A Multifaceted View on Ageing of the Hair and Scalp

Abstract

Like with skin, both men and women—regardless of ethnicity—gradually lose satisfaction with changes in hair brought about by ageing. Especially when such transition is apparent by others, and that the hair condition has a significant role in an individual’s overall physical appearance and self-perception. Beyond the familiar age-related signs such as hair greying, hair loss, and hair fragility, this review includes current knowledge of biological processes underlying hair pigmentation and hair growth, highlights variations in gender and ethnicity, as well as delineates hair fibre diameter, ellipticity, and elasticity properties that collectively contribute to the characteristics of aged hair. Additionally, in view of the rising importance of enhancing scalp skin health to promote healthy hair growth, the latter part of the review focuses on age-associated alterations to the scalp skin and its microbiome. Consideration of the morphological changes in the hair fibre, biological processes occurring within the hair follicle and its enveloping scalp environment provide a unique, holistic overview of hair and scalp changes during ageing. Finally, after acknowledging the impact caused by chronological ageing and environmental stresses, it is important to recognise that healthy tresses are largely influenced by scalp skin care, and this stimulates the advancement of appropriate cosmetic solutions that help delay or improve the appearance of aged hair.

1. Introduction

The condition of the hair entails a significant role in an individual’s overall physical appearance and self-perception. Although human hair has evolved to be unnecessary for primary survival, poor hair health and hair loss can cause detrimental emotional, psychological, and social impacts. As early as can be traced, there have been archaeological discoveries and ancient written documentations testifying humanity’s obsession with the appearance of hair [1,2]. Experts have proposed that hair presented as healthy, shiny, and strong signal overall good physical health and reproductive potential [3,4,5]. A study conducted by the University of Göttingen further showed that variations in hair colour and hair styling influenced impressions of age, health, and attractiveness [6]. Hence, in addition to facial shape and skin condition, hair also strongly contributes to the perception of beauty.

To better comprehend hair ageing, it is paramount to grasp the different aspects and dynamicity of hair growth. Human hair normally follows a lifelong, continuous cyclic pattern of growth known as the hair growth cycle. It comprises primarily of four phases: anagen—characterised by rapid growth and proliferation, catagen—a brief regression stage, telogen—a quiescent stage, and exogen—the eventual shedding of the hair shaft [7] (Figure 1). As the longest phase of the hair cycle, the duration of anagen for scalp hairs is typically 2–8 years, whilst catagen and telogen lasts approximately 2 weeks and 2–3 months, respectively [8]. Multiple factors have been shown to influence the transition between the anagen and telogen phases. In healthy conditions, approximately 85–90% of human scalp follicles are in the anagen phase, and the rest are either in catagen or telogen [9]. However, with age, the length of the anagen phase tends to shorten, and the proportion of hair follicles in anagen, with respect to telogen follicles, declines [10]. Furthermore, distinct from murine hair growth, individual human hair follicles cycle independently and asynchronously, with each hair follicle potentially capable of undergoing 10–30 cycles in a lifetime. At any one time, most individuals have an estimated average of 100,000 hairs on their scalp, with normal shedding taking place at a rate of 100–150 strands per day [8,11].

Depending on their location, hair follicles may vary in size and shape but are generally characterised by the same structural components [12]. A hair follicular unit, sometimes referred to as the pilosebaceous unit (PSU), is a naturally occurring structural unit of hair that resides within the dermis and the epidermis. It consists of 1–4 hair follicles, a sebaceous gland, and an arrector pili (Latin) muscle [7] (Figure 1). Longitudinally, the hair follicular unit is divided into three regions. The infundibulum refers to the uppermost segment of the hair follicle, which extends from the skin surface to the opening of the sebaceous duct. The middle portion between this sebaceous duct opening and where the arrector pili muscle contacts the hair follicle is the isthmus. The remaining lowermost part of the hair follicle and the hair bulb constitutes the inferior region [13]. The visible part of the hair shaft protrudes from the surface of skin. On the other end, embedded within the skin, each hair follicle is a highly compartmentalised structure made of epithelial components, such as the outer root sheath (ORS), the inner root sheath (IRS), the germinative matrix (GM), and the mesenchymal (or dermal) components, like the dermal papilla (DP) and the encapsulating dermal sheath (DS) [7] (Figure 2). Fundamentally, hair growth and follicle function are modulated by epithelial–mesenchymal interactions, as well as inter- and intra-compartmental communication [14]. It is important to mention that the ORS is a putative source of multipotent stem cells that can differentiate into several cell types such as keratinocytes and melanocytes. This stem cell pool is thought to reside in a distinct area, often called the bulge, positioned between the sebaceous gland ductal opening and the insertion of the arrector pili muscle [15]. At the bottommost follicular bulb region, the GM, which surrounds the DP, is composed of ‘transient-amplifying’ keratinocyte cells that rapidly divide and proliferate. As their volume increases, they push and move upwards and concentrically away, until they terminally differentiate and transform into a hardened material. Through a multi-step process of keratinisation and cornification, the hair shaft is formed and gradually emerges from the skin [7]. Composed primarily of keratin and macrofibrils, made up of rods of microfibrils woven together in a matrix, the hair shaft is another organisational structure consisting of the cuticle, the cortex, and occasionally the medulla. A medulla core is sometimes present in thick hairs. This is surrounded by the cortex, or cortical layer, which is the main structure of the hair shaft that determines the physical and mechanical properties of the hair fibre. Lastly, the outermost layer named the cuticle layer forms an overlapping scale-like barrier that shields against external physical and chemical damage [7,16] (Figure 2).

2. Characteristics of Ageing Hair

2.1. Hair Greying

Greying of the hair, sometimes referred to as canities, is the most visible indicator of normal ageing. ‘Grey hairs’ refer to a mixture of pigmented and non-pigmented (‘white’) hairs on the scalp, or, in some cases, a single hair strand can display a gradual loss of melanin pigment from dark to light. The onset and progression of hair greying depend on chronological age, an individual’s health, and vary amongst ethnicity, gender, and genetics. Extrinsic environmental factors like climate, seasons, exposure to pollutants and chemical toxins, and lifestyle stress can equally affect hair pigmentation as well [17,18].

Keogh and Walsh first stated the 50-50-50 rule of thumb in 1965—whereby 50% of people exhibit 50% of grey hair by 50 years of age [19]. However, a more recent survey of healthy men and women volunteers revealed that a global range of only 6–23% of people experience 50% grey hair by 50 years of age [20]. This is likely due to a varying rate of hair greying amongst different ethnicities—beginning at an average of 34 ± 9.6 years in Caucasians, late 30 s in Asians, and 43.9 ± 10.3 years in Africans [18,20,21,22]. Generally, instances of hair greying arising before 20 years of age in Caucasians, before 25 years in Asians, or before 30 years of age in Africans is deemed to be premature [22,23].

The age of onset and rate of hair greying are largely dependent on ethnic and geographical origins, but irrespective of gender. Instead, hair greying in men and women differ in terms of the incidence of grey hair and pattern of hair greying [20,22]. Based on the previously mentioned 2012 survey, within a specified age range of 45 to 65 years, more men had grey hair and significantly higher greying intensity as compared to women [20]. Another Korean study reported that greying in men initially appears at the temples and sideburns, whilst grey hairs tend to develop first along the hairline or boundaries of the scalp in women [24]. Then, whether starting from the temporal or frontal regions of the scalp, grey hairs gradually spread to the vertex and parietal and lastly show up at the occipital region [18,25]. This varying rate and timing of hair greying, as well as other hair parameters, across the different parts of the scalp may be attributed to embryonic derivation, where the anterior scalp (frontal and temporoparietal areas) originates from the neural crest and the posterior scalp (consisting of the occipital area) is derived from the mesoderm [26].

