In the aged skin of a male mouse, every third hair follicle is left without a nerve, like a house whose electrical line has been pulled away. The socket itself is intact: the neurons, tucked away in nerve ganglia along the spine, have not gone anywhere. They are alive and have no intention of dying. It is simply that their long extensions, the axons, retreat from the hair bulbs, losing their connection to the workplace.
This scenario unfolds in aging male mice, and it is far harsher than in females. By twenty months of life, about 35% of follicles in males are completely stripped of their sympathetic nerve, the very one that governs involuntary functions, including the raising of hairs in cold or fear. In females of the same age, most follicles retain their innervation. The researchers measured this using immunostaining for tyrosine hydroxylase, an enzyme found in all sympathetic fibers. Three-dimensional reconstruction showed that the nerves remaining in old males had become thinner and had moved away from the follicles.
The target tissue here is the smooth muscle that raises the hair (arrector pili). It degrades with age, especially in males, but even surviving muscles do not guarantee that the nerve will be preserved. It turned out that the aging muscle stops producing nerve growth factor (NGF), a protein that the axon reads as a signal saying "this is your home, stay." NGF levels in the skin of old males fall far more sharply than in females. An analysis of human skin data confirmed the same pattern: in women, neurotrophic support programs are preserved with age, while in men, inflammatory and remodeling programs predominate.
Why do males suffer more? It is not about the sex chromosomes but about gonadal sex, that is, which gonads were active in the animal early in life. Mice with testes lost innervation faster than mice with ovaries, regardless of their chromosome set. Gonadectomy at one month of age smoothed out the differences, while removal of the ovaries in adult females had no effect on innervation. So the fate of nerves in old age is programmed by hormones even before puberty.
The wire pulls away from the socket not because the socket has broken, but because the wall around it can no longer hold the fixture. Restore the wall's strength, and the wire is back in place. This reversibility opens a path to restoring innervation in aging tissues: the intervention must target not the neurons but their microenvironment.
In old male mice, about 35% of hair follicles are completely devoid of sympathetic nerves, yet the neurons themselves in the ganglia are intact, as if the cords were unplugged from the socket while the socket itself stays live.
The idea of reversible denervation and restoring the connection between nerve and tissue echoes a motif from William Gibson's novel Neuromancer, where damaged neural connections can be reprogrammed and restored by acting on the environment.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.