Phytochemical Interventions in Skin Aging: Experimental and Translational Evidence from Laboratory and Human Studies

1. Introduction

Ageing is a natural process that causes folds, ridges, and creases in the skin because of body mass loss, insufficient hydration, and dermal and epidermal junction degradation (Chaudhary et al., 2020). The skin's ageing process encompasses various changes that occur owing to the combination of both endogenous causes (gene mutation, cellular metabolism, & hormone factors) and exogenous factors (UV, pollutants, chemicals, & toxins) (Parrado et al., 2019). These stresses, along with internal variables, cause cutaneous ageing. Skin ageing is characterized by chronic inflammation mediated by inflammatory cytokines (IL-6, IL-8, IL-10, IL-1β, & TNF-α) and elevated levels of elastases and collagenase enzyme activity (Chaudhary et al., 2020). Pro-inflammatory cytokines like IL-6 & TNF-α stimulate MMPs and reduce collagen synthesis, weakening dermal structure and causing wrinkle formation (Zouboulis et al., 2019). UV radiation also plays an important role in skin ageing. High exposure to UV radiation triggers a 5-fold increase in matrix metalloproteinases (MMPs) levels, and overexpression of MMPs coincides with a decline in procollagen type-I expression and tissue inhibitor of MMPs (TIMPs), exacerbating dermal fibrosis that leads to skin ageing (Payne et al., 2025).

The degeneration of skin physiology and morphology is the earliest and most visible sign of the ageing process, which becomes more pronounced as one gets older. Such degeneration affects vital skin functions, including hemodynamic regulation of body temperature and maintenance of fluid and electrolyte balance. It also impairs vitamin D synthesis, immune surveillance, waste removal, and sensory perception (Ahmed et al., 2020). Other signs include dry skin, wrinkles, loss of elasticity, drooping, as well as aberrant pigmentation (Chin et al., 2023; Zouboulis et al., 2019).

Age-dependent dermal remodeling is mostly caused by the failure of long-term resident fibroblast populations. Older fibroblasts lose their capacity to form the ECM, reducing the formation of elastin and collagen (Rochette et al., 2020). Over time, ageing skin begins to lose collagen and elastin fibers, which are the fundamental components that keep the skin bright, healthy, and elastic. Skin volume decreases as glycosaminoglycan levels fall, including hyaluronic acid, which works as a natural moisturizer by absorbing water. Senescent cells have reduced proliferative capacity, resist apoptosis, and secrete inflammatory molecules that promote tissue damage (Bay and Topal, 2023). In clinical skin ageing, skin thins and dries up, causing wrinkles, drooping eyelids, loss of elasticity, and pigmentation changes. It also becomes discolored, dull, and coarse, and causes atrophy. The most noticeable signs and symptoms of clinical ageing consist of temporal hollowing, ptosis, nasojugal grooves, decrease in malar fat pads, nasolabial grooves, and cheek depression. Dyschromia, linked with hyperpigmentation due to exposure to ultraviolet radiation and hypopigmentation owing to melanocyte loss, plays a significant part in the impression of old age (Bay and Topal, 2023). This review provided a contemporary and integrated overview of bioactive plant constituents with demonstrated emerging anti-aging potential, critically appraises their mechanisms of action, and identifies key research gaps. By combining insights from pharmacognosy, dermatology, and formulation science, this review offered a forward-looking perspective that can guide researchers, clinicians, and the cosmeceutical industry toward the development of safer and more effective natural anti-aging products.

2. Methods

This narrative review was conducted through a comprehensive literature search of electronic databases, including PubMed, Scopus, Google Scholar, ScienceDirect, and the Cochrane Library. Additional searches were performed on publisher platforms such as Frontiers, Springer, MDPI, Wiley Online Library, and Taylor & Francis. The literature search used keywords related to skin aging and UV protection, combined with Boolean operators: “antiaging” OR “skin antiaging” OR “phytochemicals” AND “UV protection” “free radical scavengers” “skin moisturizers.” Searches were limited to articles published in English between 2000 and 2025. Data extraction captured the author, year, study design, sample characteristics, interventions, and outcomes using a structured form. Due to heterogeneity in study designs, interventions, and outcome measures, meta-analysis was not feasible, and findings were synthesized qualitatively.

3. Traditional Uses of Phytochemicals

Traditionally, quercetin, a flavonoid found in fruits, vegetables, and medicinal plants such as Sophora japonica and Ginkgo biloba, has been used in TCM to restore the balance of Qi, blood, Yin, and Yang, prevent disease progression, enhance blood circulation, reduce inflammation, support detoxification, and strengthen the immune system (Cherian et al., 2025). Similarly, rutin, a flavonoid glycoside present in plants like Tartary buckwheat (Fagopyrum tataricum), has traditionally been valued for strengthening blood vessels, improving circulation, preventing blood clots, supporting collagen synthesis, and lowering cholesterol and blood pressure, and has long been incorporated into foods, remedies, and supplements to enhance antioxidant defenses and overall health (Amini et al., 2025; Salkić et al., 2023).

Caffeic acid, a phenolic compound found in many Moroccan medicinal plants, has traditionally been used for its anti-inflammatory properties and contributes to compounds with antiviral, anticancer, antidiabetic, antibacterial, neuroprotective, and hepatoprotective effects (Hmidani et al., 2020; Goyal et al., 2025). Consumption of polyphenol-rich plants supports immunity, with caffeic acid acting as a potent antioxidant and protective agent (Aijaz et al., 2022). Traditionally, coffee leaves (Coffea arabica) have been brewed as tea for their ethnomedicinal benefits, with bioactive compounds such as mangiferin, trigonelline, caffeine, chlorogenic acids, and rutin providing antioxidant, anti-inflammatory, antihypertensive, anti-obesity, antimicrobial, anticancer, and neuroprotective effects (Yohannis et al., 2024).

Vitamin C (ascorbic acid) has traditionally been valued as a vital antioxidant that protects the body from free radical damage and supports essential metabolic functions, including folic acid activation, cholesterol conversion to bile acids, and tryptophan conversion to serotonin (Ali et al., 2024; Dave & Patil, 2017). It has been used to promote bone formation, wound healing, connective tissue growth, gum health, immunity, and the management of infections, as well as conditions such as atherosclerosis, cancer, the common cold, and iron-deficiency anemia (Bhoot et al., 2023). Vitamin C is absorbed through the gastrointestinal tract and metabolized via L-galactose and GDP-D-mannose pathways for distribution to body tissues (Ali et al., 2024).

Hesperidin, abundant in citrus fruits, has traditionally been applied in Ayurveda and Asian medicine for digestive, respiratory, circulatory, and skin disorders, exhibiting antioxidant, antimicrobial, anti-inflammatory, and anticancer effects (Pyrzynska et al., 2022; Man et al., 2019). Curcuma longa (turmeric) has been traditionally used to prevent and manage cancer, diabetes, arthritis, inflammation, liver, and gastric disorders (Tian et al., 2025; Iweala et al., 2023). Catechins from tea leaves and other plants provide antioxidant, antimicrobial, anti-inflammatory, anti-allergenic, and anticancer benefits, while enhancing the absorption of functional foods and bioactive compounds (Bae et al., 2020). Lycopene, present in tomatoes, acts as an antioxidant protecting cardiovascular health by improving lipid profiles, endothelial function, and reducing inflammation (Khan et al., 2021). Sulforaphane activates Nrf2 to enhance antioxidant, detoxification, and anti-inflammatory defenses (Khan et al., 2022). Soy isoflavones, particularly genistein, reduce oxidative stress, modulate signaling pathways, and improve gut and mitochondrial function (Zhang et al., 2025). Ferulic acid, found in seeds and leaves, exhibits antioxidant, anti-inflammatory, antimicrobial, antiviral, hepatoprotective, and anticancer effects while modulating enzyme activity (Pyrzynska et al., 2024) (Table 1).