The exact cellular and molecular mechanisms involved in human hair greying are not well elucidated, and the extent of genetic, metabolic, oxidative, and inflammatory contributions to greying remain unclear [25,27,28,29]. This likely arises from the insufficient understanding of physiological processes modulating human hair pigmentation [30]. Epidermal and hair follicular melanocytes may share a common origin and can be reactivated under certain circumstances [31], but their location, morphology, function, regulation, and susceptibility to chronological ageing are dissimilar [30,32,33]. Particularly, hair follicle pigmentation is closely coupled to the hair cycle [28,34] (Figure 1). Hair follicular melanocytes demonstrate an extraordinary capacity for the synthesis and storage of melanin during the anagen phase (stages III–VI). It is proposed that as few as 100 melanocytes per anagen scalp hair follicle can supply enough melanin to intensely pigment a hair fibre of up to 1.5 metres in length for 10 years [35]. In a human hair follicle, melanocytes and their precursors mainly reside at the follicular bulb matrix (above and around the tip of the dermal papilla; below the pre-cortical keratinocytes), the sub-bulge area of the ORS, and the bulge [34,36,37] (Figure 2). The bulbar melanocytes, together with the surrounding keratinocyte population, constitute the melanocytic or pigmentary unit (HFPU or hair follicle pigmentary unit). This unit, together with the melanocyte stem cell (MeSC) populations located along the hair follicle, contribute to hair fibre pigmentation, producing and transferring melanin to the cortical keratinocytes that continuously proliferate to form the hair shaft cortex, medulla, and cuticle [37,38,39].

The principal view is that hair greying stems from the reduced bulb melanin content and the depleted potential of the HFPU—as a combined result of reduced melanogenesis activity, aberrant melanin transfer to the hair shaft, and apoptosis of mature, differentiated bulbar melanocytes at the HFPU [28,40]. This phenomenon has been attributed to dysregulated antioxidant pathways and DNA damage brought about by exposure to environmental stresses like ultraviolet (UV) rays and pollutants, normal metabolism, inflammation, and genetic defects. Collectively, they trigger the formation of H₂O₂, as well as the overproduction and accumulation of free radicals and reactive oxygen species (ROS). Since mitochondria is a primary source of intracellular ROS, a mitochondrial “free radical theory of ageing” is commonly associated with hair greying [41]. Cumulative oxidative stress exacerbates apoptosis, causes defective oxidative stress protection, then leads to accumulated mitochondrial DNA damage that reduces bulbar melanocytes and causes depigmentation of the hair follicle [18,25,28,30,42,43].

Precise downstream mechanisms of how excessive oxidative stress and mitochondrial damage impact HFPU during human hair greying have yet to be identified. The process of melanin synthesis itself, or melanogenesis, inherently produces high ROS levels as a byproduct of a series of biochemical reactions involved in melanin production, such as the hydroxylation of tyrosine to L-DOPA (L-3,4-dihydroxyphenylalanine) and the oxidation of dopamine to melanin [28,30]. Previously, Van Neste suggested that the elongation rate of non-pigmented female hair follicle shafts was significantly faster than pigmented hairs when maintained in organ culture [44]. In an Asian cohort [45], hair shaft diameters were also comparatively higher in unpigmented hairs than pigmented hairs. Notably, elevated levels of keratins (KRTs) and keratin-associated proteins (KRTAPs), which form major components of the hair shaft and are essential for its mechanical properties and rigidity, were observed in these unpigmented hair bulbs. Microarray and RT-PCR analyses of the unpigmented and pigmented Asian hair bulbs showed that KRT6 (keratin 6), KRT14/16 (keratin 14/16), KRTAP4 (keratin-associated protein 4), and FGF7 (fibroblast growth factor 7) were associated with the induction of hair growth and were significantly upregulated in unpigmented hairs. Contrarily, FGF5 (fibroblast growth factor 5), a factor involved in the transition of the hair from the anagen to catagen phase and an inhibitor of hair growth [10], was downregulated in unpigmented hairs. On one hand, these findings reveal that a reduction in melanin-associated processes at the hair bulb may promote active growth by way of consolidating the follicle’s efforts to manufacture thicker fibrils at a faster rate. However, they also emphasise the high metabolic activity, redox, and genotoxic stress occurring in the hair follicle, which requires management by sophisticated antioxidant systems that include antioxidant enzymes, scavengers, etc. [25,28,30]. In addition to antioxidant metabolism in response to excessive levels of ROS, cells also recruit the DNA Damage Response (DDR) mechanism to detect and protect against the damaging effects of free radicals on DNA. One crucial component of the DDR is the Ataxia-Telangiectasia mutated (ATM) gene, which is a serine/threonine transducer kinase activated during oxidative stress. In mice, deficiency of ATM caused sensitisation and early differentiation of melanoblasts (a transient population of precursor cells derived from neural crest cells that migrate to develop into melanocytes), thereby leading to a diminished stem cell niche [46]. Correspondingly, when checked in scalp tissues collected from healthy donors, the incidence and expression level of ATM also correlated with the unpigmented status of human hair follicles [27].

Another viewpoint frequently discussed is the role of MeSCs in hair pigmentation. The MeSC population, which resides within the hair bulge–sub-bulge niche and adheres to hair follicle stem cells (HFSCs), as well as the intra-bulbar melanocyte progenitor cells, gives rise to mature melanocytes located in the hair matrix at the bulb [28]. Little is known about how the MeSC populations replenish these HFPU melanocytes, or about the cell-cycle entry and quiescence of the MeSC population during hair cycling. Based on murine models, modulation of MeSCs is critically dependent on the master regulator of melanocyte development—MITF (microphthalmia-associated transcription factor)—and its downstream target Bcl-2 (B-cell lymphoma 2) [47]. TGF-β (transforming growth factor-β) and Col17A1 (collagen XVII) expressed by surrounding HFSCs also have important roles in maintaining MSCs’ quiescence and immaturity [48,49,50]. Additionally, several other signalling pathways such as SCF/c-kit (Stem Cell Factor and its receptor c-kit), Notch, Raf and Wnt/β-catenin (together with the transcription factor Pax3), NFIB (Nuclear factor I/B), EDNRB (Endothelin Receptor Type B), and CXCL12 (C-X-C motif chemokine ligand 12) were identified to be essential for melanocyte development and MeSC homeostasis [51,52,53,54,55,56]. Maintenance of this MeSC reservoir is viewed as imperative, because the reduction in MeSCs via differentiation and/or apoptosis is hypothesised to provoke the ‘irreversible’ greying of hair [25]. Up until then, loss of pigmentation due to initial defects in the HFPU is still considered reparable if MeSC niches are still maintained [30]. Keeping in mind the fundamental differences between mouse and human models, several notable regulators of human hair follicle pigmentation are not as essential as they are in murine hair follicle pigmentation, and vice versa. Nevertheless, MITF-M, Sox10, Pax3, TYR (tyrosinase), and TYRP1 (tyrosinase-related proteinase 1) were reportedly reduced or absent in unpigmented human hair bulbs compared to pigmented hair bulbs [57]. A subsequent microarray study of human hair follicles (of varying pigmentation) further supported these observations and revealed a corresponding decrease in KIT (tyrosinekinase receptor for SCF) in unpigmented follicles [58,59]. Other theories include the involvement of aberrant DDR pathways (e.g., nucleotide excision repair (NER)) in the MeSC population and melanocytes that cause the reduction in melanin production capacity [60], as well as decelerated melanocyte migration from the MeSC ORS/bulge reservoir to the follicular bulb [18]. A recent publication conducted in mice further substantiates that the loss of hair fibre pigmentation during ageing is due to the defective migration of MeSCs into the follicular bulb matrix. Using long-term lineage tracing in vivo, researchers from the NYU Grossman School of Medicine demonstrated how MSCs are exceptionally plastic and dynamic, translocating actively between compartments of the developing hair follicle. They found that MeSCs increasingly get trapped in the follicle bulge of aged murine follicles, and their location renders these cells incapable of regenerating or maturing into pigment-producing melanocytes [61].

