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Abstract
The skin aging which entails modifications in the entire skin and skin support system is caused as a result of complex blend of intrinsic and extrinsic factors. The main objective of this review is to provide critical insights into the effect of the aging determinants (intrinsic and extrinsic) on aging skin and to focus on a few classes of natural bioactives that were reported to counteract symptoms of cutaneous aging, pose potential, and beneficial health effect on aging skin supported with relevant scientific evidence. The narrative review of this cutaneous antiaging study incorporating the literature findings was retrieved from the search of computerized databases PubMed and Scopus, hand searches, and authoritative books. The antiaging skin care approach of using bioactives are basically nutritional hormetins, available from our natural heritage, identified as potent free radical scavengers, antioxidants, moisturizers, cell repairing agents, and ultraviolet protectives which have started to seek considerable attention among researchers and consumers due to the undesirable effect of chemical-based constituents on human health and environment. With the booming antiaging strategies, beauty has become the prime factor in considering one's health and overall “wellness”. As promoting healthy aging is essential, the objective of aesthetic dermatology should shift from cosmetic interventions to the betterment of quality of life of aging society. The paper also discusses on certain artificial learning/machine-based algorithms, useful in screening of bioactive ingredients, helpful in developing of more tailored formulations. This narrative overview on skin antiaging natural bioactives and artificial learning–based bioactive screening approaches contributes for the improvement in dermatological drug discovery, in the development of novel targeted lead compounds and accelerates aging research and pharmaceutical research.
Keywords: Bioactives, extrinsic aging, intrinsic, skin anti-aging, tailored formulations
Introduction 
The skin, an intricate, self-renewing organ,[1] performs its physiological function as a primary barrier against environmental insults and acts as a social interface between an individual and society, thereby making the dermatology field and cosmetic industry to concentrate more on the prevention of skin aging.[2] An aging skin is determined primarily by a person's underlying genetics (intrinsic disposition). However, the extrinsic factors (environmental) such as food habits, lifestyle, use of drugs, alcohol, smoking, etc., in turn, regulates how the preset frame of opportunity is exploited in course of individual trajectory.[3],[4] Other environmental stressors such as climate change, exposure to pollutants also influences skin aging, with intense degradative changes brought by chronic ultraviolet (UV) irradiation resulting in a photo-damaged skin (photoaging).[3]
As age increases, the skin quality descends due to the synergistic effects of chronological aging or intrinsic aging (inevitable phenomenon), photoaging (evitable phenomenon), hormonal deficiency, and environmental factors.[5] Both the aging determinants (intrinsic and extrinsic aging) possess their distinct and overlapping features.[6] Wrinkles, fragility, easy bruisability, elasticity loss, and mottled dyspigmentation imparts the characteristics of an aging skin. In particular, an intrinsically aged skin is identified with its cell loss, thinned epidermis, dermal-epidermal junction (DEJ) flattening, and an extrinsically photoaged skin shows coarse wrinkling, dry, rough, pigmented, and abraded skin.[7],[8]
As aging compromises certain protective functions of the skin, it is of key importance that this disease progression needs to be minimized by awareness of strategies which includes a healthy diet, avoidance of exposure to UV light, and avoidance of measures that cultivates a functionally responsive integument.[9]
In the cosmetic field, antiaging formulations are predominantly demarcated as agents that act by preventing and treating skin sags and wrinkles.[10] With a focus to improve the appearance of skin, these antiaging products use cosmetic actives which act as functional agents by retarding, ceasing, or even reversing environmental and age-mediated damage that result in skin wrinkling, discolouration, and forfeit suppleness.[11]
In addition, there are studies on natural actives or bioactives, which recognize them as promising candidates who meet certain key strategies in combating cutaneous aging such as protecting against dermal photodamage, scavenging free radicals, inhibit matrix metalloproteinase-mediated collagen, and elastin damage, etc.[12] These bioactives are natural compounds that inform the potential novel applications for cosmetic applications, serve by restoring or preventing the cellular and structural modifications of the skin cells that result during aging. With respect to consumption and topical applications, these naturally derived small molecules are generally considered reliable in case of safety, when compared with that of the synthetic molecules.[13] However, despite of their availability from nature, it is important to emphasize to patients that this does not indicate their zero adverse effects; in fact, many botanicals which offer alternative biologically active ingredients pose as potential cause of allergic dermatitis.[7] Contemporarily, there is a vast growth of dermaceutical and cosmetic industries with its main attention on packaging the actives into a desirable/novel delivery system.[11]
On topical application, many bio-functional actives claim skin antiaging effects such as free radical scavenging, UV protective, cell repairing, moisturizing effects, etc., or a combination of these effects. However, particular focus is on selective substances that are supported with relevant scientific evidence contributing to skin aging prevention. This present review put forward extensively on aging skin layers, the clinical manifestations in an aging skin encountered due to intrinsic and extrinsic factors. The study also highlights the use of bio-functional ingredients used in impeding skin aging and assembles the substantial contributions of recent emerging artificial intelligence (AI)–based approaches employed in anti-aging research.
