Anti-Aging Medicine for Hair- Juniper Publishers
Juniper Publishers- Journal of Cell Science
Introduction
Aging is a natural and unavoidable consequence of
life; however, the appearance of being “aged” need not follow suit.
Indeed, the biology associated with cosmetic aging, the chemical
pathways that trigger collagen degradation and isolated areas of hyper
pigmentation in the dermis, as well as hair loss and/or graying in the
scalp, is a growing area of research, and as scientists unveil key
regulators of the aging cascade, clinicians become better equipped to
rejuvenate wrinkled skin and increase scalp hair density. In the context
of anti-aging medicine, the hair follicle is uniquely qualified to
provide a wealth of knowledge; it is easily accessible, contains
multiple distinct adult stem cell populations, and regenerates itself
cyclically. Moreover, the hair follicle constitutes a miniorgan with
environmental niches established for both quasi-permanent, slow-cycling
stem cells and transit-amplifying, highly-proliferative progenitor cells
[1]. Areas including the bulge, isthmus, and infundibulum are present
in all stages of the hair growth cycle. Unsurprisingly, multiple adult
stem cell populations have been identified in these regions,
particularly in the outer root sheath region lying directly below the
sebaceous gland, or the bulge region. On the other hand, the hair
follicle matrix and pre-cortex are only observed during the active
growth phase of the hair cycle (anagen) where they serve as reservoirs
of rapidly dividing keratinocyte progenitor cells and as differentiation
and melanin synthesis centers, respectively.
The Hair Cycle
The hair cycle begins with a short stage of
apoptotic-driven hair follicle regression (catagen) that lasts
approximately 2 weeks. During catagen, the deeper, highly proliferative
structures of the hair follicle, namely the matrix and the precortex,
are lost, while the hair shaft, along with the inner and outer root
sheaths, regress up towards the scalp surface. Following this period of
regression, the hair follicle enters a state of relative quiescence
(telogen); the dermal papilla condenses, and the hair shaft is actively
held in place by a specialized junction complex located at the base of
the bulge region. The depigmented, fully keratinized telogen hair shaft
is referred to as the “club” hair
in homage the characteristic morphology of its club-like base. Notably,
the secondary hair germ, which contains bulge stem cell-derived
progenitor cells that will eventually give rise to the anagen hair bulb,
pigmented hairs haft, and inner roots heath, manifests early in telogen
and expresses an impressive quantity of circadian clock target genes.
Deletion of two such genes, Bmal1 and Clock, delays the onset of anagen
in mice without altering the morphological appearance of the hair
follicle once growth finally ensues [2]. Interestingly, knock down of
the circadian prote in BMAL1 (orPeriod1) significantly prolongs the
anagen phase in human hair follicles already in anagen, rendering these
two chronobiological proteins potential drug targets for future hair
follicle anti-aging medication(s) [3].
Late in telogen, the secondary hair germ is
activated, and, following a period of rapid proliferation, elongates
distally into the subcutaneous tissue, enveloping the dermal papilla and
establishing itself as a matrix of proliferative transit-amplifying
cells at the base of the follicle. Cell differentiation programs are
reactivated, giving rise to the inner root sheath and hair shaft, and
differentiation of melanocyte precursors leading to melanogenesis
occurs. Meanwhile, the club hair is shed (exogen) in an independently
regulated process. Although the duration of catagen and angered main
fairly consistent from one cycle to the next, each telogen becomes
progressively longer than the one before; consequently, a progressive
asynchrony in hair follicle cycling is observed with age. Additionally,
many hair loss disorders (androgenic alopecia, alopecia are ate, telogen
effluvium) are characterized by concomitant increases in telogen and
reduction sinanagen making the telogen to anagen regulatory path way(s)
of particular importance in the rational design of anti-aging therapies.
To date, two separate signaling pathways have been linked to hair
follicle regeneration and underpin the readiness of the telogen follicle
to enter anagen. Competing gradients of their inhibitory signals (bone
morphogenetic protein (BMP) and fibroblast growth factor 18(Fgf18)) and
stimulatory signals (wingless (Wnt) and Fgf7/10) cycles lightly out of
phase with one another, thereby establishing an early refractory telogen
follicle and later competent telogen follicle [4].
