1 INTRODUCTION

The present state of skincare addresses the consequences of photodamage, hormonal influences, and the cumulative impact of exposome exposure throughout a person's life. Treatments within the aesthetic domain either harness biological pathways to achieve rejuvenation, such as retinoids and antioxidants, or suppress them, like lightening ingredients. Emerging advancements encompass techniques that stimulate the differentiation of stem cells to generate younger keratinocytes and fibroblasts, activate macrophages to diminish proinflammatory cellular waste, and restore glycosaminoglycans within the dermal matrix. While these innovations have significantly enhanced the potential of skincare to revitalize the skin in recent years, obstacles to their adoption remain substantial, including complex multistep regimens, the elevated cost of novel technologies, and limited accessibility for a majority of consumers.

The next phase of skincare innovation targets the root cause of aging, at the genetic and epigenetic level. By reversing the effect of the exposome at this level, it is conceivable that biological age and chronological age might no longer correlate. Additionally, the integration of artificial intelligence (AI), the identification of biomarkers, and improved accessibility to genetic predisposition lab testing will combine to allow for greater personalization of skincare recommendations.

2 SKIN EXPOSOME

The exposome encompasses all environmental exposures encountered throughout one's lifetime.¹ A growing body of research has been delving into the impact of the exposome on human skin, shedding light on how environmental factors trigger and alter various skin conditions, notably the process of skin aging. Both extrinsic and intrinsic factors are known to contribute to this cumulative effect including solar radiation, air pollution, tobacco smoke, nutrition, and stress, among other factors.¹

A recent consensus paper attempted to define the skin exposome and the currently available data concerning its influence on skin aging.² Ultraviolet (UV) radiation, smoking, and pollution are the three main factors proven to induce skin aging with significant data to substantiate these findings. Recent discoveries have expanded the scope of skin impact beyond UV radiation to encompass visible light and infrared exposure, which can provoke dermal matrix degradation, alter stratum corneum lipid composition, and modulate skin pigmentation.^2-4 The detrimental effects of smoking on skin aging have also been further explained, with research indicating that it increases extracellular matrix degradation by triggering the aryl hydrocarbon receptor (AhR) signaling pathways and subsequently induces matrix metalloproteinase-1 expression.⁵ Particulate matter, nitrogen dioxide, and ground-level ozone have been linked to the formation of pigment spots and wrinkles, and initial evidence suggests that some of these effects may be mediated through AhR signaling within human skin.^{2, 6}

Importantly, gaps in research pertaining to exposome factors and their influence on skin aging exist, particularly in the context of understanding how these factors interact with each other.² Most studies evaluating UV radiation, pollutants, smoking, among other factors, have been performed on a single factor at a time, not concurrently. Thus, the interactions between them and the resulting biological consequence remain poorly understood. Future research should be directed toward attaining a better grasp of the intricate interplay among distinct exposome elements and their collective impact on skin aging. Moreover, while the exposome definition excludes genetic factors, the interplay between genes and the environment constitutes an important part of the skin aging exposome.² A thorough understanding of the dynamics between genetic and environmental interactions will enable the identification of susceptible subgroups and provide the scientific groundwork for the development of tailored cosmetic solutions to combat skin aging.

3 CELLULAR SENESCENCE

Cellular senescence refers to the process by which a cell stops dividing and undergoes irreversible cell cycle arrest.⁷ Senescence can be triggered by a variety of factors, including oxidative stress, DNA damage, telomere shortening, and oncogene activation.⁸ While senescence can be a beneficial process in normal development and may have a tumor-suppressive role by limiting the proliferation of irreparably damaged cells, senescent cells likewise can have harmful effects on surrounding tissue hemostasis and can contribute to overall aging.⁹ Senescent cells are characterized by morphological and functional changes, altered metabolism, and importantly the secretion of proinflammatory molecules known as a senescence-associated secretory phenotype (SASP). It is this proinflammatory “secretome” that can precipitate the spreading of senescent features to nearby cells, which can further accelerate aging.

