Reversible, Sexually Dimorphic Sympathetic Aging: Distal Axon Withdrawal Shaped by Prepubertal Gonadal Influences
- 1Department of Stem Cell Biology and Regenerative Medicine, Keck School of Medicine of the University of Southern California
Abstract
Peripheral innervation declines with age, but whether this process is sexually dimorphic and whether it reflects neuronal degeneration or deterioration of nerve-target interactions remain unclear. Using mouse skin as a defined neuroeffector system, we show that sympathetic aging is strongly sexually dimorphic, with greater denervation in aged males. Skin-projecting sympathetic neurons remain intact, indicating that denervation reflects distal axon withdrawal rather than neuronal loss. Nerve-target interactions and the arrector pili muscle niche deteriorate with age, predominantly in males. Aged sympathetic neurons retain NGF responsiveness, and restoring NGF within arrector pili muscles promotes sympathetic reinnervation and hair regeneration in aged males. Genetic and endocrine models show that divergent aging trajectories are associated with gonadal rather than chromosomal sex and are attenuated by early gonadectomy. Together, these findings identify sympathetic aging as a reversible, sexually dimorphic distal axonopathy shaped by the target environment and gonadal influences.
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BibTeX
@misc{pangilinan2026reversible,
title = {{Reversible, Sexually Dimorphic Sympathetic Aging: Distal Axon Withdrawal Shaped by Prepubertal Gonadal Influences}},
author = {G. R. Pangilinan and S. Patil and F. Mires and G. Ye and V. Bogomilova and L. Tilley and T. Goldkorn and C. J. McGill and N. Ballou and X. Li and U. Jadhav and B. A. Benayoun and Y. Shwartz},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.03.748995},
url = {https://www.biorxiv.org/content/10.64898/2026.09.03.748995v1},
note = {CC BY-NC-ND},
}
RIS
TY - UNPB
TI - Reversible, Sexually Dimorphic Sympathetic Aging: Distal Axon Withdrawal Shaped by Prepubertal Gonadal Influences
AU - G. R. Pangilinan
AU - S. Patil
AU - F. Mires
AU - G. Ye
AU - V. Bogomilova
AU - L. Tilley
AU - T. Goldkorn
AU - C. J. McGill
AU - N. Ballou
AU - X. Li
AU - U. Jadhav
AU - B. A. Benayoun
AU - Y. Shwartz
PY - 2026
DA - 2026/09/03
PB - bioRxiv
DO - 10.64898/2026.09.03.748995
UR - https://www.biorxiv.org/content/10.64898/2026.09.03.748995v1
AB - Peripheral innervation declines with age, but whether this process is sexually dimorphic and whether it reflects neuronal degeneration or deterioration of nerve-target interactions remain unclear. Using mouse skin as a defined neuroeffector system, we show that sympathetic aging is strongly sexually dimorphic, with greater denervation in aged males. Skin-projecting sympathetic neurons remain intact, indicating that denervation reflects distal axon withdrawal rather than neuronal loss. Nerve-target interactions and the arrector pili muscle niche deteriorate with age, predominantly in males. Aged sympathetic neurons retain NGF responsiveness, and restoring NGF within arrector pili muscles promotes sympathetic reinnervation and hair regeneration in aged males. Genetic and endocrine models show that divergent aging trajectories are associated with gonadal rather than chromosomal sex and are attenuated by early gonadectomy. Together, these findings identify sympathetic aging as a reversible, sexually dimorphic distal axonopathy shaped by the target environment and gonadal influences.
ER -