The Wnt/b-catenin Pathway
The first of the two telogen to anagen regulatory pathways
is the canonical Wnt/b-catenin cycle, which is critical for
maintaining the bulge stem cells and secondary hair germ
cells in their respective undifferentiated states [5]. In the
absence of Wnt, the downstream effector molecule, b- catenin,
is inactive, and its nuclear targets, Tcf/Lef, interact with corepressor
molecules such as Groucho to actively repress gene
transcription [6]. Wnt proteins are legends for the Frizzled (Fz)
family of cell surface receptors; they undergo substantial posttranslational
modification (glycosylation, palmitolation) in the
endoplasmic reticulum and are secreted into the extracellular
milieuas glycoproteins. Binding of Wnt to their receptor
complex composed of Fz and low-density- lipoprotein-related
protein 5/6 (Lrp5/6) induces b-catenin-directed transcriptional
regulation of target genes. b-catenin is a dual function protein,
acting as both an adherens junction-associated protein and
a transcriptional co-activator. When the Fz receptor site is
vacant, cytoplasmic b- catenin undergoes targeted proteosomal
degradation via the b-catenin destruction complex, an assembly
of axin, adenomatosis polyposis coli (APC), protein phosphatase
2A (PP2A), glycogen synthase kinase 3 (GSK3), and casein kinase
1a (CK1a). GSK3 and CK1 a sequentially phosphor late a set of
conserved residues in the N-terminus of b-catenin, marking
it for ubiquitination and subsequent degradation. However,
association of Wnt with the Fz/Lrp5/6 receptor disrupts the
b-catenin destruction complex, stabilizing b-catenin within the
cytoplasm where it accumulates, travels into the nucleus, and
associates with DNA-binding proteins of the Tcf/Lef family [7]
(Figure 1).
The BMP Pathway
The second regulatory pathway known to drive hair
follicles from telogen to anagen involves crosstalk between
the mesenchymal and endothelial compartments and is
governed by BMP. In telogen, fibroblasts in the dermal papilla
and keratinocytes in the secondary hair germ express BMP4.
Additionally, fibroblasts in the dermis express BMP2. Binding of
BMP to bone morphogenetic receptor type 1A (BMPR-1A), which
is selectively expressed in the secondary hair germ during early
(refractory) telogen, inhibits Wnt expression and its downstream
effectors [8]. Noggin expression in the hair follicle epithelium
and dermal papilla beginning in late (competent) telogen marks
a transition point in the growth cycle; noggin binds BMP4 with
a 10- to 15-fold greater affinity than does BMPR-1A and may
actively reduce association of BMP4 with BMPR- 1A that is
expressed in the secondary hair germ of the telogen follicle [8].
Inhibition of BMP4 binding to BMPR-1A releases local inhibition
of the Wnt signaling pathway, leading to up regulation of sonic
hedgehog (Shh) and its receptor Patched (Ptc) and is one of the
earliest features of hair follicle formation [9].
Activation of the Telogen to Anagen Tranistion
Coordination of the Wnt/b-catenin and BMP pathways to
effect hair follicle regeneration is function not of just what is
secreted but also of when and where. Two members of the Tcf/Lef
family, Tcf3 and Lef1, are expressed in the hair follicle [10]. Tcf3
expression has been identified in the bulge and in the secondary
hair germ, where it appears to function independently of the bcatenin
interacting domain to suppress features of epidermal
terminal differentiation, thereby maintaining their stem cell
features. Lef1, which requires Wnt signaling and b-catenin
stabilization to exert regulatory control over hair differentiation,
is expressed in the dermal papilla and secondary hair germ
in late telogen through early anagen without concomitant
expression of Shh [11]. Dermal papilla cells also begin producing
Fgf7/10 ligands and BMP inhibitors in late (competent) telogen, both
of which contribute to the progression of the hair follicle
into anagen. Specifically, Fgf7/10 stimulate the secondary hair
germ and (to a much lesser extent) the bulge to proliferate
through FGFR2-111b binding events. This is in stark contrast to
the dermal papilla secretary profile in early (refractory) telogen,
at which point FGF18 is predominantly expressed and actively
inhibits bulge cells through association with FGFR3.