The subject of cellular senescence in the context of skin aging has garnered growing interest, with mounting evidence suggesting that fibroblast senescence plays a pivotal role in the deterioration and aging of the skin.¹⁰ Senescent fibroblasts in skin have demonstrated suppressed deposition of components of the extracellular matrix, as well as enhanced release of various factors that change the microenvironment of surrounding cells. These include various cytokines such as interleukin-1 (IL-1), IL-6, IL-8, IL-18, matrix metalloproteinases, numerous chemokines, lipids, and micro-RNA that modulate neighboring cells.^10-13 These factors increase inflammation in surrounding tissues and can prompt neighboring cells to enter a senescent state, consequently fostering the aging process of the skin.

Because of the role senescent cells play in age-related tissue decline, targeting and clearing senescent cells portends a promising approach in reducing age-related skin damage. Clearing senescent cells can reduce inflammation and enhance the function of stem cells.¹⁴ Several approaches have been recognized for targeting senescent cells, referred to as senotherapeutics, encompassing senolytics and senomorphics. Senolytics are agents that selectively induce the death of senescent cells, while senomorphics, also known as senostatics, inhibit the production or release of SASP factors.

Various senotherapeutic agents have been evaluated in the context of systemic disease and skin aging. The combination of two senolytic agents such as dasatinib and quercetin has entered clinical trials for treatment of conditions such as pulmonary fibrosis and kidney disease.^{15, 16} The search for senotherapeutic agents targeting skin aging is underway as well. In one study, a plant extract from Solidago virgaurea displayed senolytic activity and substantial suppression of the SASP, along with some rejuvenating effects on human skin equivalents.¹⁷ Topical rapamycin was shown in vivo to reduce fine wrinkles and sagging and increase dermal volume.¹⁸ A number of flavonoids have also been proposed as senotherapeutic agents.¹⁹ Further research is likely to show promise of senotherapeutics in the future of antiaging skincare.

4 DNA AND EPIGENETIC REPAIR

Biological aging and senescence are closely linked to the underlying changes that occur in the genome. DNA damage can be caused by a myriad of factors. Damage occurs due to both endogenous threats, such as DNA replication errors, spontaneous hydrolytic reactions, and reactive oxygen species, as well as exogenous threats, such as environmental toxins and radiation.²⁰ As mutations accumulate, disruptions in cellular function occur, cells have an increased risk of further mutations, and ultimately cells face either apoptosis or senescence. Cells have evolved numerous mechanisms to repair DNA damage, and research is helping to elucidate these complex pathways, including nucleotide excision repair, base excision repair, mismatch repair, Fanconi anemia pathway, DNA double-stranded break repair pathways, nonhomologous end-joining, and homology-directed repair.^{21, 22} Defects in DNA repair pathways have long been known to be culprits in a number of systemic and cutaneous pathologies. Recent research evaluating DNA repair mechanisms in fibroblasts found delayed kinetics of DNA double-stranded breaks processing in both normal and pathological aging, which may suggest that decreasing efficiency in repair processes may contribute to genome instability with aging.²³ However, another study evaluating DNA repair kinetics in fibroblasts concluded that residual DNA damage level with aging cells is unlikely to be a result of less efficient DNA repair.²⁴ Further research is needed to understand how DNA repair mechanisms are altered with age and the role these play in aging skin.

The epigenome is also subject to change over time with aging cells. In normal conditions, the epigenome incurs chemical modifications, such as DNA methylation, histone modifications, chromatin remodeling, and noncoding RNA, which influence how genes are turned on or off without changing the underlying DNA sequence.²⁵ Epigenome aging involves changes in these epigenetic marks over time, and several specific histone acetylation and methylation patterns have been identified as age-associated epigenetic markers.^{26, 27} Epigenetic stressors have been studied as inducers of senescence as well. For example, a key target of epigenetic stress that promotes senescence may be the INK4a/ARF locus, which is repressed in proliferating cells.²⁸ Epigenomic aging can affect gene expression patterns and contribute to the aging process by influencing cellular function and response to environmental factors.

