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)-kappa B, and GnRH pulses were controlled by oscillations in the transcriptional activity of NF-kappa B. Exposure to testosterone under pro-inflammatory conditions stimulated both NF-kappa B 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. The hypothalamus controls systemic aging via involving the production of gonadotropin-releasing hormone (GnRH). The authors show that aging is preceded by irregularity and acceleration of GnRH pulses, while lowering GnRH pulse frequency by castration or optogenetically slows aging and promotes longevity.

Automated summary

The study reveals that changes in GnRH pulse frequency and irregularity precede aging, while lowering GnRH pulse frequency after castration can lead to long-term anti-aging effects and lifespan extension by preventing elevation of luteinizing hormone (LH) levels. Reprogramming GnRH pulses through optogenetics can either accelerate or slow down aging in male mice, showing the important role of GnRH in aging regulation.