Senolytics show potential to protect against coronavirus in older mice
Cellular senescence, an aging mechanism in which cells lose normal function, may contribute to a worse response in human cells to COVID-19 and in older mice to a similar coronavirus — but a class of drug known as senolytics decreased adverse responses and increased survival for the mice. The preclinical findings from a study funded in part by NIA were recently published in Science.
Aging is a major risk factor for almost all chronic diseases in adults, partly driven by the increasing number of senescent cells (SnCs) with age. These cells result in inflammation and can interfere with the immune system. However, it was not known whether SnCs and their inflammatory factors contribute to the increased severity or deaths of the chronically diseased and older adults after COVID-19 infection. Researchers from several NIA-funded laboratories at the University of Minnesota, Mayo Clinic, and Indiana University used human cells and tissues and mouse models to study the response of SnCs under coronavirus infection and the effect of eliminating or reducing senescent cells.
The scientists exposed cell and tissue samples, donated from humans, to SARS-CoV-2, a human coronavirus responsible for COVID-19. SnCs had an amplified response compared to healthy cells, and increased production of inflammatory factors. This response suppressed viral defense mechanisms and increased the expression of cell surface receptor proteins that the virus attaches to in order to enter the cell. Similarly, in mouse models infected with a beta-coronavirus closely related to the COVID-19 virus, SnCs made the infection and responding inflammation worse.
The viral exposure was fatal in nearly 100% of the older mice, while the younger mice did not experience the increased SnCs burden and 89% survived. The findings support SnCs as a cause of worse outcomes in older mice newly exposed to an infecting coronavirus. But the treatment of older mice with senolytics, a class of drug that eliminates or reduces SnCs, decreased inflammation signals, improved the immune response, and increased the survival rate by 50%.
These findings suggest that senolytics may boost protection for older adults, as well as others with higher SnCs due to chronic conditions, from COVID-19 virus infection and improve survival. While the survival percentages of older mice treated with senolytics varied by sex, the ages were not identical so further research is needed to explore whether there is a sex difference for survival. Next, the researchers have begun clinical trials to test a senolytic drug in hospitalized, older COVID-19 patients and older COVID-19 patients living in nursing homes.
This research was supported in part by NIA grants RO1AG063543-02S1, P01AG043376, U19AG056278, RO1AG063543, P01AG062413, R37AG013925, P30AG050886, U24AG056053, R00AG058800, and R01AG053832.
Reference: Camell CD, et al. Senolytics reduce coronavirus-related mortality in old mice. Science. 2021;373(6552):eabe4832. doi: 10.1126/science.abe4832.