At the onset of anagen, expression of BMP4 and BMPR-1A
are down regulated in the germinative compartment of the hair
follicle (i.e., the matrix), leading to a high rate of keratinocyte
proliferation [8]. Moreover, in late anagen noggin expression
extends from the dermal papilla and cyclic epithelium (i.e., the
matrix and precortex) to the surrounding connective tissue. Shh is
expressed in unilateral clusters of hair matrix keratinocytes, and
Lef1 is observed in the matrix and precortical zone, prompting
entry of progenitor cells within these regions into postmitotic
hair lineages. Bulge stem cells continue to cycle slowly
throughout anagen, but the precise mechanism(s) shielding this
cell population from the increasing gradient of stimulatory cues
has yet to be determined. However, it is speculated that bulge
stem cells sparingly supply cells to extend the outer root sheath
and refresh the pool of matrix progenitor cells that terminally
differentiate after several proliferative cycles. As a result, the
bulge has been deemed the “engine maintaining the (hair
growth) process” by Greco et al. in their 2008 Cell Stem Cell
journal article (DOI10.1016/j.stem.2008.12.009) [11].
Vitality of the Hair Follicle Bulge Region
The importance of the bulge in the hair follicle growth cycle
cannot be overemphasized. As mentioned previously, cells in the
lower portion of the bulge undergo gene expression changes
that transform them into the secondary germ cells at the end
of catagen. The progeny of multipotent bulge cells generates
the new lower anagen follicle in response to the cellular
and environmental cues discussed above. However, immune
histological studies of alopecic scalps have revealed persistent in
filtrates of activated T cells in the bulge region of the transitional
calp, that is, the region of scalp lying at the intersection of
balding scalp and hair-retaining scalp [12]. Secondary to
this prolonged inflammation, in fundable widen and become
blocked by laminated keratin, trichogenic elements are replaced
with fibrous tracts, and (critically) anagen follicles are rare.
Immune response genes are known to be up regulated in early
catagen and throughout telogen in normal hair follicles; the
infundibulum is an established early target of acute and transient
T- cell mediated-protein expression. Indeed, the formation of
desmosomes, the proteins responsible for anchoring telogen
“club hairs” in place, is perpetuated via translocation of nuclear
factor of activated T cells (NFAT) in to the nucleus of bulge cells
during telogen [13]. Clearly activation of the immune response
is necessary for maintaining hair cycle homeostasis, yet the
mechanistic link between androgens and T cell dysregulation
remains unclear.
Nevertheless, clinical manifestations of androgenic alopecia
(AA) support an immune- mediated attack on the bulge. The
time course of AA progresses as follows: hair shafts become void
of pigmentation; the diameter of individual hair shafts decreases
while total hair count remains stable; finally, hair count begins
to decline while follicular unit density remains stable. In the
hair follicle regeneration cascade, arrest of melanogenesis (i.e.,
pigment production) precedes that of keratinocyte proliferation,
as evidenced by the un pigmented base of the “club” hair in
normal telogen. Thus, one may conclude that in the wake of
replicative exhaust, depigmentation would be the first clinical
manifestation regardless of the source of melanocyte stem cells
and matrix transit-amplifying progenitor cells. However, unlike
telogen, AA-associated depigmentation extends the entire hair
shaft, indicating that transit-amplifying cell populations are
continually being replenished by the bulge while melanocyte
stem cells, which are located at the base of the bulge, are
not. With the passage of time, the bulge region responsible
for fueling matrix keratinocyte populations also become
compromised, and hair shaft diameter begins to decrease.
Once trichogenic elements in the bulge are fully replaced with
fibrous tracts, the asynchrony of hair follicle growth becomes
apparent. Individual hair follicles within a given follicular unit
and receiving progenitor cells from the same bulge region may
exist at different states of proliferative potential; therefore, they
may reach replicative senescence at significantly later times.