The role of epigenetics in skin aging is an avid new area of research. Modifications in DNA methylation patterns, histone variants, and RNA-mediated silencing are all epigenetic changes that have been identified in aging skin.²⁹ Patterned changes in DNA methylation have been linked to cellular senescence in fibroblasts.³⁰ MicroRNA-217 has been found to promote fibroblast senescence by suppressing DNA methyltransferase-1-mediated methylation of p16 and pRb.³¹ Specific histone variants, which appear during senescence, have also been identified, including H2A.J and H3K27me3, and play a role in skin aging.²⁹ Changes in histone acetylation, with subsequent downregulation of genes such as SIRT1, which are critical in skin homeostasis, are also implicated in keratinocyte and fibroblast aging.²⁹

Some areas of the chromosome are particularly susceptible to age-related deterioration, specifically telomeres, which in most somatic cells cannot be replaced in the event of damage due to the absence of telomerase. With continued DNA damage in these regions, there is progressive loss of telomere-protective sequences, and telomere exhaustion eventually leads to senescence and/or apoptosis.²⁵ Experimental studies in mice have shown that aging can be reversed by telomerase activation, where systemic viral transduction of telomerase delayed normal physiological aging without increasing the incidence of cancer.³² The latest research on telomeres has shown that dysfunctional telomeres without detectable telomere shortening are a marker of senescence, and interestingly, that senescent melanocyte SASP induces telomere dysfunction in a paracrine manner.³³

Utilizing the growing knowledge of genome repair mechanisms, the therapeutic potential of genome editing has become an avid new area of research. Potential treatment modalities in the form of precise genome editing technologies with designer nucleases, such as the Clustered Regularly Interspaced Palindromic Repeat (CRISPR-Cas) systems, are being studied in the setting of treating various human genetic and other systemic disorders.²¹ Given the impact DNA damage and cellular senescence have on skin aging, genome editing agents targeting related underlying genetic changes could portend a future treatment avenue for skin in the future. Pilot studies in mice have been performed utilizing CRISPR-Cas9 systems for the treatment of a variety of skin conditions including genodermatoses, melanoma, cutaneous bacterial and viral infections, androgenetic alopecia, and inflammatory skin disorders, among others, but further research is needed to determine to the efficacy, safety, and long-term effects of genome editing therapies for skin conditions and skin aging in particular.^34-37

The recent discovery of Yamanaka factors portends further potential therapeutic avenues in the world of cellular senescence and skin care. Yamanaka factors are a cohort of four transcription factors integral to making pluripotent stem cells: octamer-binding protein 3/4, Sox2, Krüppel-like factor 4 (KLF4), and c-Myc.^{38, 39} By combining these four factors, Takahashi and Yamanaka were able to generate pluripotent stem cells, termed induced pluripotent cells, from fibroblast somatic cells. Discovery of these factors has opened the door for cellular reprogramming. Clinical trials utilizing these technologies in various forms are underway for numerous medical conditions such as macular degeneration, spinal cord injury, and type 1 diabetes.⁴⁰ Studies evaluating Yamanaka factors in the skin are already underway. For instance, KLF4 was found to be a regulator of keratinocyte precursor fate, whereby KLF4 downregulation in human-embryonic stem-cell-derived keratinocytes increased the efficiency of skin-orientated differentiation and was associated with improved generation of the epidermis.⁴¹

From a similar angle, exosomes derived from human induced pluripotent cells (iPSC-Exo) were found to stimulate the proliferation and migration of fibroblasts and may signify a related treatment avenue.⁴² The iPSC-Exo reduced the expression of senescent markers such as senescence-associated β-galactosidase (SA-β-Gal) and matrix metalloproteinase-1/3 and restored the collagen type I expression in senescent human dermal fibroblasts. These findings add to a growing body of data that targeted growth factors, such as Yamanaka factors and exosomes derived from pluripotent cells, may hold therapeutic potential for somatic rejuvenation and the treatment of aging skin.

