GnRH pulse frequency and irregularity play a role in male aging.

Gonadotropin-releasing hormone (GnRH) has a role in hypothalamic control of aging, but the underlying patterns and relationship with downstream reproductive hormones are still unclear. Here we report that hypothalamic GnRH pulse frequency and irregularity increase before GnRH pulse amplitude slowly decreases during aging. GnRH is inhibited by nuclear factor (NF)-κB, and GnRH pulses were controlled by oscillations in the transcriptional activity of NF-κB. Exposure to testosterone under pro-inflammatory conditions stimulated both NF-κB oscillations and GnRH pulses. While castration of middle-aged mice induced short-term anti-aging effects, preventing elevation of luteinizing hormone (LH) levels after castration led to long-term anti-aging effects and lifespan extension, indicating that high-frequency GnRH pulses and high-magnitude LH levels coordinately mediate aging. Reprogramming the endogenous GnRH pulses of middle-aged male mice via an optogenetic approach revealed that increasing GnRH pulses frequency causes LH excess and aging acceleration, while lowering the frequency of and stabilizing GnRH pulses can slow down aging. In conclusion, GnRH pulses are important for aging in male mice.