TY - JOUR
T1 - GnRH pulse frequency and irregularity play a role in male aging
AU - Wang, Zhouguang
AU - Wu, Wenhe
AU - Kim, Min Soo
AU - Cai, Dongsheng
N1 - Funding Information:
We thank the Cai laboratory members for technical support, A. Wolfe (Johns Hopkins University) for the Gnrh -Cre mouse model, P. Mellon (University of California, San Diego) for GT1-7 and LβT4 cells, and the IVIS facility at Einstein for in vivo imaging assistance. This study was supported directly or indirectly through Einstein resources and NIH grants R01 AG031774, DK121435 and HL147477 (all to D.C.).
Funding Information:
We thank the Cai laboratory members for technical support, A. Wolfe (Johns Hopkins University) for the Gnrh-Cre mouse model, P. Mellon (University of California, San Diego) for GT1-7 and LβT4 cells, and the IVIS facility at Einstein for in vivo imaging assistance. This study was supported directly or indirectly through Einstein resources and NIH grants R01 AG031774, DK121435 and HL147477 (all to D.C.).
Publisher Copyright:
© 2021, The Author(s), under exclusive licence to Springer Nature America, Inc.
PY - 2021/10
Y1 - 2021/10
N2 - 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.
AB - 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.
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U2 - 10.1038/s43587-021-00116-5
DO - 10.1038/s43587-021-00116-5
M3 - Article
AN - SCOPUS:85117924611
VL - 1
SP - 904
EP - 918
JO - Nature Aging
JF - Nature Aging
SN - 2662-8465
IS - 10
ER -