4. Ageing Mechanism

As skin ages, levels of hyaluronic acid and glycosaminoglycans decline, while loss of collagen and elastin leads to disorganized connective tissue, resulting in wrinkles (Liang et al., 2023). Systemic aging is characterized by nine interrelated hallmarks: stem cell exhaustion, telomere shortening, epigenetic alterations, mitochondrial dysfunction, loss of proteostasis, deregulated nutrient sensing, genomic instability, altered intercellular communication, and cellular senescence. Cutaneous aging is influenced by transcriptional dysregulation, stem cell depletion, accumulation of advanced glycation end-products (AGEs), and extracellular matrix degradation (Liang et al., 2023). Classic theories explaining skin aging include oxidative stress and free radicals, inflammatory aging, photoaging, and nonenzymatic glycation (He et al., 2023). Telomere shortening, increased ROS, decreased molecular chaperones, and elevated retinoic acid receptor-α (RAR-α) have long been considered key aging mechanisms (Bay and Topal, 2023).

Hussein et al. emphasized that aging is a gradual decline in physiological function, increasing vulnerability to disease. Skin aging results from the interaction of intrinsic and extrinsic factors, producing clinical manifestations such as wrinkles, pigmentation changes, loss of elasticity, and altered texture (Hussein et al. 2025) (Figure 1). Understanding these mechanisms is essential for developing preventive and therapeutic strategies.

4.1. Intrinsic Factors

Intrinsic skin aging is a natural process driven by time, genetics, and hormonal changes (Chin et al., 2023). It manifests as reduced blood flow, loss of rete ridges, decreased fat content, collagen decline, pale and dry skin, fine wrinkles, reduced firmness, and impaired healing (Karim et al., 2021). Cellular mechanisms include telomere shortening, decreased DNA repair, oxidative stress, limited cell divisions, and cell cycle arrest (Karim et al., 2021; Dorf et al., 2024). Overproduction of mitochondrial reactive oxygen species (ROS) is a major driver of cellular senescence (Dorf et al., 2024). Biomarkers of intrinsic aging include SA-β-gal, p¹⁶INK4a, p²¹CIP1, p27, p53, DNA-SCARS, SAHF, telomere shortening, & lamin B1 downregulation (Dorf et al., 2024). Skin aging can also be measured non-invasively via AGEs (Dorf et al., 2024).

Intrinsic factors also affect systemic health and functional decline. De Almeida et al. reported that among 267 elderly individuals (76.8% women, aged 60–90 years, mean 70.22 ± 7.30), intrinsic risk factors for falls and fractures included older age, poor self-perception of vision, and poor self-rated health (De Almeida et al. 2012). Bonté et al. noted that intrinsic aging impairs dermal ECM integrity, leading to senescent cells and reduced repair capacity (Bonté et al. 2019). Hussein et al. further highlighted that intrinsic mechanisms such as genetics, metabolism, telomere shortening, oxidative stress, hormonal, and immune changes interact with extrinsic factors to accelerate skin aging (Hussein et al. 2025).

4.2. Extrinsic Factors

Extrinsic skin aging, also called environmental or photoaging, results from external influences such as UV exposure, sunlight, pollution, chemical exposure, trauma, cigarette smoking, malnutrition, and lifestyle factors (Bay and Topal, 2023; Ratanapokasatit et al., 2022; Irene et al., 2024). Photoaging is the most common extrinsic aging form, with long-term solar radiation contributing to up to 80% of premature facial aging (Lucas et al., 2019). Clinical signs include rough, dehydrated skin, deep wrinkles, loss of elasticity, and uneven pigmentation, especially on the face, neck, and dorsal forearms (Liang et al., 2023). Chronic sun exposure promotes collagen degradation, epidermal atrophy, and elastic fiber fragmentation (Liang et al., 2023). Lifestyle factors, including poor nutrition, smoking, alcohol use, inadequate sleep, and improper skincare, worsen skin function and visible aging signs (Irene et al., 2024; Chin et al., 2023). Skin serves as a model for studying extrinsic aging, as exposomal factors interact with genetic predisposition to induce macromolecular damage and senescent fibroblast accumulation in the dermis (Krutmann et al., 2021).

5. Role and Potential of Phytochemicals in Skin Anti-Aging

Plant-derived phytochemicals provide multiple skin benefits, including matrix protection, UV defense, hydration, and antioxidant activity (Cole et al. 2018) (Table 2; Figure 2). Many compounds have been investigated in vitro, but further clinical studies are needed to determine optimal formulation, safety, effective concentrations, and duration of anti-aging effects. Bioactive compounds from traditional medicine have long therapeutic value, particularly for skin disorders. Skin aging is a natural process involving progressive structural, functional, and appearance-related alterations (Cole et al. 2018).

Yuan et al. reviewed 210 articles, covering acne, vitiligo, psoriasis, and scabies. Current treatments reduce aging signs but have side effects. Medicinal plants show promise for skin regeneration, anti-aging, and stem cell proliferation with fewer adverse effects (Yuan et al. 2025). Abdolmaleky et al. highlighted that the skin, composed of three layers, acts as a barrier and contains stem cells for hair and epidermal regeneration. Aging reduces stem cell function, wound healing, hair growth, and collagen production, causing wrinkles, sagging, and reduced firmness. Genes such as SOX9, NOTCH, TGFBs, CTGF, AGR3, DSTYK, TPCN2, and collagen are critical for integrity (Abdolmaleky et al. 2025). Environmental factors (pollutants, UV radiation, infections, & microbiome dysbiosis) damage skin, while nutrients, phytochemicals (curcumin, quercetin, rosemary, phenolic acids, & sesamin), and microbiome health support function and prevent premature aging (Abdolmaleky et al. 2025).

5.1. Skin-Matrix Defenses

The extracellular matrix (ECM) undergoes continuous degradation and repair, which becomes imbalanced with age, reducing structural support, elasticity, and firmness. UV exposure upregulates MMP-1, -3, & -9, degrading collagen and elastin, and accelerating wrinkles and sagging (Akbari Kordkheyli et al., 2019). Flavonoids and phenolics inhibit pro-inflammatory cytokines and stimulate collagen synthesis, reducing visible aging. Curcumin reduces MMP-1 expression, while dandelion water extracts protect fibroblasts from UV-induced oxidative stress (Safitri et al., 2024).