Methods The literature findings for this skin antiaging study were retrieved from the search of computerized databases PubMed and Scopus from the year 2004 to 2022, using the key search terms 'skin aging, epidermal aging, artificial intelligence for aging research, and bioactives used in dermatology'. In addition to the electronic databases, the results of this narrative overview were collected from authoritative texts and hand searches. For drawing the chemical structures of the active constituents, the ACD/Labs 2021.2.1 (File version C35E41) Software was used in the present study.
Selection criteria–employed for writing the overview
The inclusion criteria employed for including the articles in this study were based mainly on the articles that explained briefly about the intrinsic aging and photoaging of the epidermal and dermal layers of the skin and the papers that updated on the natural bioactives used to impede skin aging. Whereas the articles of early research (old data) and those articles for which full text were unavailable or were not in English were excluded from the selection criteria.
Discussion Epidermis
Viewing the skin as a complex biological system, it is prerequisite for the emergence and advance of research that necessitate the study on skin layers or cell types to have more complete and comprehensive therapies.[14]
The epidermis, a rapidly proliferating and self-renewing tissue,[15] acts as a decisive component for maintaining body homeostasis. Despite of acting as a mechanical barrier, the epidermis is a metabolically active tissue in constant dynamic balance, ensures its cell components the required flexibility, and capability of response to different stimuli. As a complex system, the epidermis is assembled by multiple superposed cell layers that form an effective protection barrier,[14] which upon distinguishing histologically shows the following layers: the stratum basale, the stratum spinosum, the stratum lucidum (in palms and soles), the stratum granulosum, the stratum corneum, and stratum disjunctum.[16]
Also, the epidermis is composed of several cell types such as Keratinocytes (constituting 80%-95% of epidermal cells), Melanocytes, Langerhans cells, and Merkel cells,[14] required for the structural and functional integrity of the epidermis.[17] These epidermal cells have the ability to divide only a finite number of times, before they attain permanent cell division arrest lasting until their death. This phenomenon is termed as replicative senescence,[15] a process which entails an irreversible growth arrest and has an unselected evolutionary consequence of contributing to aging.[18] In the epidermis, the proliferation in transit-amplifying cells and their progeny are restricted due to telomere shortening, a process which occurs during every normal DNA replication by the so-called end replication problem and telomere end processing. However, it is observed frequently that several strategies such as cancer, epidermal carcinomas, and melanoma allow circumventing of this mechanism.[15]
The major characteristics of aging cells are replicative senescence, reduced keratinocyte proliferation, and clonogenesis.[19] Moreover upon aging, the basal keratinocytes show increasing atypia, whereas in case of a photodamaged aged skin, the expression of some β 1- integrins are downregulated by these basal keratinocytes, thereby indicating an abnormal proliferation and adhesion of keratinocytes.[6]
Epidermal aging
On considering age-related changes, it is counter-intuitive to suggest that dermal aging is more marked than epidermal aging, but nevertheless is the case, as the epidermis do demonstrate some important age-related changes.[20]
An aged skin exhibits downregulation of many molecular pathways associated with stratum corneum (SC) lipid metabolism with the cholesterol being affected the most. Also, there are certain molecular mechanisms differentiated from the epidermis such as the profilaggrin-derived Natural Moisturizing Factors[14] which help to retain sufficient amount of water in the SC.[21] This epidermal function of maintaining the balance of water and ions in the body is highly influenced by aging. It is noted that with age, there is fall in the lipid synthesis with a reduction in the secretion of lamellar bodies in SC giving rise to an extra cellular matrix (ECM) which is more porous and less capable in preserving the water-ion balance in the organism.[14]
On considering the barrier function, an aged skin (>80 years) is found to be more readily disrupted by the sequential tape striping, on compared to a young skin (20-30 years) with overall reduction in the SC lipids which influences the “mortar” that binds the corneocytes together. Whereas a moderately aged skin (50-80 years) shows abnormal stratum corneum integrity, ion transport, turnover, exhibits delayed lipid processing, and delayed permeability barrier recovery due to abnormal acidification of SC.[6] In addition to the altered function of the “mortar” of the skin barrier, the “bricks” are also affected by aging as well. Also an age-related downregulation is observed in genes associated with keratinocyte differentiation, including keratins and cornified components of the envelope.[22] An aged epidermis with reduced barrier integrity contributes to a skin exhibiting increased susceptibility to environmental insults as well as reduced capacity to recover from these environmental stimuli.[23]
As the epidermal primary functions may falter gradually over years, the molecular, cell-related, and morphological changes observed in an aged epidermis compromises its protective role. In addition, also contributes to skin symptoms such as excessive dryness, pruritus, increased predisposition to formation or deepening wrinkles, dyspigmentation, fragility, difficulty to heal injuries, reduced ability to sense and respond to mechanical stimuli, altered permeability of the skin to drugs, appearance of skin irritation, and tumor incidence.[14][Table 1] compares the characteristic traits of an epidermal layer, observed during intrinsic and photoaging.