Taken together, the hair greying phenomenon is not monocausal but the outcome of a myriad of factors [30]. Beyond the complex network of controls and mechanisms that regulate human hair pigmentation, it is vital to also account for the functionality of the whole HFPU unit in conjunction with its unique microenvironment within the scalp skin (more details in Section 3). On a positive note, this multifactorial process presents opportunities where pigmentation of the hair follicle can be reversed or restored as long as MeSC and melanocyte populations of the hair follicle are not completely lost. Indeed, reversal of hair greying is perhaps not too inconceivable, considering the correlation between hair pigmentation patterns (HPPs—a single hair fibre that exhibits greying and reversal transitions) and psychological stressors [62], suggesting that management of psychological stress can pose as a potential avenue for controlling hair greying.

2.2. Hair Loss During Ageing

Much like hair greying, hair loss is another common occurrence that is part of the natural ageing process. While an individual typically sheds approximately 100 hairs a day, excessive hair loss leads to balding. This loss or absence of hair from areas of the body where it is expected to be found is medically termed as alopecia [8,11,63]. Alopecia can manifest as localised—specific areas on the skin (in patches) or diffuse—general thinning, partial or complete loss of hair, and can be temporary or permanent [64]. The most prevalent type of hair loss is androgenetic alopecia (AGA), although other alopecia types are also observed as well, such as alopecia areata, traction alopecia, telogen effluvium, scarring (cicatricial) alopecia, etc. [65]. Since senescent alopecia (SA) and AGA are both age-related hair loss conditions, we have chosen to focus on these two alopecia types in the subsequent paragraphs. Regardless of the form of alopecia, hair loss and reduced hair growth is caused by disruption to the hair growth cycle and/or damage to hair follicles due to various systemic and local factors like genetic predisposition, lifestyle and nutrition choices, hormone imbalances, medical conditions, and ageing [8,66].

Located at the base of the hair follicle is the DP, which consists of a specialised population of mesenchymal cells formed during hair follicle development (Figure 2). As an instructive niche, DP cells maintain an active communication with its precursors and the epithelial compartment—to direct keratinocytes in follicle growth and production of hair shaft, as well as to regulate hair shape, size, and colour [67,68,69]. It was first reported that the size of the hair follicular bulb (including both DP and GM) was correlated to the health of human hair follicles, suggesting that the hair follicle size and volume of hair fibre could be determined by DP size [70]. A subsequent study by Elliott et al., 1999 [71] demonstrated that the reduction in DP volume, due to a decrease in DP cell number, was associated with vellus hairs. More clearly, in the context of progressive hair loss, the size of the follicle and hair it produces was shown to gradually reduce in successive hair cycles until the hair follicle reaches miniaturisation [72]. Several studies have proposed that hair loss treatments involving IGF-1 (insulin-like growth factor 1) and FGF-7 upregulate Wnt/β-catenin signalling in DP, thereby stimulating anagen entry and hair growth. Another well-studied growth factor, EGF (epidermal growth factor), also plays an important role in regulating hair follicle growth. However, recent findings indicate that EGFR signalling downregulates Wnt/β-catenin signalling to delay differentiation and lineage commitment, thereby helping to coordinate normal hair follicle formation [73]. Alternatively, because the telogen phase is more than just a resting state—it is a crucial period where the DP compacts in preparation and awaits signals that reactivate hair regeneration—attention has been focused on transitions to and from the resting telogen phase as part of successful maintenance of DP for hair growth [67]. Other emerging solutions include the inhibition of senescence of hair follicular DP cells—for example, the use of veratric acid [74]—as well as senolytic treatments with dasatinib and quercetin, which specifically target and effectively reduce the number of senescent DP cells and restore inductive properties of hair follicles, thereby allowing them to regenerate and promote new hair growth [75].

Epithelial–mesenchymal interactions between the DP and HFSCs are critical for powering the cyclic growth of the hair follicles and maintenance of follicle morphogenesis [76,77]. Most HFSCs reside within the bulge region of the ORS, which is located between the opening of the sebaceous gland and the attachment site of the arrector pili muscle (Figure 2). These bulge HFSCs are a multipotent adult stem cell population that have high proliferative potential. They harbour the ability to generate several epithelial lineages of the skin—in addition to new hair follicles, they are also able to give rise to the epidermis and sebaceous glands during wound healing [78,79]. Because the hair follicle is an integral component of the skin, the growth and activity of HFSCs are regulated by various neighbouring cells, such as the DP, adipocytes, immune cells, and nerves, which together form a specialised microenvironment called the HFSC niche [80]. Within this HFSC niche is the constantly opposing activating and inhibitory signals, mostly driven by the activating Wnt/β-catenin signalling and the inhibitory BMP (Bone Morphogenetic Protein) signalling. Transition between the activated state or quiescent state of HFSCs is dependent on the final readout summation of the counteracting signals. Other signalling pathways that further add to the HFSC niche’s complexity and heterogeneity include Hedgehog (Hh), Notch, PI3K/AKT, RAS/MAPK, TGF-β2, Foxp1, and oncostatin M [76,80,81,82]. Upon stimulation, quiescent HFSCs become activated, initiating the onset of anagen that drives the start of a new hair cycle.

Mostly demonstrated in murine studies, many changes have been noted in hair follicles during ageing. For example, the lengthening of the telogen phase whilst the anagen phase is shortened, extended dormancy and inability to re-enter the hair growth cycle, as well as the miniaturisation of hair follicles, are cited to result in shorter and more scattered hairs and eventually hair loss [8,81,83,84,85]. While it is still uncertain if the number of HFSCs varies with age, there is a general agreement that the function of these HFSCs diminish with advanced age [81,86,87,88]. In-depth in vivo fate analyses revealed that aged HFSCs are cyclically eliminated from the murine skin via the proteolysis of COL17A1/BP180 by neutrophil elastase in response to DNA damage. COL17A1 plays an essential role of maintaining HFSC health and function, and its depletion led to the stepwise miniaturisation of the murine hair follicles and eventual hair loss. In the same study, gene set enrichment analysis of telogen hair follicles between young and aged mice also showed that Wnt signalling was less activated in aged HFSCs [83]. Further supporting this view, Tiwari et al., 2021 [89] showed that Wnt target genes—Axin-2, Lef-1, Lgr-6, and c-Myc—were downregulated in HFSCs upon ageing. Nuclear localization of β-catenin was also markedly decreased, and the canonical Wnt signalling was antagonised by non-canonical Wnt5a-Cdc42 signalling in aged HFSCs. On the other hand, it is proposed that the changing activity and loss of function of aged HFSCs supersedes the importance of the HFSC population size. Murine aged HFSCs have been shown to grow slower in vitro, exhibiting decreased activity and capacity to form colonies as compared to young HFSCs [84]. While there is yet an established, direct causal relationship between alopecia occurrence and senescent HFSCs [86], the abovementioned studies provide hints at potential links—hence spurring stem cell-based therapy approaches focused on replenishing HFSCs or reactivating HFSCs with adequate signals and environments. From the transplantation of multipotent stem cells, derived from adipose tissues, bone marrow, umbilical cord, and hair follicles from unaffected scalp areas, to the application of stem cell-derived conditioned media and stem cell-derived exosomes, clinical studies have shown promising results with improved efficacies, albeit with their respective limitations [90]. Ultimately, in addition to the HFSCs’ actual activity, its niche and microenvironment have an essential role in influencing HFSCs and should not be overlooked [88].