Uriostegui-Pena et al. noted that skin aging leads to wrinkles, pigmentation irregularities, decreased elasticity, dryness, and roughness, largely driven by oxidative stress. Phytochemicals mitigate damage but face challenges in solubility, stability, and bioavailability. Nanoformulations improve these properties and inhibit aging enzymes (collagenase, tyrosinase, & hyaluronidase) while enhancing superoxide dismutase, catalase, and collagen levels (Uriostegui-Pena et al. 2025).

Luo et al. emphasized that chronic UV exposure disrupts genomic stability and cellular homeostasis, accelerating skin aging. Natural compounds like polyphenols, flavonoids, polysaccharides, terpenoids, and alkaloids protect against UV-induced oxidative stress, inflammation, and ECM degradation, supporting anti-photoaging product development (Luo et al. 2025).

Devi et al. highlighted that intrinsic factors (genetics & metabolism) and extrinsic factors (UV, pollution, & lifestyle) drive aging, causing wrinkles, pigmentation changes, and elasticity loss. Phytoextracts (resveratrol, curcumin, & ginseng) counter oxidative stress, inflammation, and collagen depletion, and nanocarriers enhance their efficacy, though clinical validation is still required (Devi et al. 2025).

However, the study relies on in vitro or animal models, which limit their applicability to humans. Small sample sizes, varied doses and formulations, and inconsistent outcome measures contribute to heterogeneity (Devi et al., 2025). The study also lacked randomization, blinding, or appropriate controls, increasing the risk of bias (Uriostegui-Pena et al., 2025). Evidence regarding nanoformulation safety, stability, and cytotoxicity remains limited (Luo et al., 2025), and reported effects vary between collagen and antioxidant enhancement and anti-inflammatory or photoprotective outcomes.

5.2. UV Protectant

UVB induces MMPs via the MAPK pathway activation, promoting photodamage. Catechin prevents UVB-induced photoaging by scavenging ROS, suppressing MMP, and increasing type I pro-collagen (Chaiprasongsuk & Panich, 2022). Cruciani et al. demonstrated that SPF creams protect fibroblasts, stem cells, and keratinocytes from UV-induced oxidative stress, DNA mutations, and premature aging, enhancing repair and maintaining youthful phenotypes (Cruciani et al. 2025).

Shubayr et al. noted the importance of plant-derived antioxidants and phytochemicals in photoprotection, with extraction methods affecting composition, stability, and bioavailability (Shubayr et al. 2023). Stoykova et al. emphasized the multi-target protective effects of plant compounds against UV-induced oxidative stress, inflammation, DNA damage, ECM degradation, photo-senescence, and cell death (Stoykova et al. 2025). Chaiprasongsuk et al. also highlighted Nrf2-activating phytochemicals, which restore homeostasis, reduce inflammation, improve pigmentation, and delay photoaging (Chaiprasongsuk et al. 2022).

However, the study by Shubayr et al. largely relied on in vitro assays, which limit the direct translation of findings to human skin (Shubayr et al., 2023). Similarly, the review by Stoykova et al. included studies with heterogeneous experimental models, varying doses, and inconsistent outcome measures, which may reduce the reliability and generalizability of the reported protective effects (Stoykova et al., 2025).

5.3. Skin Moisturizers

Hyaluronic acid (HA) is a key ECM component essential for hydration and anti-aging (Papakonstantinou et al., 2012). Supplementing with phytochemicals can enhance hydration and elasticity by boosting collagen and HA synthesis (Göllner et al., 2017). Romes et al. emphasized that environmental pollutants and UVA/UVB radiation drive the development of plant-based nanoemulsions. Phyto-antioxidants (catechin, quercetin, & gallic acid) provide antioxidative, antityrosinase, antiviral, and antimicrobial effects. Nanoemulsions improve bioavailability and stratum corneum penetration, enhancing skin repair and rejuvenation, meeting growing consumer demand (Romes et al. 2021).

5.4. Free Radical Scavengers

Plant-derived phytochemicals act as antioxidants. Flavonoids and phenolics neutralize free radicals via hydroxyl groups. Ferulic acid and anthocyanins reduce oxidative damage (Varma et al., 2017). Un Nisa et al. noted that intrinsic and extrinsic factors, including UV and free radicals, accelerate aging, suppress immunity, and increase cancer risk. Plant phenolics improve longevity via MPK-1/ERK, SIR-2.1/DAF-16, and IGF-1 signaling, scavenging ROS, reducing melanin, protecting against UV, modulating cancer signaling, and inducing apoptosis and cell cycle arrest (Un Nisa et al. 2024).

Tomas et al. reported that carotenoids, vitamins, fatty acids, and polyphenols protect skin by acting as antioxidants, inhibiting degradative enzymes (hyaluronidase, collagenase, & elastase), lowering inflammatory markers (IL-6, & IL-8), reducing MMP-1 and MMP-2, improving elasticity, preventing protein breakdown, reducing hyperpigmentation, and supporting wound healing (Tomas et al. 2025).

6. Phytochemicals with Skin Anti-Ageing Activity

Photochemical with skin antiaging activity refers naturally occurring bioactive Phytochemicals with skin anti-aging potential are naturally occurring plant-derived compounds that help delay, prevent, or even reverse both visible and functional signs of skin aging (Pejčić et al., 2019). Their protective actions involve scavenging reactive oxygen species, reducing oxidative damage, and modulating inflammatory pathways. Notable examples include curcumin, resveratrol, and quercetin, which exhibit strong skin-protective and rejuvenating effects (Liang et al., 2023) (Figure 2; Table 3; Table 4).

6.1. Quercetin

Quercetin (3,3,4,5,7-pentahydroxyflavone) is a flavonoid abundant in fruits, vegetables, seeds, and medicinal herbs, including apples, grapes, red onions, garlic, berries, cilantro, dill, and red wine (Derosa et al., 2021; Ulusoy & Sanlier, 2020; Akbari Kordkheyli et al., 2019; Singh et al., 2021). Present in plants as glycosides like rutin, isoquercetin, and hyperin, quercetin exhibits potent antioxidant, anti-inflammatory, antibacterial, antiviral, and antitumor properties (Grewal et al., 2021; Yang et al., 2020a; Zaborowski et al., 2024). Capers (170 mg/100 g) and red onions (33 mg/100 g) contain the highest concentrations (Pejčić et al., 2019). The compound scavenges ROS, protects against lipid peroxidation, and reduces oxidative stress in vitro and in vivo (Oh et al., 2019; Manca et al., 2014).

In skin aging and photoaging, quercetin improves hydration, collagen content, and antioxidant defense. In an in vivo study on female albino mice, topical quercetin increased skin moisture to 43.0 ± 1.2% compared to 28.2 ± 0.9% in UV-exposed controls, reduced TBARS from 20 to 12.5 nM/mg, and elevated reduced glutathione by 1.5-fold (Joshan & Singh, 2013). It inhibits matrix metalloproteinase activity, reducing collagen degradation linked to inflammation and extrinsic aging factors (Hatahet et al., 2016). Quercetin exerts long-lasting anti-inflammatory effects by modulating NF-κB and p38 MAPK in various cell types (Yang et al., 2020; Li et al., 2016). In AD NC/Nga mice, quercetin-3-O-(200-gallate)-α-L-rhamnopyranoside lowered IL-4, IL-5, IL-13, serum IgE, eosinophil counts, iNOS, and COX2 (Karuppagounder et al., 2016).

