Testosterone ameliorates vascular aging via the Gas6/Axl signaling pathway

Abstract

Low serum testosterone level is associated with aging-related vascular stiffness, but the underlying mechanism is unclear. The Growth arrest-specific protein 6 (Gas6) /Axl pathway has been proved to play important roles in cell senescence. In this study, we intend to explore whether Gas6/Axl is involved in the effect of testosterone on vascular aging amelioration. Vascular aging models of wild type and Axl -/- mice were established by natural aging. Mice of these two gene types were randomized into young group, aging group and testosterone undecanoate (TU) treatment group. Mice were treated with TU (37.9 mg/kg) in the TU group, which treated with solvent reagent served as control. The aging mice exhibited decreases in serum testosterone, Gas6 and Axl levels and an increase in cell senescence, manifested age-related vascular remodeling. Testosterone treatment induced testosterone and Gas6 levels in serum, and ameliorated cell senescence and vascular remodeling in aging mice. Furthermore, we uncover the underlying molecular mechanism and show that testosterone treatment restored the phosphorylation of Akt and FoxO1a. Axl knockout accelerated cell senescence and vascular remodeling, and resisted the anti-aging effect of testosterone. Testosterone might exert a protective effect on vascular aging by improving cell senescence and vascular remodeling through the Gas6/Axl pathway.

Cellular senescence as a possible link between prostate diseases of the ageing male

“…Although this effect has not yet been confirmed in humans, the involvement of senescence in the process is very likely. Hence, testosterone appeared to play a protective role against ageing in a mouse model of age-related vascular disease, while reduced testosterone levels were associated with increased cell senescence and vascular remodelling 63 .…”

Identification of novel proteins and mechanistic pathways associated with early-onset hypertension by deep proteomic mapping of resistance arteries

“…Although their role in ECM stability in the vascular wall is yet to be determined, our data suggest downregulation of these proteins in hypertension could destabilize the arterial ECM. Notably, the studies referred to here (28)(29)(30) investigated individual proteins and their pathological association to remodeling. While our MS method detected these proteins, our approach also identified many other co-clustering proteins J o u r n a l P r e -p r o o f that were regulated and thus a more complex interplay between ECM proteins.…”

GAS6 ameliorates advanced age-associated meiotic defects in mouse oocytes by modulating mitochondrial function

“…The increase in meiotic defects with reproductive aging leads to increased rates of infertility, miscarriage and fetal trisomy [ 30 ]. In rodents, GAS6 levels in tissues and serum decrease with aging, which may contribute to the aging process [ 31 ]. Here, we report that the expression of Gas6 also decreases with aging in mouse oocytes.…”