Table 1: Comparison of the characteristic traits of intrinsic and photoaging of the epidermal layer[24]Dermal-epidermal junction aging
The most consistent change observed in an aged skin is the retraction of the rete ridges which results in DEJ flattening and this interdigitation reduction between the epidermis and dermis results in reduced resistance to shearing forces, reduced oxygen and nutrient supply,[6] and age-associated increased fragility of the skin.[20]
Dermis
The dermis, found beneath the epidermis, is connected to it by the DEJ and formed by the dermal connective tissue.[2] It is a mucopolysaccharide matrix consisting predominantly of ECM proteins such as collagen (COL) and elastin fibers accompanied with a variety of cells such as the mast cells, fibroblasts, macrophages, and Langerhans cells responsible for the immune responses observed in certain skin pathologies.[17] These mesenchymal differentiated dermal fibroblasts cells are responsible for the synthesis and degradation of the fibrous and amorphous ECM proteins. It is observed that the functions and interactions of these dermal resident cells are very crucial for dermal aging,[25] any dysfunction of these dermal fibroblasts exhibits a significant impact on the skin connective tissue properties.[26]
The COL fibers accounting 75% of dry skin mass is the most abundant component of the ECM, responsible for tensile strength and elasticity.[25] Considering the elastic fibers, accounting less than 1%-2% of dermal weight is found composed of elastin and fibrillin, which contributes mainly in resisting deformational forces and in providing elasticity.[2] The other miscellaneous ECM components, accounting for 0.2% of dry weight of the dermis such as the proteoglycans and glycosaminoglycans (GAG), have the capacity to absorb water 1,000 times their volume, thereby performing their role in regulation of water.[25]
Dermal aging
With increasing age, there is reduced collagen synthesis and unregulated degradation by the proteases, resulting changes in the ECM.[27] This cutback in COL production and rise in COL fibril fragmentation results in a deficit of net COL,[19] thus resulting in clinical changes such as wrinkling of skin and elasticity loss.[25]
Certain proteases such as the matrix metalloproteinases (MMP) 1, 8, 13, and 14 play a crucial role in aging by initiating the COL fibril fragmentation, of which the MMP-1 plays a key factor. It is observed that aging increases MMP-1 constitutively, whereas the same is increased transiently on UV exposure or on wounding.[28] Studies have reported that in an early phase of long-term UV exposure (<1 minimal erythemal dose), a marked reduction of skin elasticity is observed, accompanied with elastic fiber network degeneration. The studies also reported on the damage of elastic fiber network as a result of deep involvement of elastases,[29] a member of chymotrypsin family of proteases accountable for elastin breakdown.[30] Also, it is speculated that this fibroblasts elastase plays a significant role in contributing to wrinkle formation through the degradation of elastic fibers.[29]
On the other hand, in skin homeostasis and in functional and architectural properties of the cutaneous tissue, a central role is played by the proteoglycans, the ubiquitous macromolecules of certain intracellular granules, cell surface, and ECM, thereby contributing to tissue hydration, resistance, and resilience.[31] The Hyaluronan (HA, Hyaluronic acid), a nonsulfated GAG, found predominantly in skin,[32] has the capacity to bind water pertaining to skin moisturization. As any modification of the oligosaccharide unit of the GAG enables a loss in the water binding capacity of the compounds, an aged skin shows a deduction in the hyaluronan levels and in polymer size resulting in loss of skin moisture.[19][Table 2] compares the characteristic traits of the dermal layer, observed during intrinsic and photoaging.