Barbosa et al., using in silico analyses, evaluated quercetin, astaxanthin, curcumin, and resveratrol against skin aging. Protein-protein interaction networks revealed oxidative stress, vascular and immune abnormalities, and inflammation as major processes. Bottleneck genes identified included TNF-α (quercetin), IL-6 (general/astaxanthin), TAB1 (curcumin), and TP53 (resveratrol), suggesting that these compounds can mitigate oxidative stress and inflammation to prevent cellular aging (Barbosa et al., 2026).

Okselni et al., conducted a meta-analysis of 65 studies showing quercetin significantly reduced MDA, ROS, and LPO while increasing GSH, CAT, and SOD. It suppressed NF-κB, AP-1, ERK, JNK, TNF-α, IL-6, IL-1β, IL-8, MCP-1, COX-2, iNOS, MPO, and increased IL-10. Quercetin also reduced IL-4 and IFN-γ, improved fibroblast distribution, epithelialization, collagen, angiogenesis, inhibited tyrosinase, reduced melanin, DNA damage, melanoma cell viability, and tumor formation (Okselni et al., 2025). Chondrogianni et al., demonstrated that quercetin and quercetin caprylate act as proteasome activators, enhancing survival, lifespan, and rejuvenation in HFL-1 primary fibroblasts (Chondrogianni et al., 2010). These compounds restored youthful morphology in senescent cells and induced whitening effects.

However, Barbosa et al.’s in silico analysis is limited by its predictive nature, which reduces direct biological applicability (Barbosa et al., 2026). Okselni et al.’s meta-analysis is constrained by heterogeneity in study designs, dosages, and outcome measures, as well as potential publication bias, which may affect the reliability of pooled results (Okselni et al., 2025). Chondrogianni et al.’s findings are limited to in vitro fibroblast models and lack in vivo validation, restricting their generalizability (Chondrogianni et al., 2010).

Figure 3. Chemical structures of important natural compounds with potent skin anti-aging effect.

Figure 3. Chemical structures of important natural compounds with potent skin anti-aging effect.

6.2. Rutin

Rutin (2-(3,4-dihydroxyphenyl)-5,7-dihydroxy-3-[α-l-rhamnopyranosyl-(1→6)-β-d-glucopyranosyloxy]-4H-chromen-4-one), also called vitamin P, is a naturally occurring lipophilic flavonoid with a polyphenolic structure (Semwal et al., 2021). It is a quercetin glycoside composed of quercetin and rutinose and exhibits anticarcinogenic, neuroprotective, cytoprotective, vasoprotective, and cardioprotective effects (Ganeshpurkar & Saluja, 2017). Rutin originates from Ruta graveolens and is known for its antioxidant and anti-inflammatory mechanisms, though poor water solubility limits stability and bioavailability (Mauludin et al., 2009; Semwal et al., 2021).

Choi et al., investigated rutin’s effects on UVB-induced inflammation in mouse skin (Choi et al., 2014). Topical application 30 minutes before UVB exposure reduced inflammatory protein expression, epidermal hyperplasia, COX-2, and iNOS, likely via inhibition of p38 MAP kinase and JNK signaling. Similarly, rutin-containing hydrogels in rats decreased wound area, lipid peroxidation, protein carbonyl content, oxidative stress, and enhanced catalase activity (Almeida et al., 2012). Choi et al., examined rutin’s anti-aging effects on human dermal fibroblasts (HDFs) and human skin. In vitro assays included cell viability, senescence-associated β-galactosidase, RT-qPCR, and ROS scavenging, while a double-blind clinical study with 40 subjects (30–50 years) assessed dermal density, elasticity, and wrinkles over 4 weeks. Rutin increased COL1A1 mRNA, decreased MMP1 mRNA, enhanced ROS scavenging, improved skin elasticity, and reduced wrinkle length, area, and number (Choi et al., 2016).

Girsang et al., evaluated rutin and caffeic acid for antioxidant and anti-aging activity using DPPH, H₂O₂, ABTS, FRAP, and collagenase, elastase, hyaluronidase, and tyrosinase inhibition assays. Rutin showed IC50 values of 5.79 µg/mL (DPPH), 12.09 µg/mL (H₂O₂), 16.59 µg/mL (ABTS), FRAP 480.08 µM Fe (II)/µg, and inhibited collagenase (104.70 µg/mL), elastase (46.88 µg/mL), tyrosinase (55.65 µg/mL), and hyaluronidase (114.07 µg/mL), confirming strong antioxidant and anti-aging potential (Girsang et al., 2020). Wang et al., studied rutin as the main bioactive component in Jueyin granules (JYG) for psoriasis. In vitro, HaCaT cell proliferation and TNF-α/IL-6 expression was assessed, while modular pharmacology identified hub genes and AGE-RAGE signaling pathways. In vivo, imiquimod-induced psoriasis in BALB/c mice showed that rutin reduced lesions, inhibited cell proliferation, and downregulated AGE-RAGE signaling, demonstrating anti-inflammatory effects (Wang et al., 2023).

Pyo et al., addressed rutin’s poor solubility by producing nanocrystals (mean size 300 nm) via bead milling and high-pressure homogenization, incorporated into hydroxypropyl cellulose gel. The DPPH assay demonstrated 90% antioxidant activity in nanocrystal gel, superior to raw rutin and commercial products. Tape-stripping studies on porcine skin showed deeper stratum corneum penetration, improving bioavailability for topical application (Pyo et al., 2016).

However, both Choi et al. & Almeida et al. in vivo studies used small sample sizes and short treatment durations, limiting the generalizability of their findings (Choi et al., 2014; Almeida et al., 2012). The human clinical trial included only 40 participants over 4 weeks, which may be insufficient to detect long-term effects or rare adverse events (Choi et al., 2016). Heterogeneity in formulations, dosages, and outcome measures makes direct comparison across studies difficult (Pyo et al., 2016; Girsang et al., 2020), and some studies lacked blinding or detailed randomization procedures, raising the potential for bias (Choi et al., 2016; Wang et al., 2023).

6.3. Ascorbic Acid

Vitamin C (ascorbic acid) is a major antioxidant in human tissues, first isolated in 1928 by Albert Szent-Györgyi, who received the Nobel Prize in 1937. While most plants and animals synthesize it from glucose, humans lack the enzyme L-glucose-γ-lactone oxidase and must obtain it from dietary sources such as kakadu plum, oranges, limes, peppers, liver, codfish, and cow’s milk (Ravetti et al., 2019; Gęgotek & Skrzydlewska, 2022). The recommended daily intake is 75 mg for women and 90 mg for men. Ascorbic acid’s polyhydroxyl structure confers strong reducing properties, allowing it to act as a hydrogen or electron donor and cofactor in enzymatic processes, supporting collagen formation, wound healing, vascular integrity, leukocyte microbial uptake, cholesterol reduction, blood pressure control, and mitigation of skin aging (Gęgotek & Skrzydlewska, 2022).