Senescent/Senile Alopecia and Androgenetic Alopecia

Senescent alopecia or senile alopecia (SA) is described as a non-androgen-based, diffused hair loss that can involve all hairs of the human body (not only the scalp). It is thought to affect individuals above 50 years of age with no family history of patterned balding [91]. Separately, the more widely known AGA, or, male or female-patterned alopecia, is regarded as a genetically predetermined disorder, which is caused by an excessive sensitivity to androgens. Its prevalence differs across race and gender—possibly affecting up to 85% of men and approximately 40% in women. In some cases, hair thinning may begin as early as after puberty in adolescents [92,93]. To date, there still exists much debate to whether SA or AGA represent two distinct entities [94]. Various studies like Deng et al., 2023 [86] and Whiting, 2011 [91] have indicated significant overlap between SA and AGA in terms of reduced total hair counts, reduced hair follicle size and hair fibre diameter, decreased anagen-to-telogen ratios, and higher terminal-to-vellus hair ratios. Indeed, the incidence and prevalence of AGA increases with age. However, the diagnoses of AGA are not limited to older people. In the first comparative histopathology study of SA and AGA, Kligman, 1988 [95] reported that, while SA was characterised by a modest reduction in hair follicle size, AGA was observed to be associated with hair follicle miniaturisation, inflammation, and fibrosis. The absence of fibrosis in SA was a likely explanation why hair growth may still be stimulated by pharmacological means. A more recent study of gene expression profiles of scalp biopsies of SA and AGA male subjects, as well as control group (with no visible hair thinning), revealed that both phenotypes represent different entities [96]. As expected, hair development and function were the most significant physiological parameters altered in both SA and AGA. Notably, there was an upregulation of the androgen receptor (AR) in AGA, but not in SA. This corroborates previous studies that have demonstrated that genetic variability in the human AR is the main prerequisite of the early onset of AGA [97,98]. Additionally, unique to SA, genes involved in transcription (FOS, FYN, JUN, JUNB, MYC, NAB1), growth factors (CTGF, TGFα), and mitochondrial function (JAK2, PRKD3, AK2, TRAP1, TRIO, ATP12A, MLL4, STK22B) were significantly downregulated, whilst expression levels of oxidative stress and inflammatory response genes were upregulated [94,96].

With most studies conducted in AGA subject cohorts, major developments have been made in understanding androgen metabolism and how androgen-regulated factors operate through the DP [94]. This has led to the development of widely prescribed 5α-reductase inhibitors, which are known modulators of androgen metabolism, such as finasteride and dutasteride. However, there remains limited success with these hair loss treatments [99]. The primary concerns are that these oral medications may cause persistent adverse effects and that there is a lack of studies examining their safety and effects in females with AGA [100]. Additionally, in hair follicles of AGA men aged between 18 and 30 years, there were significantly higher levels of 5α-reductase types 1 and 2 receptors and ARs in the frontal follicles compared with the occipital follicles. This finding was also almost a two-fold increase compared to hair follicles collected from SA men [101]. This in part explains why the efficacy of using 5α-reductase inhibitors could decrease in men at advanced ages [94]. Another well-known treatment for AGA in both men and women is minoxidil. Initially developed as a hypertension medication to treat high blood pressure by dilating blood vessels, it was unexpectedly found to also promote hair growth, thereby driving its later development as a hair growth solution. Mechanisms of how minoxidil on the hair follicle are proposed to be multifarious and not fully understood, although animal studies have shown that topical minoxidil induces premature entry of resting hair follicles into anagen and prolongs the anagen phase, with a potentially similar mode of action in humans. Moreover, minoxidil is described to stimulate vascular endothelial growth factor (VEGF) expression, cell proliferation, and prostaglandin synthesis, whilst inhibiting collagen synthesis in various skin and hair follicle cell types [102,103]. Notably, VEGF has an important role in angiogenesis by promoting the formation of new blood vessels and ensuring an adequate supply of blood flow to the hair follicles. Overall, topical minoxidil is generally well tolerated, with more common side effects like skin irritation and itching. Yet a notable drawback is that it must be used indefinitely to provide continuous support and maintenance of any hair regrowth experienced [104].

It is important to also consider other potential hair loss factors like oxidative stress, follicular microinflammation, and fibrosis [94]. In assessing the effect of topical application of linolein hydroperoxides on murine skin, which causes free radicals that induce early catagen, there was increased apoptosis of murine hair follicle cells. Moreover, cultured human epidermal keratinocytes subjected to linolein hydroperoxides also showed an upregulation of apoptosis-associated gene expression [105]. In another study, isolated DP cells from AGA scalps grew significantly slower in culture than DP cells from non-balding scalps. The authors demonstrated that the loss of proliferative capacity in balding DP cells may be related to downregulated levels of proliferating cell nuclear antigen and Bmi-1, along with corresponding enhanced expressions of senescence-associated β-galactosidase, p16^INK4a/pRb, and other markers of oxidative stress and DNA damage such as heat shock protein-27, superoxide dismutase catalase, ATM kinase, and Rad3-related protein. In particular, the association of cultured balding DP cells with increased p16^INK4a/pRb implies a heightened sensitivity to environmental stress [106]. Beyond determination by genetics, progressive hair loss is equally susceptible to changes brought about by chronological ageing and hormones, as well as external environmental, dietary, and lifestyle factors. Furthermore, several other studies have proposed that a chronic, low-level, microscopic follicular inflammation, referred to as ‘microinflammation’, may contribute as a cause of hair loss [107,108,109]. This should not be confused with the classical, more destructive inflammatory process involved in scarring (cicatricial) alopecia disease [107]. Morphometric studies conducted by Whiting, 1993 [110] provided early evidence that AGA scalps with significant microinflammation and fibrosis had reduced likelihood of hair regrowth in response to treatment. It is unclear how inflammation is generated around the hair follicle, since it is likely a consequence of multiple factors triggered by a primary event. In more deteriorating conditions of hair loss, it has been suggested that there could be growing clusters of perifollicular macrophages and cumulative physiological degeneration of selected hair follicles, where malfunctioning or defective follicles are eventually removed—similar to a programmed organ deletion process [111].

2.3. Changes in Morphology and Properties of Hair During Ageing

Beyond the loss of pigmentation in hair fibres during ageing, greying hair is observed to be frequently coarser, wirier, and more unmanageable compared to its pigmented equivalent (Figure 3). The absence of melanin accentuates changes in the chemical and physical properties of the post-pigmented hair fibre [35,112]. More specifically, hair fibre properties like diameter, ellipticity, and fibre elasticity vary according to normal chronological ageing [94]. It has long been recognised that there are many underlying differences in fibre properties between ethnicities; hence, it is important to also expect ethnic-associated variations during hair ageing [42].

Age-associated hair diameter changes appear to have a significant contributory effect on the overall perception of hair thinning and are not solely due to reduced hair density [113]. Past studies have so far indicated a general trend towards hair shaft diameter decrease with increasing age. In Japanese and Caucasian male study cohorts, hair shaft diameter increases and peaks during the late teenage years. After which, from approximately 25 years of age to late 40s and up to 89 years, the hair shaft diameter steadily decreases [114,115,116]. Contrary to men, hair shaft diameters are not linearly proportional to age in women. Rather, both Caucasian and Asian women tend to follow a curvature that reaches a maximum at about 40–46 years, before it starts declining [113,114]. In addition, physiological and hormonal effects as women approach and experience menopause are suggested to also influence changes in female hair diameters. For example, a comparison between premenopausal and postmenopausal Caucasian women reported a significantly smaller diameter of the scalp hairs of postmenopausal women [117]. However, if hormonal level changes (throughout menopause) could be monitored together with scalp hair diameters, this physiological effect would be further validated. Recently, X-ray diffraction studies have suggested that the hair shaft shrinking phenomenon does not simply consist of producing a smaller shaft diameter but also involves the implementation of an ‘aged hair program’ that begins in the hair follicle. Age-associated thin hairs were found to exhibit changes in the expression of hair keratins and keratin-associated proteins, as well as alterations in the intermediate filament structural organisation that forms the hair cortex—the middle layer of hair shafts known to confer strength, texture, and colour. Furthermore, the thinner hairs exhibit a decreased hair ellipticity, fewer cuticle layers, and lower frequency of a medulla, the innermost core of the hair fibre that is usually absent in finer hairs. Collectively, these modifications could have resulted in modifications in mechanical properties such as increased rigidity, reduced viscosity, and decreased water diffusion coefficient that make hairs more susceptible to breakage and damage [118].