Table 2: Comparison of the characteristic traits of intrinsic and photoaging of the dermal componentsAdipose tissue and its aging
The adipose tissue, being the largest energy reservoir and endocrine organ, is associated with the maintenance of energy balance, glucolipid homeostasis, and immune dysfunction, experiences considerable changes during various facets of aging. Age-related changes in adipose tissue involve whitening of brown adipose tissue, redistribution of white adipose tissue and ectopic deposition, and modifying several biological and physiological processes which in turn influences the overall wellbeing of the organism.[34],[35]
Considering the adipose tissue aging interventions, the investigation of its aging within several cell types is possible with the evolution of single cell technologies and unveiling the detailed mechanism underlying this fat aging requires intense research further.[34]
Skin protection with bio-active based cosmeceuticals
In the modern society, there is a search for new therapeutic options and an alternative for skin protection is offered by the natural bio-functional ingredients. The present study focused on few classes of bioactives of natural origin that are supported with clinical data and are reported to have antioxidant, photoprotective, hydrating properties, and improve skin elasticity and appearance of wrinkles [Table 3]. The chemical structures of the active constituents have been drawn using the ACD/Chemsketch Software [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14], [Figure 15], [Figure 16], [Figure 17], [Figure 18], [Figure 19], [Figure 20].
Table 3: List of natural bio-actives with skin antiaging properties supported with level of studiesTogether, based on the comprehensive approaches of exploitation and research of plants and other natural resources, potential lead compounds with skin antiaging activity may be developed but more robust levels of scientific evidence are required.
Emergence of artificial intelligence in aging research: A future outlook
The advancement of modern AI has substantial contributions in the field of healthcare, aging research, pharmaceutical industries such as identification of aging biomarkers, optimization of chemical synthesis, drug pharmacological property evaluation, drug-induced hepatotoxicity analysis, etc., Among several AI-driven companies, “Bioage” is one which used machine learning algorithms and genomic data for the purpose of aging biomarker development and for invention of antiaging drugs. With the aim of finding novel antiaging solutions using advances in genomics, AI and big data analysis, “Insilico Medicine” another end-to-end, AI-driven pharma-technology company, employs Deep Learning–based algorithms and deploys an integrated AI pipeline for its antiaging research. The emergence of AI-based algorithms offers tremendous oppurtunities in the development of aging biomarkers and in exploration of antiaging drugs.[36]
Artificial intelligence/machine learning–based approaches for bioactive screening
To secure product safety, the AI/ML-based tool “Skin Bug” is used to anticipate the reaction between active molecules and skin microbes and to ascertain if it can be biotransformed or metabolized to other products. Concerning the health benefits, the genomic technology and AI jointly is employed by an Irish biotech company “Nutritas” for the purpose of identification and extraction of distinctive biopeptides/bioactive peptides. With the objective to recommend the appropriate cosmetic product for specific skin and health requirements, the AI-powered skin analysis employs face mapping technology to detect the aging signs, pigmentation, skin tone, elasticity, skin quality, moisture content, etc., Similarly, another AI-driven start up “Atolla” has advanced in skin-specific customized serums with the help of AI and states its constituents to be vegan, cruelty-free, devoid of fragrance, nonallergenic, and responsibly farmed. These AI-based tools, besides being employed for bioactive ingredient selection, are also used for formulation selection and helps in providing customized cosmetic formulations as per skin concerns and goals.[37]
Limitations to the overview
Addressing the weaker points inherent to this study includes the need to retrieve more articles from the databases, in addition to those used for creation of this overview.
Conclusion An implacable systemic process of human life is skin aging. As promoting healthy aging is essential, it is important to protect the skin from external influences. Regardless the availability of several treatments for cutaneous aging, the best way to impede skin aging is to avoid the factors engendered by extrinsic determinant and supplementing the skin with vital antiaging natural bio-based ingredients that pose potential and beneficial health effects. Concerning the toxicity of the chemical-based ingredients on human health and their impact on the environment, it is important to replace the harmful, synthetic cosmetics with hypoallergenic natural bio-based cosmetic ingredients. To drive the skin antiaging effects a step higher, each ingredient contained in the formulation should be scientifically assessed and developed according to the customers' therapeutic benefits. With the use of recent advanced technologies and suitable drug delivery approaches, it is possible to produce tailored medicine, as per specific skin concerns and goals.
Acknowledgments
I wish to express my sincere gratitude to my guide Professor Dr. V. Gopal, who supported me and offered deep insights into the study. Also, I would like to thank Mr. Srinivasan. S, associate scientist at Pfizer, for the assistance provided in using the software for drawing chemical structures that were used in the study.
Financial support and sponsorship
Nil
Conflicts of interest
There are no conflicts of interest.
References 
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