Ascorbic acid also modulates inflammation. Dietary intake may reduce plasma C-reactive protein (CRP), and intracellularly it influences pro-inflammatory mediators such as IL-6, IFN-γ, and NFκB/TNFα pathways, while potentially modulating anti-inflammatory IL-4, thereby dampening inflammatory signaling (Gęgotek & Skrzydlewska, 2022). Skin aging manifests as decreased firmness and density, uneven tone, wrinkles, erythema, and hyperpigmentation. Sensitive skin, triggered by stinging, burning, itching, and redness, affects approximately 50% of Europeans. Jaros-Sajda et al., evaluated the effects of vitamin C applied via sonophoresis and microneedling on photoaged reactive skin. Both treatments significantly improved skin elasticity and reduced erythema, with the greatest effect on the cheeks using microneedling plus vitamin C, and were well tolerated (Jaros-Sajda et al., 2024).

However, sample sizes were relatively small, particularly in the clinical components, limiting statistical power and generalizability (Garre et al., 2018; Ryu et al., 2022). Participants were predominantly healthy women with varying age ranges, which may not reflect broader populations (Garre et al., 2018; Ryu et al., 2022). Both Garre et al., & Zerbinati et al. studies relied on ex vivo or in vitro models, which may not fully replicate in vivo physiology or long-term effects (Garre et al., 2018; Zerbinati et al., 2021). In addition, short follow-up durations (2–4 weeks), lack of randomized or blinded designs, and differences in serum formulations and delivery systems further limit comparisons and increase the risk of bias (Garre et al., 2018; Ryu et al., 2022; Zerbinati et al., 2021).

6.4. Caffeic Acid

Caffeic acid (CA, 3,4-dihydroxycinnamic acid) is a hydroxycinnamic acid in the phenolic acid family, with a C6–C3 phenylpropanoid backbone and a 3,4-dihydroxylated aromatic ring linked to a carboxylic acid via a trans-ethylene chain. Dietary sources include propolis, apples, cider, blueberries, and coffee. CA exhibits strong antioxidant activity, modest antibacterial effects, anticancer potential, and may prevent atherosclerosis and other cardiovascular disorders (Espíndola et al., 2019; Spagnol et al., 2019). CA captures reactive species such as O2•− and HOCl/OCl−, inhibiting myeloperoxidase activity and modulating neutrophil microbicidal processes, which may reduce inflammation and tissue damage (Spagnol et al., 2019).

Kim et al., developed a lipophilic CA derivative, CAD, by conjugating CA with 3,4-DHPEA from olive oil to improve dermal absorption. CAD exhibited higher antioxidant activity than CA in DPPH and ABTS assays. In B16F10 melanoma cells, CAD inhibited melanin production without cytotoxicity at lower concentrations, reduced intracellular ROS, inhibited tyrosinase activity, downregulated TYR, TRP-1, and TRP-2 expression, suppressed MITF phosphorylation, and reduced ERK and JNK phosphorylation. In a 3D human skin model (Melanoderm™), CAD demonstrated dose-dependent skin-lightening effects and histological improvement (Kim et al., 2025).

Jokubaite et al., incorporated CA into hydrophilic gels using poloxamer 407, carbomer 980, and their mixture. Increasing polymer concentration raised viscosity and slowed CA release (Jokubaite et al., 2024). These gels showed antioxidant activity and antimicrobial effects against Staphylococcus aureus and Candida albicans, indicating potential as topical delivery systems.

Girsang et al., evaluated CA and rutin for antioxidant and anti-aging effects using DPPH, H₂O₂, ABTS, FRAP, and collagenase, elastase, hyaluronidase, and tyrosinase inhibition assays. Results included IC50 values: DPPH (rutin 5.79 µg/mL, CA 8.72 µg/mL), H₂O₂ (rutin 12.09 µg/mL, CA 15.23 µg/mL), ABTS (CA 6.23 µg/mL, rutin 16.59 µg/mL), FRAP (rutin 480.08 µM Fe(II)/µg, CA 526.50 µM Fe(II)/µg), collagenase (CA 74.42 µg/mL, rutin 104.70 µg/mL), elastase (rutin 46.88 µg/mL, CA 76.95 µg/mL), tyrosinase (rutin 55.65 µg/mL, CA 145.91 µg/mL), and hyaluronidase (rutin 114.07 µg/mL, CA 244.45 µg/mL) (Girsang et al., 2020) . These findings confirmed strong antioxidant and anti-aging potential.

Lee et al., synthesized CA–APPPKK, a CA peptide conjugate, to evaluate its cosmetic anti-aging potential. Cytotoxicity was assessed using CCK-8 assays, ROS scavenging, and NO assay for anti-inflammatory activity. CA–APPPKK reduced cell viability dose-dependently, enhanced oxidative stress resistance, and exhibited anti-inflammatory effects, supporting its use as a cosmetic anti-aging biomaterial (Lee et al., 2017). Spagnol et al., compared CA delivery in films and emulsions using modified Franz diffusion cells with cellulose and biological membranes. Both systems released high CA, but skin permeation was limited, favoring retention in the epidermis/dermis. Film formulations showed higher CA concentrations than emulsions, with diffusion-controlled release following Higuchi kinetics, demonstrating efficient, safe, and transportable delivery suitable for cosmetic applications (Spagnol et al., 2017).

However, Kim et al. was limited by its reliance on in vitro and 3D skin models without in vivo validation, which restricts clinical applicability (Kim et al., 2025). Jokubaite et al. did not assess the long-term stability of their hydrophilic gels and lacked comprehensive skin penetration studies beyond viscosity-dependent release (Jokubaite et al., 2024). Girsang et al. presented extensive IC50 data, but cellular and tissue-level effects were not evaluated, and heterogeneity in assay conditions complicates direct comparisons (Girsang et al., 2020). Lee et al. reported dose-dependent cytotoxicity of the CA–peptide conjugate, raising safety concerns for topical use (Lee et al., 2017). Spagnol et al. used ex vivo diffusion models, which may not fully replicate in vivo skin absorption (Spagnol et al., 2017).

6.5. Hesperidin

Hesperidin, a bioflavonoid abundant in citrus fruits, especially orange peels, lemon, lime, and grapefruit varies in concentration depending on species, variety, growing conditions, and processing methods, with higher amounts typically in the peel; methanol extraction of lemon seeds can yield even more hesperidin (Man et al., 2019). It possesses multiple skin-beneficial properties, including antioxidant, anti-inflammatory, photoprotective, anticancer, antibacterial, and skin-lightening activities, making it valuable for cosmetics, cosmeceuticals, and pharmaceuticals (Rodrigues & Pintado, 2024; Amiri et al., 2024). Mechanistically, hesperidin scavenges free radicals, inhibits pro-oxidative enzymes, chelates transition metals involved in reactive oxygen species generation, enhances antioxidant enzymes such as catalase and superoxide dismutase, and has stronger iron-chelating activity than deferoxamine, a standard treatment for chronic iron overload (Pyrzynska, 2022). It also stimulates tissue inhibitors of metalloproteinases (TIMPs) that inhibit MMPs and protects skin from oxidative stress through direct interaction with ROS (Rodrigues & Pintado, 2024).

Stanisic et al., reported a solvent-free, low-energy extraction of hesperidin from orange (Citrus sinensis) bagasse, achieving ~98% purity with a 1% yield. The bioflavonoid was nanonized and incorporated into oil-in-water creams suitable for tropical climates targeting dark eye circles. Using an in vitro study design on 3D reconstructed human skin derived from post-plastic-surgery residues, the nanoemulsion creams were tested without human or animal use; one formulation demonstrated superior skin compatibility and cosmetic potential (Stanisic et al., 2020).

