Differences by Sex Observed in BCL-2/BCL-xL Senolytic Treatment for Intervertebral Disc Degeneration
A number of prevalent age-related conditions are notably different in timing and progression between the sexes. No doubt the list of differences by sex will grow as the research community explores the first therapies that target important mechanisms of aging. Here, researchers report on an attempt to treat intervertebral disc degeneration in mice using a senolytic drug that selectively destroys the BCL-2 and BCL-xL proteins that a senescent cell needs in order to resist programmed cell death. There is a reasonable weight of evidence to point to senescent cell accumulation as an important contribution to intervertebral disc degeneration, but the outcomes here are somewhat less than hoped. Male mice suffer a greater level of pathology from the condition in this model, but also benefit to a greater degree from the senolytic therapy. BCL-2 and BCL-xL may not be the best targets for removal of senescent cells in this condition, or alternatively, the burden of senescence in this condition may be different in character or degree by sex.
The senolytic PROTAC (753b) eliminates senescent cells (SnCs) by targeting ubiquitin-mediated destruction of the anti-apoptotic BCL-2/BCL-xL proteins. Here, systemic treatment with 753b was tested for reduction of age-related intervertebral disc degeneration (IDD) in mice. Five aging male and female mice were intraperitoneally injected with 753b or vehicle between 16 and 22 months of age. Among vehicle controls, intervertebral disc (IVD) histology using Safranin-O/Fast Green staining of paraffin embedded transverse sections revealed significantly greater IDD in 22 month old males than age-matched females.
In 22-month-old males, 753b treatment significantly reduced matrix metalloproteinase (MMP)-mediated aggrecan proteolysis as shown by Western blots, loss of disc matrix aggrecan by immunohistochemistry, age-related histomorphologic features of IDD, and serum protein levels of IL-6 and TNFα protein in treated male mice. While expression of IVD cellular senescence markers IL-6, IL-8, TNFα and p16INK4a assessed by RT-PCR of IVD tissue increased with age in both 22 month old female and male mice, expression of these markers was not reduced by 753b treatment.
These results demonstrate that 753b treatment of aging mice reduced IDD in males but not females, which suggests sex-based differences in the role of senescence in IDD and may have an impact on the potential for females to benefit from anti-senescent therapies for IDD. The observed therapeutic effects of 753b on IVDs of the male mice suggest a global reduction of cellular senescence burden through systemic, non-cell autonomous processes.