5 BIOMARKERS OF SKIN AGING

Investigators have aimed to identify biomarkers of senescence to help not only quantify senescent cells but also to elucidate this process. To date, no universal biomarker of senescent cells has been identified, but novel research has provided multiple leads. As previously discussed, senescent cells have altered metabolism, and a key metabolic change that occurs is the activation of SA-β-Gal, a lysosomal enzyme that catalyzes the breakdown of β-galactosidase to monosaccharides. The ease of detection of SA-β-Gal has made it the most widely used biomarker for detection of senescent cells.⁴³ However, it has many limitations, the primary being that it can be detected in skin appendages such as hair follicles and sebaceous glands in both young and old skin.⁴⁴

The heterochromatin in the nuclei of senescent cells undergoes punctate changes known as senescence-associated heterochromatin foci (SAHF), which contribute to the exit of these cells from the cell cycle.⁴⁵ Proteins such as p16 and high-mobility group A have both been shown to accelerate the formation of SAHF and could be potential targets for future antiaging therapies.⁴⁶ Nuclear lamin B1, an intermediate filament protein that helps maintain the shape and size of the nucleus, is also heavily involved in genomic stability.⁴⁶ It is decreased in cells undergoing replicative senescence, oncogene-induced senescence, UV-induced senescence in vitro, and during chronological aging in human skin in vivo, and is also a viable biomarker for senescence cells.⁴⁴

Lastly, tracking some of the factors known to be components of SASP may aid us in identifying senescent cells.⁴⁶ However, research so far has primarily focused on identifying them in fibroblasts in vitro, and it is not known if the concoction of SASPs varies by cell type. With the skin being a multicompartment organ with appendages, this may be a great limitation of studying SASPs as potential biomarkers for senescence.

6 AI AND DIGITAL THERAPEUTICS TO ENHANCE OUTCOMES

AI refers to a computer mimicking intellectual processes that are characteristic of humans.⁴⁷ In skincare, the assessment of different skin-aging metrics such as fine lines, dyschromia, erythema, pore size, among others, is already widely available in digital applications and allows for greater assessment of treatment outcomes. More frequent remote screenings and monitoring will not only allow patients to track and see live results of their progress but will also decrease costs and barriers to accessing healthcare. AI can also be used to help create data sets specific to each demographic and age group, allowing clinicians to more accurately predict outcomes and help set realistic goals for patients.⁴⁸ In doing so, patients will have a greater understanding of the expected results and be motivated to adhere to their treatment plan. By deploying this at the population level, via wide adoption and use of these cell phone apps, there is enormous potential for outcome assessment of skincare products that far surpasses the relatively smaller clinical trials currently being performed.

Digital therapeutics (DTx) are evidence-based behavioral treatments delivered online. They offer another option to improve outcomes by changing or reinforcing behavior using digital tools.⁴⁹ In the last few decades, DTx have been extensively used for diabetes prevention, and results demonstrate consistently favorable outcomes, such as long-term reduction in body weight and hemoglobin A1c.⁵⁰ DTx have also been used to track medication adherence and subsequent outcomes. One study assessed patients' adherence to oral hepatitis C treatment and their virological outcomes, with results demonstrating that those with poorer adherence had worse outcomes and that DTx can serve as a useful tool to optimize adherence and thus overall outcomes.⁵¹ In skin care, DTx has the potential for improving outcomes by promoting better adherence to a topical regimen.

7 CONCLUSION

The future of skincare looks beyond the effects of DNA and epigenetic damage, and damage done by senescent cells, to reverse and prevent genetic damage and senescence in the first place. The next phase of skincare's evolution centers on tackling the root causes of aging at the genetic and epigenetic levels. By reversing exposome-related effects and utilizing AI and biomarker discoveries, personalized skincare recommendations hold promise in decoupling biological age from chronological age. Moreover, emerging fields such as cellular senescence, genome repair, and the application of Yamanaka factors offer exciting avenues for therapeutic interventions in skin aging. The pursuit of biomarkers and the integration of AI and digital therapeutics may further enhance the precision and efficacy of skincare strategies, ultimately paving the way for a more comprehensive and personalized approach to combating the effects of aging on the skin. As research in these domains continues to expand, a new era of skincare is on the horizon, one that aims not just to address the visible signs of aging, but to target the underlying molecular and genetic mechanisms that contribute to skin vitality and longevity.

CONFLICT OF INTEREST STATEMENT

Dr Lain serves as a consultant, advisor, speaker, and/or investigator for L'Oreal, Kenvue, Beiersdorf, Galderma, and Pierre Fabre.