Man et al., further highlighted that hesperidin provides cutaneous benefits beyond cardiovascular, anti-inflammatory, and type II diabetes effects, including wound healing, UV protection, antimicrobial activity, anti–skin cancer effects, skin-lightening, and maintenance of epidermal barrier homeostasis in young and aged skin. These actions are mediated by antioxidant activity, inhibition of MAPK-dependent pathways, and stimulation of epidermal proliferation, differentiation, and lipid synthesis (Man et al., 2019). Its low cost, wide availability, and safety support its use in skincare.

Bellavite et al., systematically reviewed 20 years of experimental evidence on UV-induced skin damage and photoaging, focusing on hesperidin and its derivatives (hesperetin, hesperidin glucoside, hesperidin methylchalcone). Including murine models, the review showed that these compounds protect against oxidative stress, aging, and tissue damage through Nrf2/ARE activation, regulation of CISD2, and modulation of MAPK and PI3K/Akt pathways, with efficacy observed after both dietary intake and topical dermocosmetic application (Bellavite et al., 2025).

However, Stanisic et al. used in vitro 3D reconstructed human skin, which may not fully replicate in vivo physiology (Stanisic et al., 2020). Man et al. relied primarily on literature-based preclinical evidence, leaving uncertainties regarding dosing, long-term safety, and effects across diverse skin types (Man et al., 2019). Bellavite et al.’s review included mainly murine models and heterogeneous study designs, limiting translation to humans (Bellavite et al., 2025). Additionally, variability in models, formulations, and outcomes, along with potential publication bias, further challenges the consistency of the findings (Stanisic et al., 2020; Man et al., 2019; Bellavite et al., 2025).

6.6. Resveratrol

Resveratrol (3,4′,5-trihydroxystilbene) is a polyphenol, phytoestrogen, and phytoalexin with a stilbene structure, naturally found in grapes, mulberries, raspberries, tomatoes, strawberries, and almonds, and is extracted from over 100 plant species across 34 families, including Vitaceae, Moraceae, Liliaceae, and Leguminosae (Leis et al., 2022; Ahmad et al., 2024). The trans-resveratrol form is physiologically active and widely used in cosmetics for its antioxidant and anti-inflammatory properties. In vitro studies demonstrate that resveratrol neutralizes reactive oxygen species, inhibits protein oxidation and lipid peroxidation, and exhibits higher antioxidant activity than vitamin C and E (Ndiaye et al., 2011; Janssens-Böcker & Kerscher, 2021). It also enhances skin thickness, suppleness, moisture, and slows aging by modulating Bcl-2 phosphorylation, cell adhesion kinase activity, hydroperoxide formation, and B and C protein kinase activity. Mechanistically, resveratrol inhibits phosphorylation of survivin, nuclear factor kB, cyclins D1 and D2, matrix metalloproteinases, and MAPK, while reducing UVB-induced inflammatory processes and skin edema. Resveratrol is particularly effective in isobutyrate and butyrate forms, increasing collagen A1 levels, decreasing MMP-9 via gene interaction, and modulating tissue inhibitors of metalloproteinases and fibrillin 1. It also affects aging markers such as nerve growth factor, proliferating cell nuclear factor, 5α-reductase, and calcium-binding proteins A8, A9, and S100 (Patricia Farris et al., 2013; Subedi et al., 2013; Leis et al., 2022).

Brinke et al., conducted a clinical observational study on 20 subjects using a 2% trans-resveratrol emulsion applied once daily for eight weeks. The treatment improved skin barrier function, increased elasticity by 5.3% and density by 10.7%, reduced roughness by 6.4% and dispensability by 45.9%, decreased redness, and received high satisfaction ratings for smoothness and moisture (Brinke et al., 2021). Rao et al., performed a double-blind, randomized, placebo-controlled clinical trial in women aged 40 and above, administering oral (75 mg) and topical (1.5%) trans-resveratrol for eight weeks. Out of 134 participants, 122 completed the study. Combined oral and topical treatment significantly reduced wrinkle scores, while topical groups increased U-zone sebum levels (Rao et al., 2022). Serum trans-resveratrol levels rose in the oral and combined groups, and all interventions were safe with only mild adverse events. Leis et al., reviewed resveratrol’s dermatological applications, highlighting its roles in wound healing, collagen synthesis, UVB protection, wrinkle reduction, and tissue regeneration through MAPK, FOXO3, TGF, metalloproteinase-1, and VEGF pathways, emphasizing its potential use in cosmetology, dermatology, plastic surgery, and pharmacotherapy for skin disorders (Leis et al., 2022).

However, Brinke et al.’s observational study had a small sample size (n = 20) and lacked a control group, which limits the ability to draw causal conclusions (Brinke et al., 2021). Rao et al.’s randomized trial was more robust but included only women aged 40 and above and had a short treatment duration, factors that may affect generalizability and adherence (Rao et al., 2022). Leis et al.’s narrative review summarized mechanistic and clinical evidence but may be subject to publication bias (Leis et al., 2022). Additionally, differences in formulation, treatment regimens, outcome measures, and limited long-term safety data complicate comparisons across studies (Brinke et al., 2021; Rao et al., 2022; Leis et al., 2022).

6.7. Curcumin

Curcumin, an active phenolic compound from the rhizome of Curcuma longa and other species such as C. aromatica, C. phaeocaulis (3%), C. zedoaria (0.1%), C. mangga, C. xanthorrhiza (1–2%), Costus speciosus, and Zingiber cassumunar, is an orange-yellow crystalline powder constituting 2–5% of the spice (Panknin et al., 2023; Zia et al., 2021). Its poor water solubility limits bioavailability. Curcumin exhibits potent antioxidant activity in vitro, including DPPH, ABTS, O₂•−, DMPD radical scavenging, hydrogen peroxide scavenging, metal chelation, and reducing power, surpassing standard antioxidants such as α-tocopherol, BHA, BHT, and trolox (Ak & Gülçin, 2008). These properties contribute to anti-aging effects by reducing oxidative stress and inflammation, preventing collagen degradation, promoting collagen synthesis, enhancing skin elasticity and hydration, and increasing glutathione levels, thereby mitigating wrinkles and loss of skin firmness (Voulgaropoulou et al., 2019). Curcumin also inhibits prostaglandin synthesis via COX-2, LOX, and iNOS inhibition, affecting carcinogen metabolism and tumor proliferation (Voulgaropoulou et al., 2019).

Threskeia et al., conducted a systematic review of 805 articles and included nine in vivo studies on curcumin’s photoprotective effects. Oral or topical curcumin reduced oxidative stress, inflammatory cytokines, epidermal thickness, and wrinkles while increasing collagen density in UV-exposed skin. Both pure curcumin and Curcuma extracts showed similar efficacy, supporting its use alongside sunscreen and cosmetic products (Threskeia et al., 2024). Kasprzak-Drozd et al., reviewed curcumin from Curcuma longa L., highlighting its anti-inflammatory, antioxidant, antimicrobial, antiviral, antimutagenic, and antifungal effects. Curcumin accelerates wound healing, enhances collagen deposition, and increases fibroblast and vascular density, providing protection against UVB-induced skin damage (Kasprzak-Drozd et al., 2024).