A hair fibre’s ability to stretch (elastic modulus or Young’s modulus), bend (bending modulus), and twist (torsional modulus) before permanent deformation has been shown to be proportional to hair fibre diameter [119,120,121]. As the hair shaft diameter reduces with age, the fibre’s ability to withstand these three stresses correspondingly decreases. A comparison among three different age groups—children (1–10 years), young adults (25–35 years), and the elderly (50–60 years)—demonstrated that elastic modulus and hardness were higher in young adults than in the elderly. This may in part explain the decreased tactile perception of hair with advanced age [122]. Considering the variations in gender, Caucasian and Asian men start to observe a deterioration in the mechanical properties of their scalp hairs in their 20s, while Caucasian and Asian women only exhibit signs of weakening mechanical properties in their early 40s [123].

Persaud and Kamath’s development of a single hair fibre torsional pendulum method additionally suggests that reinforcement of the hair cuticle layers has a more significant role towards strengthening torsional resistance than in elasticity [121]. This presents as another contributory factor to how hair’s physical properties can change. Indeed, there is a gradual loss of hair cuticles with age, as Plott et al., 2020 [124] found a decreased abundance of cuticular proteins with increasing age. This corroborates with an earlier key study by Thibaut et al., 2010 [125]. Given the known variations in hair cuticle characteristics across ethnicities, it is conceivable how the hair fibre’s ability to resist mechanical stresses at advanced ages may differ across populations.

Hair fibre curvature also has an important effect on the appearance of hair. In a study group of Japanese females, aged from 10 to 70 years, it was found that the decrease in hair lustre corresponded to irregular increase in hair fibre curvature during ageing [126]. This is likely due to an inhomogeneous amino acid deposition of hair keratins that varies the internal structure of the outer and inner regions of the fibre, giving rise to the curvatures [127]. Altogether, this lack of alignment within an assembly of hairs shows up as frizziness or a reduction in hair lustre. Moreover, notable increases in cysteic acid residues and decreases in cysteine found in grey hairs imply a weakening of the hair fibre’s strength and structure, which causes heightened sensitivity to weathering and reactivity to reducing and oxidising agents [33,128]. Lastly, without the photochemical protection due to loss of hair melanins, hair proteins progressively become degraded and lost, altering the composition of hair shaft layers. Caught in a negative cycle, grey or non-pigmented hairs increases sensitivity to ultraviolet radiation (UVR) [129].

Although hair lipids form a small part of the composition of hair, they are as essential as hair proteins, minimising moisture loss, providing a permeability barrier, and maintaining hair integrity. Besides its physical properties, lipid metabolism contributes by modulating modifications to signalling proteins, like Hhs and Wnts, which are necessary for hair follicle morphogenesis and hair growth cycling [130,131]. The two major sources of hair lipids are the follicular bulb matrix cells and follicular sebaceous glands (Figure 2; left). Amidst ongoing hair shaft production and melanogenesis, the hair bulb matrix also produces integral lipids, which are incorporated during keratinisation and the formation of the IRS. These lipids are embedded within the keratinised cell membranes, providing structural integrity and protection like a lipid envelope [132,133]. Overall, human scalp hair lipids mainly comprise fatty acids, wax esters, ceramides, squalene, and cholesterol. Together, they account for about 0.7–1.3% of the total chemical content of hair [94,131,132]. It was reported that because Asian hairs have more integral hair lipids, they exhibited significantly lesser damage compared to Caucasian and African hairs after exposure to UVR irradiation [131]. Nevertheless, the overall lipid content of the hair cuticle, cortex, and medulla has been shown to decrease during the pigmented-non-pigmented hair transition and with advancing age [134]. Importantly, 18-methyl eicosanoic acid (18-MEA), the most abundant fatty acid found in hair, is covalently bound to proteins of the cuticle cell outer layers via thioester bonds. This constitutes the fatty layer, sometimes referred to as the F-layer, which is responsible for the surface and tactile properties of the hair fibres and gives the hair a smooth, shiny, and silky texture [134,135]. 18-MEA in hair strands is easily damaged and lost through dyeing, perming, and other chemical processes and external factors. Through these daily stresses, the amount of 18-MEA naturally decreases with age, with studies showing more pronounced loss of total 18-MEA content starting from age 50 [136]. These hair lipids are distinct from the sebum production of the sebaceous glands that secrete a waxy, oily substance to lubricate emerging hair shafts, conferring shine, smoothness, and softness [137]. The amount of sebum production is dependent on the size of sebaceous glands, which is generally known to be low before puberty, rapidly increases at puberty, remains at relatively high levels, and declines at 45–50 years of age [138]. Decreasing exogenous and endogenous lipid contents of the hair cuticles, cortex, and medulla with advancing age, including diminishing 18-MEA levels and de novo dihydroceramide synthesis, causes unpigmented hair fibres to have an overall lower capacity of water absorption and higher water diffusion, thereby leading to greater stiffness and permeability [125,139,140,141,142]. This causes unpigmented hairs to be more susceptible to brushing and mechanical stresses, further accelerating loss of the cuticle barrier that prompts the occurrence of more hair breakage [143,144].

3. Ageing Scalp Skin

3.1. Age-Related Changes in the Scalp Skin

While variations in hair volume, density, pigmentation, and texture have been extensively studied and reported during chronological ageing, age-related changes in the scalp skin are relatively less understood. Similarly to other skin sites, the scalp skin likely evolves with age. On the other hand, it is prudent to first note the functional distinctions between the stratum corneum (SC) of the scalp skin, the face, and other sites of the body. In a study of Japanese patients with alopecia areata and AGA [145], physiological differences in water barrier function (TEWL values), skin surface hydration, and skin surface lipids were found to vary across the scalp, cheek, and volar forearm skin test sites. Moreover, superficial corneocytes of the scalp skin appeared significantly larger in size than the cheek skin, but smaller than the volar forearm skin. Given that corneocyte size is inversely correlated with epidermal proliferative activity, the epidermal proliferative activity of the scalp skin, with an estimated turnover rate of about 10 days, is hence slower than that of facial skin. With the growing prominence of scalp ageing and the acceleration of the ‘skinification’ of the hair initiative in recent years, the focus has now shifted to deeper understanding of, and better care suited for, the hair source—that is, the scalp skin—in order to stimulate or maintain healthy hair growth [146,147,148].

Conceivably, the intertwined structural arrangement of the scalp skin and hair fibres implies an interdependent relationship between both components. While the hair strands protect and shield the scalp from mechanical stresses and UVR, the scalp, conversely, serves as an incubatory environment that supports hair growth [94,149]. Continuous cycling of the hair follicles requires considerable remodelling of the scalp dermal environment. In fact, a transplant study in mice performed by Cao et al., 2016 [150] provided evidence of the importance of the hair follicle dermal environment in growth and maintenance of hair follicles. Young and aged murine follicles transplanted into young host nude mice began to establish blood vessel connections in 2 weeks and promoted hair shaft growth by the 4th week, implying that the young host dermal environment could have rejuvenated the aged follicles through efficient angiogenesis and that ageing was potentially reversible. Conversely, there was no regrowth of hair shafts observed when both young and aged follicles were implanted into aged host nude mice. Further substantiating this concept is an earlier referenced study by Ge et al., 2020 [88], who demonstrated how aged murine HFSCs could be reinvigorated when transplanted into the neonatal dermis, but young HFSCs are not well supported by the aged dermis and failed to regenerate hair follicles.

There are apparent differences in the physiological characteristics amongst androgen-sensitive (vertex) scalp areas, androgen-insensitive (occipital) scalp areas, and non-balding scalps, which indicate underlying alterations of the scalp skin structure and barrier function upon hair loss. While TEWL showed no significant changes, the vertex scalp of AGA male subjects exhibited lower SC hydration level and skin surface lipid content, both of which positively correlated to the severity of hair loss [145,151]. Two treatment studies conducted by The Procter and Gamble Company (P&G) directly demonstrated that the scalp condition can influence hair growth and physical attributes of post-emergent hair fibres. Likewise, this impact to the hair cuticles was reversible upon restoration of scalp skin health [149,152]. Further supporting this notion, earlier published epidemiological studies comparing healthy individuals and patients with psoriasis, dandruff or seborrheic dermatitis, and atopic dermatitis showed that these patients exhibited premature hair loss, as well as thicker cuticular edges, increased roughness and surface pitting, and decreased shine of hairs from diseased scalps [94,153]. Interestingly, these observations of perturbed hair cuticles were suggested to resemble hair cuticles of the chronologically aged; thus, hair produced from unhealthy scalps can be referred to as ‘prematurely aged’ hair [125,153].

