Deletion of p16 expressing senescent cells improves muscle mass and age‐dependent outcomes in multiple organ systems

Abstract

BackgroundCellular senescence is defined as permanent cell cycle arrest due to upregulation of cyclin dependent kinases such as p16. Senescent cells accumulate with age and can contribute to aging related pathologies. Recently, deletion of p16 expressing senescent cells in vivo has been shown to increase healthspan and lifespan, and ameliorate some tissue specific pathologies in mice. However, it is unknown whether cellular senescence plays a role in age associated declines in skeletal muscle function. We hypothesized that deletion of p16 expressing senescent cells will preserve age‐induced declines in muscle function and mass.MethodsTo eliminate senescent cells in vivo, we utilized p16‐3MR transgenic mice in which administration of the drug ganciclovir will induce cell death in p16 expressing cells. Mice were treated with 25 mg/kg ganciclovir or saline (control) intraperitoneally for 5 days at monthly intervals from 20–26 months of age. Animals were sacrificed at 26 months of age, muscles were weighed, and gastrocnemius muscles were tested for force production in vivo, while extensor digitorum longus and soleus muscles were tested in vitro. Muscle fiber cross sectional areas and fiber type were determined by immunohistochemistry. Additional organs were snap frozen for downstream protein, cytokine, and RNA analyses. mRNA expression was measured using qPCR.ResultsMice that were treated with ganciclovir lived longer and had a lower incidence of cancer than control mice. Muscle masses of the soleus, tibialis anterior and gastrocnemius were greater in ganciclovir‐treated mice compared with controls. The higher muscle mass in treated mice was not associated with any shift in fiber type distribution, increase in fiber cross‐sectional area, or any expansion of the volume of extracellular matrix, suggesting the higher muscle mass was due to preservation of fiber number. There was no effect of p16 deletion on muscle force production. However, upon examining muscle, spinal cord, serum and lung tissue, p16 deletion impacted age‐dependent changes in gene expression and cytokines.ConclusionsDifferential effects of senescent cell deletion on skeletal muscle mass and function suggests the role of senescent cells in skeletal muscle aging may be context specific. Further studies are needed to more thoroughly determine tissue‐specific benefits, but our work suggests that deletion of senescent cells even late in life may provide protection against global aging processes.Support or Funding InformationAG051442K12GM111725This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.