Zia et al., reported that curcumin and its metabolites prolong lifespan in model organisms (C. elegans, D. melanogaster, yeast, mice) through enhanced superoxide dismutase (SOD) activity and reduced malondialdehyde (MDA) and lipofuscin levels (Zia et al., 2021). These effects involve IIS, mTOR, PKA, and FOXO signaling pathways, demonstrating curcumin’s anti-aging, antioxidant, anti-inflammatory, anticancer, and antimicrobial potential. Thangapazham et al., reviewed curcumin’s chemopreventive effects in skin disorders, including psoriasis, vitiligo, and melanoma. Curcumin scavenges free radicals, inhibits NF-κB, modulates TGF-β and MAPK pathways, and enhances phase II detoxification enzymes (Thangapazham et al., 2013). It also promotes skin regeneration and wound healing, and recent transdermal delivery approaches improve bioavailability, though further clinical trials are needed.

However, Threskeia et al.’s review included only nine in vivo studies out of 805 screened, reflecting a limited sample size and potential selection bias (Threskeia et al., 2024). Both Threskeia et al., & Kasprzak-Drozd et al. studies relied on animal models or UV-exposed skin, which may not fully translate to humans, and variations in curcumin formulation, dosage, and administration route introduce heterogeneity (Threskeia et al., 2024; Kasprzak-Drozd et al., 2024). Kasprzak-Drozd et al. noted that much of the evidence came from in vitro studies, raising concerns about external validity (Kasprzak-Drozd et al., 2024). Zia et al.’s lifespan studies in model organisms are limited by species-specific responses, making extrapolation to human skin uncertain (Zia et al., 2021). Additionally, inconsistencies in outcome measures, reporting of adverse effects, and the use of curcumin in isolation versus complex extracts further limit comparability and generalizability (Threskeia et al., 2024; Kasprzak-Drozd et al., 2024; Zia et al., 2021; Thangapazham et al., 2013).

6.8. Catechins

Tea leaves (Camellia sinensis and Camellia assamica) are rich sources of catechins, a class of polyphenolic compounds including epigallocatechin gallate (EGCG), gallocatechin, epicatechin, epicatechin gallate, epigallocatechin, and gallocatechingallate, with epicatechin, epicatechin gallate, epigallocatechin, and EGCG being the most abundant (Frei & Higdon, 2003). Catechins exert multiple skin-protective effects by scavenging ROS, reducing oxidative stress, and preventing extracellular matrix degradation caused by intrinsic aging and UV-induced photoaging. They also promote collagen synthesis and inhibit MMP enzymes, enhancing skin elasticity, hydration, and structural integrity (Frei & Higdon, 2003; Bae et al., 2020).

Cheng et al., demonstrated in vitro and animal models that catechins increase anti-inflammatory cytokines (IL-4, & IL-10) while reducing pro-inflammatory cytokines (IL-1α, IL-1β, IL-6, & IL-12p35) and inflammatory enzymes (iNOS, & COX-2), modulating AMPK, FOXO3a, SIRT1, and NF-κB signaling to counter TNF-α-induced inflammation (Cheng et al., 2019). Lee et al., reported that (-)-catechin from Ulmus davidiana var. japonica suppressed TNF-α-induced ROS accumulation, inhibited MAPK, Akt, and COX-2 activation, prevented collagen degradation, and reduced IL-1β and IL-6 in human dermal fibroblasts, mitigating intrinsic and extrinsic skin aging (Lee et al., 2020).

Bae et al., highlighted catechins as safe polyphenols with antioxidant, antimicrobial, antiviral, anti-inflammatory, anti-allergenic, and anticancer activities, enhancing the bioavailability and efficacy of functional foods and topical cosmetics (Bae et al., 2020). Kanlayavattanakul et al., standardized Assam tea extract (ATE) for catechin content, including EGCG, and demonstrated in vitro antioxidant activity, suppression of UV-induced IL-6, IL-8, MMP-1, and MMP-9 in co-cultured keratinocytes and fibroblasts, and promotion of hyaluronic acid and collagen synthesis in ex vivo human skin, maintaining chemical stability for six months (Kanlayavattanakul et al., 2024). Zheng et al., reviewed in vivo and in vitro studies, confirming green tea catechins’ antioxidant, anti-carcinogenic, anti-inflammatory, wound-healing, DNA-repair, and UV-protective effects, supporting their inclusion in skincare formulations to prevent both intrinsic and extrinsic aging and related dermatological conditions (Zheng et al., 2024).

However, Cheng et al., 2019; Lee et al., 2020., & Kanlayavattanakul et al. evidence comes from in vitro or animal studies, often with small sample sizes and short durations, limiting direct extrapolation to humans (Cheng et al., 2019; Lee et al., 2020; Kanlayavattanakul et al., 2024). Variability in catechin sources, doses, extraction methods, and experimental conditions creates inconsistencies, and potential risks of bias include selective reporting and lack of blinding (Bae et al., 2020; Cheng et al., 2019; Kanlayavattanakul et al., 2024; Zheng et al., 2024).

6.9. Lycopene

Lycopene is a fat-soluble carotenoid present in orange, red, and yellow fruits and vegetables, biosynthesized by plants, fungi, and some bacteria (Balić & Mokos, 2019). Its multiple conjugated double bonds confer potent antioxidant activity. Lycopene exhibits singlet oxygen quenching capacity ten times higher than α-tocopherol and twice that of β-carotene in in vitro studies. Lycopene, along with β-carotene, constitutes a major carotenoid antioxidant in the skin, efficiently neutralizing free radicals and other reactive species (Joshi et al., 2020). In hairless SKH-1 mice and human keratinocytes, lycopene reduced UVB-induced cell proliferation, increased apoptosis, decreased CDK2 and CDK4 expression, and prevented overexpression of HO-1 induced by UVA1 and UVA/B (Darvin et al., 2008; Imran et al., 2020).

Tarshish et al., conducted a 16-week clinical study with 60 participants to evaluate an oral tomato-based supplement (Lycoderm) containing lycopene and other phytonutrients. Skin carotenoid levels, wrinkle grading, photographic analysis, and questionnaires showed significant increases in skin carotenoids, reductions in wrinkles, and improvements in skin brightness, hydration, and overall condition compared to placebo (Tarshish et al., 2020). Cefali et al., developed a topical emulsion containing lycopene extracted from salad tomatoes. The emulsion was evaluated for physicochemical stability, rheology, cytotoxicity, antioxidant activity, and skin permeation (Cefali et al., 2015). It demonstrated stable physicochemical properties, effective skin penetration, antioxidant effects, and potential as a cosmeceutical for combating skin aging.