One of the first few studies providing an overview of the changes in male and female scalps across ages [154] documented how the female scalp dermal and hypodermal thicknesses evolved with age—achieving maximum thickness at 35 years, declining until 70 years, and then thickening again by 85 years of age. Contrastingly, the male scalp dermis reaches maximum thickness at 55 years and decreases until 80 years of age. In general, the scalp epidermal thicknesses appeared to differ with age, but only total scalp thicknesses displayed both gender- and age-related variations. While probing into the biophysical characteristics of healthy Caucasian women [155], it was reported that Caucasian women of an older age group (mean age: 62 ± 2 years) exhibited significantly lower values of TEWL and decreased scalp surface temperatures at the scalp vertex, while there were no notable changes in the sebum and SC hydration levels or SC thicknesses compared to a younger age group (mean age: 30 ± 3 years). Despite no significant differences in Caucasian female scalp SC thicknesses, the thickness of the scalp epidermal layer was found to significantly reduce with age. In comparison, a similar study conducted in a Korean population evaluated potential differences between two age groups—20s (mean age: 24 years) and 50s (mean age: 54 years)—in both females and males [156]. As expected, all participants in the 50s age group had significant decreases in hair densities when compared to the 20s age group. However, it was discovered that there were more changes in scalp biophysical parameters between the 20s and 50s age groups of women than the 20s and 50s age groups of men. For instance, women from the 50s age group had significantly lower sebum output levels, increased skin firmness, increased degrees of yellowness and redness, and reduced pH levels at the vertex and temporal scalp regions. Contrarily, men in the 50s age group showed only reduced TEWL at the scalp occipital and more pronounced yellowness than men from the 20s age group. One notable similarity that both genders shared was a significant decrease in microvasculature of blood vessels (not lymphatics) in the aged scalp skin [157]. In view of these studies, it can be deduced that there are diverse findings on the physiological changes in the aged scalp for both men and women. Whether due to gender or ethnic differences, or to the specific selection of scalp sites or age range, certain structural and physiological characteristics of the ageing scalp mentioned—such as decreased TEWL, lower sebum secretion, a thinning epidermal layer, and reduced blood microvasculature—resemble skin ageing at other anatomical sites [145,154,156,158,159]. These differing characteristics are depicted in the summary visual comparing healthy young and aged human skin (Figure 3).

A more recent histochemistry and immunohistochemistry study [160] examining scalp biopsies of Caucasian females aged between 19 and 81 years confirmed the reduction in epidermal thicknesses and particularly highlighted decreases in scalp skin rete ridges and sebaceous glands, and thus lower sebum secretion during ageing. Diminished rete ridges were similarly observed in the scalp skins of aged Korean men, although their epidermal thicknesses remained unchanged and dermal thicknesses decreased with age instead [161]. In greater detail, Williams et al., 2021 [160] revealed how the papillary reticular boundary of the younger female scalp skin (below 40 years of age) was more indistinguishable than the older female scalp skin (above 40 years of age), which displayed delineation of the papillary dermal architecture from the reticular dermis. This is in combination with significant changes in the expressions of ECM (extracellular matrix) proteins, including podoplanin (PCPN), versican (VCAN), and matrix metalloproteinase 1 (MMP1); papillary collagen organisation and deposition; as well as an elevated cartilage oligomeric matrix protein (COMP) level (a dermal sheath protein that facilitates fibrillar collagen assembly)—changes that were uniquely detected in the proteomic analysis of the aged dermal fibroblast culture secretome. These changes in the hair dermal environment and function appear to reflect the characteristics of solar elastosis, which imply that the female scalp dermis is equally susceptible to UV-induced photoaging [160].

Solar, or actinic, elastosis occurs when there is accumulation and disorganisation of abnormal elastotic fibres at the middle and upper dermal layers, which results in tissue stiffness and thickening [162,163]. In addition, upregulated MMP1, MMP2, and MMP3 levels in aged interfollicular dermal fibroblast and hair follicle dermal sheath cell cultures could also contribute to increased collagen degradation, as has been previously established in skin ageing [160,164,165]. There was also an overall higher prevalence of miniaturised hair follicles, resulting in markedly lesser hair follicles embedded within the dermal adipose tissues of aged scalp skins [160]. In human scalp skin, the bulbs of healthy, terminal anagen hair follicle typically penetrate the dermal white adipose tissue (dWAT) layer of the hypodermis [164]. These differences have also been included in Figure 3. It remains to be determined how the composition and volume of dWAT changes during scalp skin ageing, or how the scalp dWAT alters with human hair follicle cycling. But the significance of adipocytes in hair growth is gaining traction when treatments of autologous adipose-derived stromal vascular cells (ADSVCs) significantly improved alopecia areata symptoms by increasing hair densities and diameters in both men and women [166]. Additionally, another study demonstrated how dWAT could be modulating human hair growth and pigmentation through the hepatocyte growth factor (HGF)/c-Met signalling pathway [167]. Recalling the importance of HFSCs in hair growth, HFSC activity has also been associated with dWAT thickness, as well as regulated by mature adipocytes and immature adipocyte precursor cells in dWAT [81,168,169]. Also found within the dermis and hypodermis of the skin, the remodelling of vasculature and lymphatic capillary networks is in dynamic crosstalk with HFSCs and can affect one another during hair follicle regeneration [81,170,171,172].

The final notable feature is the increased areas of inflammatory infiltrate under the papillary dermis and around the sebaceous glands in aged Caucasian female scalp skin [160]. This indicates the presence of a low-grade inflammation in the ageing scalp skin, which has also been identified to be closely associated with skin ageing [173]. Frequently linked to increased levels of pro-inflammatory cytokines, proteolytic enzymes, and ROS, oxidative stress and free radical damage to DNA, proteins, and lipids within the interfollicular environment possibly elevate until antioxidant defences are exceeded, further driving the production of collagen-degrading MMPs [164,174]. Collectively, these documented changes present an aged hair phenotype. They accelerate collagen degradation and fibril fragmentation until it gives way to a physically modified interfollicular environment that hinders the active movement of the hair follicles throughout cycling and remodelling [160,164].

Similarities between dermal ageing and scalp ageing have spurred additional postulations that senescence may also be correlated with decreasing cell–cell interactions within scalp environment [164]. Single-cell transcriptomic analyses of young (28–37 years old) and aged (54–86 years old) healthy Caucasian inguinal iliac skin showed partial loss of dermal cell identities, reduced dermal fibroblast ‘priming’, and thus a corresponding decrease in predicted interactions between the dermal fibroblasts and other skin cell types [175]. Such loss of cellular identity during ageing has been previously described in mice [176]. With regard to the ageing scalp, a lack of interactions between the DS, DP, and undifferentiated bulb matrix keratinocytes can conceivably influence the growth and maintenance of the hair follicle. Furthermore, another murine study found that ageing weakened the commitment of the hair follicle epithelial bulge cells to the hair follicles and instead favoured the alternative differentiation into epidermal keratinocytes [83]. With additional hypothesised evacuation of the hair follicle DS cells as observed in alopecia patients [177], the continuous depletion of both follicular stem cell niche and DS population may jointly lead to age-related hair follicle miniaturisation. Taken all together, while much of the underlying structural, organisational and functional changes during scalp ageing still require complete elucidation. It is important to realise that the health and condition of the scalp skin can directly affect growth and homeostasis of hair follicles.

