Paus R
Department of Molecular Medicine, Max-Planck-Institute for Biochemistry, Martinsried, and Department of Dermatology, University Hospital Hamburg-Eppendorf, Hamburg, Germany

Both intrinsic and extrinsic ageing impact on hair follicle (HF) growth and pigmentation. This must be distinguished from phenomena that get more prominent with increasing age, yet are not identical with senescence (e.g. androgenetic alopecia). However, hormonal effects on the HF may also modulate HF ageing as such, and no reliable markers exist to discriminate between these processes. Moreover, almost no hard data are available on what happens to the HF as it ages. While, therefore, any excursion into HF gerontobiology, is currently a “walk in the dark”, the HF deserves to be discovered as a supremely interesting ageing model. Reportedly, total hair follicle density, duration of anagen, and hair shaft diameter all decline with increasing age. The underlying mechanisms are still obscure, but likely reflect general mechanisms of senescence (e.g. increasing oxidative damage by reactive oxygen species and genetic instability along with declining DNA repair capacity, accumulation of mitochondrial genome damage, progressive telomer shortening). The HF must also display unusually efficient repair/protective systems since it can retain full functions even in very old individuals. This is due to the exquisite regenerative potential and relative protection from apoptosis of its epithelial, mesenchymal and neural crest-derived stem cell populations, the expression of ROS scavenging enzymes and telomerase, and the generation of potent ROS scavengers like melanin and melatonin - making the HF one of the most ageing-resistant organs in mammalian biology. Among HF stem cells, neural crest-derived stem cells seem to be the most ageing-sensitive ones, with hair turning gray as a consequence of defective self-maintenance of HF melanocyte stem cells (e.g. due to relative Bcl2 deficiency). Given the importance of hair cycle- (and androgen-?) dependent, bi-directional trafficking of fibroblasts between the connective tissue sheath and the dermal papilla of the HF for hair growth and size, these fibroblast activities may also change over time, thus indirectly affecting the capacity of the HF epithelium to repair and regenerate. It is unclear how many hair cycles any given HF can traverse during its lifetime (estimated for man: 10-20). This may be determined by a (genetically coded?) timing device linked to the "hair cycle clock", yet distinct from it. Cycling-terminated and malfunctioning hair follicles may be deleted by macrophage-mediated “programmed organ deletion" (POD) - a physiological process that may be stimulated/accelerated by intrinsic and extrinsic ageing-related signals which determine onset and progression of the age-related decline e.g. in scalp HF density. In short, the study of HF gerontobiology and exploitation of the HF’s anti-ageing devices promise fundamental new insights into the general mechanisms of ageing at the cross-roads between chrono- and gerontobiology, and into how these may be countered most effectively.