That is, if one hair shaft in a follicular unit has been in anagen
for 6 years, its matrix cell population may be more “exhausted”
than a neighboring hair shaft that has only been in anagen for 6
months. As a result, when the older hair reaches senescence and
the fibrous bulge is unable to regenerate the secondary germ
during telogen, anagen does not accompany exogen. However,
the younger hair may remain intact for several more years since
anagen can persist for decades in humans, but follicular unit
density will be down, and the growing hair will like lypresent
with a small diameter.
Medical Treatments to Combat Hair Loss
How then can clinicians roll back the clock on a cellular
destructive process? The answer may be summed up by the
age-old adage; an ounce of prevention is worth a pound of cure.
Begin with early intervention. Anti-inflammatory medications
such as minoxidil and cyclosporine A would reduce immunemediated
“attack” on bulge stem cells by preventing mast cell
degranulation. Furthermore, minoxidil is known to exert antiproliferative
effects on dermal fibroblasts, decreasing collagen
synthesis and there by reducing fibrosis in the susceptible hair
loss regions. Experimental stage therapies, including methyl
vanillate, aminotic membrane, and WNT-Act, may stimulate
anagen-inducing and/or transitional elements. Topical
application of methyl vanillate, for example, has been found to
increase hair count and hair mass index in women by 6% and
12% in women following 6 months of use, respectively. The active
ingredient is a suspected Wnt-activator given the concomitant
32% increase in Wnt10B expression in the temporal scalp
[14]. Treatment of mice with amniotic membrane has similarly
shown up regulation of anagen stimulatory signals, specifically,
increased FGF7 and proliferating cell nuclear antigen. Mice
treated with topical amniotic membrane expressed similar levels
of hair regeneration as those treated with 5% minoxidil [15].
Additional drug therapies may target extra follicular domains,
such as adipocyte precursors whose generation begins in late
catagen. Release of platelet derived growth factor (PDGF) from
these cells is linked to the suppression of BMP and subsequent
on set of anagen. Autologous platelet rich plasma (PRP) is rich
in PDGF and has been shown to increase hair density by 50% at
6months.
Prescription medications like finasteride have also proven
beneficial. Regulation of Wnt signaling in dermal papilla cells has
demonstrated an androgen dependence in AA. Dermalpapilla
harvested from the scalps of AA patients express increased
levels of androgen receptor (AR), which is a member of the
nuclear receptor super family that translocates to the nucleus
upon binding ligand where it functions as a ligand-dependent
transcription factor [16]. Thus, in AA patients, increased
AR expression is associated with increased translocation of
testosterone-(T) or dihydrotestoster one- (DHT) bound AR.
This nuclear complex interacts with b-catenin to inhibit Wntmediated
transcriptional activity, and the result is keratinocyte
growth suppression in the matrix. Additionally, AR enhanced
nuclear translocation of b-cateninin pre-adipocytes, ultimately
preventing their differentiation. The sum effect is suppressed
hair growth in anagen follicles. Since finasteride is a selective
5a-reductase inhibitor that blocks the conversion of T into DHT
(which binds AR with a slightly higher affinity than T [17], the
medication may be considered a Wnt up regulator.
Oral finasteride formulations have been associated with
increased scalp hair density in men, gaining widespread
attention under the trade name Propecia in the late 1990s.
However, the medication does not stop the hair loss process
and must be taken perpetually to prevent relapse. Since the oral
formulation is associated with a number of undesirable side
effects (including sexually function), patient compliance is an
issue that topical finasteride formulations could conceivably
bypass. Although topical formulations are in their infancy of use,
remarkable improvements in hair density have been observed,
and, in that regard, may represent the best available anti-aging
medication for hair at present. In summary, the factors governing the hair follicle cycle are
vast and rather complex. Two inter-related path ways (Wnt/bcatenin
and BMP) have been examined in great detail, but the
exact trigger mechanism pushing refractory telogen follicles to
become competent follicles remains unknown. Extra follicular
players, particularly adiposity precursors, appear to be involved.
Similarly, androgen sensitivity is a suspected culprit in immune
deregulation leading to bulge region fibrosis and eventual
demise of the entire hair follicle. Therefore, anti-aging efforts
should begin early with anti-inflammatory agents, adipocyte
supporters (like PDGF), and Wnt cycle promoters (such as
topical finasteride, methyl vanillate, and amniotic membrane).
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