3.2. Scalp Skin Microbiome and Ageing

The human scalp is described as an anatomical area bordered anteriorly by the face, and laterally and posteriorly by the neck. It consists of soft tissue layers that envelope the cranium, extending from the supraorbital foramen margins to the occipital protuberance and superior nuchal lines [178]. The scalp skin is commonly characterised by high densities of hair follicles and sebaceous glands, which create a unique microenvironment of temperature, pH, moisture, and sebum content, providing a rich and conducive climate for microorganisms [94].

In general, the scalp skin is often described to exhibit a comparatively lower microbial diversity. The healthy scalp microbiome is mainly composed of particularly high abundances of Cutibacterium spp. (predominantly C. acnes), Staphylococcus spp. (majority being S. epidermidis), and Malessezia spp. (mostly made of M. restricta and M. globosa), alongside lesser abundant species such as Corynebacterium spp., Streptococcus spp., Acinetobacter spp., Prevotolla spp., as well as Ascomycota (Acremonium spp., Didymella bryoniae), Coniochaeta spp., Rhodotorula spp., and other Basidiomycota (like Cryptococcys liquefaciens and C. diffluens) [179,180,181,182]. These proportions vary across populations from different countries and genders. For example, a lower representation of the Cutibacterium spp. has been observed in scalp colonisation in males [183]. Typical scalp microbiome sampling methods include skin swabs, pore and tape strips, as well as cyanoacrylate gel biopsies [179,184]. These techniques have helped identify resident skin microbiome communities; however, they may fail to sample the deeper regions of the hair follicle epithelium and are unable to distinguish between hair follicular and skin microbiomes [179,184,185,186,187]. Alternatively, plucking hairs, as a means of sample collection, causes the detachment of the essential lower hair follicle mesenchyme from other components of the hair follicle epithelium and mesenchyme [188]. Studies examining the deeper, anaerobic regions of the scalp hair follicles are scarce. An early study by Matard et al., 2012 [189] captured the presence of bacterial biofilms, morphologically resembling C. acnes, below the infundibulum, by field emission scanning electron microscopy (FESEM) and confocal laser scanning microscopy (CLSM). More recently, another study coupling laser-capture microdissection (LCM) with 16S rRNA gene sequencing [184] additionally revealed variations in taxa abundances depending on the hair follicular compartments—namely, the infundibulum, isthmus, and the inferior sections (Figure 2). Interestingly, the isthmus and inferior segments were shown to share more similarities in identified genera than with the upper section of the hair follicle. The observed microbiome differences likely substantiate the follicular compartmental variations in terms of availability of nutrients, metabolites, antimicrobial peptide (AMP) production, and human hair follicle immunological characteristics, as previously reported, which in turn favour the growth of specific bacterial species [190,191]. With the hair follicle known to enjoy an immune-privileged status within the skin, there is growing evidence suggesting how microbial colonisation and dysbiosis at different follicular compartments, like the stem cell niche, can adversely affect hair follicle growth and cycling. Some examples of hair follicle-associated diseases that have been linked to specific anatomical areas of the hair follicle include acne vulgaris and hidradenitis suppurativa, which are mostly associated with the infundibulum, while alopecia areata is associated with the hair bulb region [192,193].

Compared to studies profiling the skin microbiota on the forehead, cheeks, forearms, axilla, inguinal creases, and feet, there are limited investigations on the human scalp, and even lesser reports on scalp skin commensals during ageing. Like various body sites, the scalp skin gradually experiences a reduction in sweat, sebum production, and immune function over time, leading to significant modifications in skin surface physiology like pH, SC hydration levels, decreased sebum content, and lipid composition [160,180,194,195,196]. These biophysical modifications may bring about changes in the skin ecology that influence growth of the resident skin microbiota. In a comparison between younger (21–37 years of age) and older (60–76 years of age) healthy Japanese women [181], the authors proposed that age-related modifications of the skin microbiome are skin-site dependent. Out of the four skin sites tested, the scalp exhibited the most significant difference in OTUs (Operational Taxonomic Units) or species numbers (α-diversity) between the younger and older cohorts, in contrast to the cheek, forehead, and forearm sites. Notably, while Cutibacterium still remained the most abundant genus on the scalp, previously minor species in the younger scalp, such as Acinetobacter, were significantly increased in the older scalp microbiomes. Their findings further identified normal oral cavity bacteria in the higher microbial diversity of the older female scalp microbiomes as well. This observation of a microbial signature in aged skin was intriguing given that the prevalence of oral cavity bacteria had also been reported in the skin microbiomes of atopic dermatitis patients, of which the mean age was 23.1 years [197]. Just as scalp microbiome diversity is correlated to decreased sebum secretion in aged skin [180], excessive sebum production at the scalp occipital region has been shown to be associated with the onset of sensitive scalp. Significant increases in free fatty acids, cholesterol esters, and squalene levels in the occipital regions of sensitive scalp subjects, compared to non-sensitive scalp subjects, have changed the scalp’s environment and pH, with a preference for Cutibacterium and supporting a lower microbial diversity [198]. However, it is not shown in this study which strains (pathogenic or non-pathogenic) of C. acnes were found to be elevated. Throughout the ageing process, ROS levels accumulate, and reduced presence of enzymatic and non-enzymatic protectors contributes to oxidative stress [199]. It is thus important to point out that the prevalence of Staphylococcus (particularly S. aureus) and Malassezia, which result in skin microbiome perturbation, has previously been reported as a source of oxidative stress [200,201,202]. Correspondingly, oxidative stress has in turn been shown to negatively impact the pre-emergent hair condition that causes pre-mature hair loss [94,203]. Striking the right balance between the skin microbiota and host environment (i.e., strain-specificity and context-dependence) is ultimately key, as in converse, there is new, promising data indicating that the commensal microbiome (also including S. aureus) is able to promote regeneration of hair follicles by stimulating keratinocyte HIF-1α (hypoxia-inducible factor 1-α) signalling and glutamine metabolism in the murine wound-induced hair follicle neogenesis (WIHN) model [204]. While the WIHN phenomenon is not evident in human skin, commensal microbes, such as S. aureus, are able to accelerate wound healing in mouse and human [204], which suggests an overlapping mechanism. Collectively, it appears that the ageing-related alteration of skin microbiota may be more correlated to changes in the skin’s biophysical parameters than ageing itself, as illustrated in Figure 3. In fact, these physiological changes in the skin are subject to both intrinsic and extrinsic ageing. Finally, it could be interesting to consider whether these distinctive microbial profiles could be used as an indicator to quantify the biological age, instead of the sole assessment based on an individual’s chronological age.

4. Hair and Scalp Care

Across ethnicities and societies, it is generally accepted that fading hair colour, hair volume loss, and changing hair texture, such as loss of hair lustre, increasing dryness, and brittleness, are common signs of ageing hair. In addition to the effect of intrinsic ageing, external factors like mechanical, UV, heat, and chemical stresses, to which we are inevitably exposed to over time, also inflict considerable damage on our hair strands [42]. Mechanical damage refers to the accumulative friction brought about by daily habits of combing, brushing, teasing, and styling. If ranked according to increasing severity, the next and most frequent type of damage would be excessive exposure to the sun and UVR, results in the ‘weathering’ effect of hair [205]. Hair strands at this stage appear less pigmented, stiffer, rougher in texture, and less shiny. An early study by Hoting et al., 1995 [206] demonstrated that it is less of visible light but more of UVA and UVB irradiation that is responsible for the photochemical impairment of hair. Both collectively cause degradation and loss of hair proteins and hair pigments. While UVB is confined to the cuticle layers of the hair shaft, UVA is able to penetrate past the cuticles and enter deep into the cortex. It is precisely UVB’s restricted depth of penetration that causes more destructive morphological damage to hair cuticles [207]. The most severe forms of damage are heat and chemical stresses, which include perming, straightening, Brazilian keratin treatments, dyeing, and bleaching of the hair. Permanent modification of hair bonds and colour requires the usage of chemicals and high heat, which tends to remove the protective hair cuticles, exposing the hair cortex and increasing the hair fibre’s susceptibility to breakage [42].

