidly evolving body of research. Animal studies suggest that strategies targeting senescent cells, which are in a state of growth arrest, could combat age-related dysfunction and illness in humans. Mayo Clinic researchers hypothesize that drugs targeting senescent cells or the senescence-associated secretory phenotype (SASP) could be used to slow or prevent the onset of multiple age-related conditions, including idiopathic pulmonary fibrosis, cardiovascular disease, hepatic steatosis, osteoporosis, diabetes, physical decline and brain dysfunction.
Led by Nathan K. LeBrasseur, Ph.D., M.S., a team of Mayo Clinic researchers is exploring whether the SASP, comprising products robustly released by senescent cells, is a potential driver of age-related dysfunction. Dr. LeBrasseur is co-chair of Physical Medicine and Rehabilitation research at Mayo Clinic's campus in Rochester, Minnesota.
The SASP is a key pathogenic feature of senescent cells and an indicator of systemic senescent cell burden. Dr. LeBrasseur and colleagues hypothesize that SASP abundance may be associated with chronological aging and accelerated biological aging. In a study published in JCI Insight in 2020, Dr. LeBrasseur and co-authors explored the link between circulating concentrations of SASP proteins and age-related changes and dysfunction in humans.
Methods
Dr. LeBrasseur's team first screened a variety of senescent human cell types to identify a biomarker candidate panel of 24 SASP proteins measurable in human blood. Cell types included in this screening phase were endothelial and epithelial cells, fibroblasts, preadipocytes, and myoblasts. They then conducted a retrospective cross-sectional study of a community-based sample of people ages 20 to 90 years to analyze associations between those biomarker candidates and chronological age. Next, they examined associations between circulating SASP protein levels and clinical manifestations of biological age, assessed using a frailty index, in three groups of older adults. During the study's final step, Dr. LeBrasseur's team studied whether circulating SASP factors can predict adverse health outcomes after surgery in individuals affected by distinct age-related diseases.
Findings and conclusions
Dr. LeBrasseur notes that overall, the findings showcased important details about the SASP. "We saw that senescent cells produce a robust and distinct SASP and that SASP proteins were positively associated with chronological age, frailty and adverse surgical outcomes."
Using machine learning, the researchers identified a panel of seven SASP factors that predicted adverse events — including surgical complications, ICU admissions and rehospitalizations — markedly better than did a single SASP protein or age:
- Growth differentiation factor 15 (GDF15)
- Tumor necrosis factor receptor superfamily member 6 (TNFRSF6)
- Osteopontin (OPN)
- TNF receptor 1 (TNFR1)
- Activin A
- Chemokine (C-C motif) ligand 3 (CCL3)
- Interleukin-15 (IL-15)
According to Dr. LeBrasseur, understanding that circulating SASP proteins serve as biomarkers of age-related health means that SASP quantification could be useful in both research and clinical settings. In the future, SASP protein levels may help guide clinical researchers as they work to develop and assess interventional "pre-habilitation" measures, such as drugs, diet and exercise, to address a broad range of age-related decline and dysfunction.
"SASP levels could serve as a measure of clinical response to emerging therapies, as surrogate endpoints in associated clinical trials, and as the basis for improving the precision of clinical decisions and options for patients identified as having advanced biological age," explains Dr. LeBrasseur.
For more information
LeBrasseur NK, et al. The senescence-associated secretome as an indicator of age and medical risk. JCI Insight. 2020;5:e133668.