Correspondingly, also in progressive severity, mildly damaged hair is described as showing visible wear and tear, fraying in relatively intact hair cuticle scales—this largely results in only a loss of shine. Moderate damage is characterised as having cracks along the hair fibre, cuticle edges become uplifted and dislodged in some areas, and the loss of the essential 18-MEA lipid layer, leading to a dry, dull appearance and texture, a loss of elasticity and manageability, and an increased occurrence of frizzy and flyaway hairs [208]. Gradually, without protection from the cuticles and 18-MEA, the hair cortex is exposed and repeatedly subjected to further damage, becoming more porous and giving rise to fractured hairs and split ends. In the most severe cases, individuals experience hair breakage and hair loss [42,209].

Since our hair fibres are deemed as ‘dead’ and non-renewable upon production at the follicle, damage to our hair is irreversible and cumulative over time. Fortunately, there are readily available cosmetic solutions such as hair conditioners that temporarily confer ‘repairing’ or ‘restorative’ effects to damaged hair strands. Conditioners act primarily by neutralising the negative charges along the hair fibre with positive charges and providing lubrication to hair cuticles by increasing hydrophobicity. These anti-static and lubricating agents are broadly categorised into five main groups: polymers, oils, waxes, hydrolysed amino acids, and cationic molecules [209,210]. Out of all these materials, possibly the most frequently used are silicones. There exist different types of silicones with varying degrees of deposition, adherence, and washout capacity, which can be fine-tuned to achieve different conditioning performances [211]. For a natural option, botanical extracts and oils have long been used as an emollient to moisturise hair strands. Due to their natural composition consisting of myristic acid, stearic acid, linoleic acid, palmitic acid fatty acids, and antioxidants like tocopherol, Vitamin E, carotenoids, and cysteine, these extracts have also been associated with other anti-inflammatory, anti-bacterial, anti-fungal, and photoprotection properties as well [212,213]. Similarly, natural bee products containing mixtures of honey and royal jelly have demonstrated hair protective and repair effects towards hair fibres subjected to environmental stressors of extensive UVA exposure and particulate matter 10 (PM10) [214,215]. Regardless, an ideal hair conditioner restores fibre hydrophobicity, seals and protects hair cuticle scales, and mimics the natural 18-MEA lipid layer of the cuticles. Together, they help reduce friction and frizz, improve combability, and enhancing lustre, smoothness, and manageability of hair strands.

Another means to improve hair growth or prevent damage to hair shafts is to focus on the hair scalp. For decades, scalp care, for the most part, has been concerned with the treatment and reduction of hair dandruff. Spurred by COVID-19, lockdowns, and social restrictions in 2019, the ‘skinification’ of scalp and hair care increasingly gained popularity, with an influx of commercial products promoting the care of the scalp beyond basic needs [146,147,148]. Essentially, this concept of the skinification of hair revolves around providing our scalp with the same ingredients, nourishment, care, and attention as we give to facial skin. For example, there has been increasing integration of well-known skincare ingredients such as collagen, niacinamide, salicylic acid, hyaluronic acid, and copper peptides in new hair product launches, such as shampoos, in recent years [216]. It could involve addressing moisturising, hydration, sensitivity management, greasiness and oil control, exfoliating, and anti-ageing concerns, using familiar ingredients commonly incorporated into face serums, creams, and cosmetics. These, in addition to more commonly seen caffeine, adenosine, and biotin, can be formulated into hair products [217,218,219]. Although scientific evidence supporting these ingredients are varying and show limitations, further optimisation of dosage and delivery, as well as large-scale clinical validation is required. Alternatively, new and emerging stem cell-based and exosome therapies are still in the early stages of research and development and are still considered to be experimental solutions [217]. While the effect of probiotics on various skin conditions have yet to be thoroughly explored, several beneficial effects have been documented for topical probiotic treatment of several inflammatory skin diseases like acne, rosacea, psoriasis, atopic dermatitis, and dandruff/seborrheic dermatitis [220,221]. Particularly, a patent (EP2149368B1) describes the use of probiotic Lactobacillus paracasei for the management of dandruff by increasing the hydration of scalp skin and restoring the barrier function of the scalp [222]. It is proposed that the incorporation of probiotics and prebiotics in hair care products promotes the growth of beneficial bacteria and stimulates their production of specific metabolites and antimicrobial peptides, thereby restoring the balance of a healthy scalp skin microbiome community that enhances skin barrier function and modulates adverse immune responses [220,223]. To support this notion, clinical studies by Woo et al., 2022 [224], de Jesus et al., 2023 [225], Tsai et al., 2023 [226], and Mori-Ichioka et al., 2024 [227] showed that topical treatment with lysates of lactic acid bacteria or inactivated probiotic bacteria has led to improvements in greasy or dandruff-prone scalps, and increased hair growth.

Often, consumers look for natural, botanical extracts or phytochemicals as safe, effective alternatives to current hair medications and drugs [148,228,229]. Since single compounds derived from natural plant extracts have long been used in the development of dermatological treatments protecting against environmental stressors like ultraviolet rays and pollution, as well as the alleviation of skin inflammation and keloid scarring, it is conceivable how these extracts and compounds have been explored for their potential applications in hair health [230,231]. Previous studies have shown that well-selected, natural botanical extracts and compounds enhance cell proliferation, cell survival, and cell cycle progression, upregulate IGF-1, VEGF, HGF, and KGF (Keratinocyte Growth Factor, or FGF7) growth factors, and suppress cellular senescence and apoptosis, all of which contribute to the induction and lengthening of the anagen phase and the corresponding delayed entry into the telogen phase of the hair cycle. Furthermore, several of these natural extracts and phytochemicals have been found to be associated with the stimulation of diverse signalling pathways mediated by protein kinase B (PKB, or AKT), extracellular signal-regulated kinases (ERK), Wnt/β-catenin, sonic hedgehog (Shh), JNK (c-Jun-N-terminal kinase), and JAK (Janus-activated kinase)/STAT3 (Signal transducer and activator of transcription-3), as well as to downregulate TGFβ and BMP, and exhibit 5α-reductase inhibitory properties [230,231]. As mentioned above, these signalling pathways have been shown to be involved from the early stages of hair follicle induction and morphogenesis to the maintenance of homeostasis and hair regeneration processes [130,131,232,233]. For example, a natural bee product consisting of a combination of four honeys and royal jelly in a hair follicle–dermis–epidermis model potentially promoted the pigmentation of hair and hair growth by the upregulation of krüppel-like factor 4 (KLF4), which indicated a proliferation of hair bulb SC population [234]. Taken together, these options seek to improve scalp skin health, laying a solid foundation for the growth and production of lustrous and healthy tresses.

5. Concluding Remarks

Understanding hair growth and how the hair fibre is produced involves a multi-disciplinary approach: hair biology allows the elucidation of the hair follicle cycle regulation and cellular processes governing follicle growth; hair physics interrogates the mechanics and physical properties of the protruding, non-living hair shaft; and chemistry of hair investigates the structural assembly and chemical composition of the hair strand. However, the increasing number of studies on scalp health in recent years has expanded our understanding that achieving healthy hair and scalp requires a multifaceted overview, which involves not only the hair follicle but also its surrounding scalp skin environment and supporting skin microbiome. In these present times, it is no longer sufficient to consider individual aspects of hair science separately, but rather to embrace a holistic perspective, recognizing that all these factors can collectively influence age-related changes in the hair and scalp. Notably, various differentiations of the hair and scalp across gender and ethnicities that were addressed in the text should be contemplated as well. Equipped with more integrated knowledge, together with recent advances in omics platforms for the discovery of active ingredients, developing research on stem cell-based therapeutic solutions, and the optimisation of delivery systems of actives, they will all help drive future research in hair ageing. Ultimately, deeper and more well-rounded understanding can aid scientists to better match the performance of hair care formulations to the needs of their target consumers. Furthermore, continued investigation of these aspects will aid in the elucidation of hair ageing and pave the way for the identification of novel and more effective strategies to address the different aspects of ageing hair.