Li et al., investigated lycopene in vitro using aged primary skin fibroblasts and in vivo in aged rats. Lycopene reduced ROS, β-galactosidase, and AGEs, while increasing ATP, NAD+/NADH, mitochondrial membrane potential, Fibrillin-I, and VEGF expression. In aged rats, lycopene reversed capillary loss, mitochondrial dysfunction, and insulin resistance, suggesting protective effects via microvascular regeneration and SIRT1-mediated pathways (Li et al., 2022). Darvin et al., conducted a non-invasive in vivo study on 20 volunteers aged 40–50 years to analyze the relationship between skin lycopene levels and skin roughness. A strong correlation was observed between higher lycopene concentrations and lower skin roughness, supporting its role as an antioxidant in preventing photoaging (Darvin et al., 2008).

However, Tarshish et al. had a small sample size (n = 60) and relied on subjective measures, such as questionnaires, which may limit generalizability (Tarshish et al., 2020). Cefali et al. was conducted largely in vitro, so the clinical relevance of the topical emulsion remains uncertain (Cefali et al., 2015). Li et al. used rodent models and in vitro fibroblasts, limiting the direct translation of findings to human skin (Li et al., 2022). Darvin et al. included a small observational cohort (n = 20), increasing the risk of confounding and selection bias (Darvin et al., 2008). Additionally, inconsistencies across studies in dosage, formulation, intervention duration, and outcome measures make direct comparisons difficult (Tarshish et al., 2020; Cefali et al., 2015; Li et al., 2022; Darvin et al., 2008).

6.10. Sulforaphane

One dietary isothiocyanate, sulforaphane [1-isothiocyanato-4-(methyl-sulfinyl) butane], belongs to the –N=C=S group of phytochemicals typical of organic isothiocyanates. Broccoli, a Brassica vegetable, is the richest source, with significant amounts also in Chinese kale, Brussels sprouts, broccoli florets, cauliflower, turnip leaves, and green cabbage (Houghton, 2019; Farag & Motaal, 2010). Sulforaphane protects skin against UV-induced damage by promoting sunburn cell formation in human epidermis ex vivo, reducing sunburn cells by up to 29% at 10 μM 48 hours post-UV exposure, whereas 300 mJ/cm² UV increases sunburn cells fivefold within 24 hours (Sikdar et al., 2016). UV-induced ROS triggers receptor-initiated signaling, activating kinases that induce AP-1 and NF-κB transcription factors. AP-1 decreases collagen I and III expression in fibroblasts and promotes MMP production by keratinocytes and fibroblasts, degrading mature collagen. Sulforaphane prevents UVB-induced AP-1 activation, reduces collagen degradation, and inhibits NF-κB-mediated inflammatory cytokines, limiting neutrophil recruitment and collagenase release, thereby protecting against skin aging (Sikdar et al., 2016).

Sulforaphane activates Nrf2, a transcription factor that enhances cellular tolerance to ROS. Chemical modification of Keap1 cysteines by sulforaphane prevents Nrf2 degradation, allowing Nrf2 to accumulate in the nucleus and upregulate cytoprotective enzymes, including quinone oxidoreductase-1 (QO-1) and glutathione S-transferase (GST) (Petkovic et al., 2021; Sikdar et al., 2016). Acting as an indirect antioxidant, sulforaphane does not directly scavenge ROS but promotes expression of phase II antioxidant enzymes, enhancing cellular defense against oxidative stress. By modifying Keap1 and enabling Nrf2 nuclear translocation, sulforaphane stimulates antioxidant gene expression, contributing to skin protection and anti-aging effects (Sikdar et al., 2016).

Petkovic et al., investigated the effects of sulforaphane (SFN), an isothiocyanate derived from Brassicaceae vegetables, on intrinsic skin aging in male C57BL6 mice (young: 2 months; & old: 21 months) over a 3-month dietary supplementation at 442.5 mg/kg. SFN-treated old mice exhibited increased Nrf2 mRNA and protein expression, upregulated target genes NQO1 and HO1, decreased ROS and MMP9, and improved collagen deposition. Histological analysis showed that dermal thickness was lower in old compared to young mice, while epidermal thickness remained unchanged (Petkovic et al., 2021). These results demonstrate that SFN ameliorates age-related skin changes via Nrf2-mediated antioxidant and anti-aging mechanisms.

Zhang et al., examined sulforaphene (SFE), an isothiocyanate from radish seeds, on d-galactose-induced skin aging in mice. SFE treatment improved both macro- and micro-morphology of dorsal skin, decreased oxidative stress biomarkers, enhanced the activity of antioxidant enzymes, preserved collagen mRNA, reduced pro-inflammatory cytokines, and downregulated MAPK-related proteins. SFE also lowered lipid metabolites and elevated amino acids including L-cysteine and L-histidine, suggesting it protects against oxidative stress-induced skin aging through modulation of both redox balance and amino acid metabolism (Zhang et al., 2025).

Ko et al., evaluated SFN effect on PM2.5-induced premature skin aging using keratinocyte/melanocyte and keratinocyte/fibroblast coculture models. SFN inhibited ROS generation in keratinocytes exposed to PM2.5, suppressed melanogenic paracrine factors such as endothelin-1 and prostaglandin E2, reduced melanogenic proteins (MITF, TYR, & TYRP1), and lowered melanin levels in melanocytes. In fibroblasts, SFN reduced NF-κB-mediated cytokines (IL-1β, IL-6, TNF-α, & COX-2), decreased phospho-NF-κB, Cyr61, and MMP-1, and enhanced procollagen type I synthesis, collectively maintaining collagen homeostasis and preventing UV- or pollutant-induced photoaging (Ko et al., 2020).

Du et al., combined integrative network pharmacology and proteomics in 18-month-old aging mice to uncover SFN molecular mechanisms in intrinsic skin aging. Two months of SFN supplementation improved skin morphology, redox homeostasis, and immune cell composition. Proteomic analysis identified 233 differentially expressed proteins (DEPs), with upregulated DEPs highly enriched in the apelin signaling pathway. Immune analysis revealed restoration of dermal T cell populations, indicating SFN’s role in enhancing skin structure and immune function via the apelin signaling pathway (Du et al., 2025).

Du et al., explored SFN therapeutic effects in inflammatory and autoimmune skin diseases using IMQ-induced psoriasis-like mice (55.3–110.6 μmol/kg) and lupus-prone MRL/lpr mice (82.9 μmol/kg). In psoriasis-like mice, SFN reduced PASI scores, acanthosis, dermal inflammatory cell infiltration, and Th1/Th17 cell proportions, while increasing antioxidant gene Prdx1 expression. In lupus-prone MRL/lpr mice, SFN improved renal pathology, decreased MDA levels, modulated immune cells including plasma cells, follicular helper T cells, neutrophils, and dendritic cells, increased Prdx1 expression, and extended lifespan (Du et al., 2022). These findings support SFN potential as a natural therapeutic for both oxidative stress-induced skin aging and immune-mediated dermatologic conditions.

However, Petkovic et al., 2021; Du et al., 2022, & Ko et al., 2020 studies were limited by small sample sizes, single-strain models, variable doses (442.5 mg/kg vs. 55–110 μmol/kg), and the use of in vitro models that may not fully replicate in vivo physiology (Petkovic et al., 2021; Du et al., 2022; Ko et al., 2020). Omics-based studies carry risks of type I errors and limited validation (Du et al., 2025). Additional potential biases include unclear randomization, lack of blinding, reliance on histological and biochemical endpoints, and heterogeneity in aging induction methods (Petkovic et al., 2021; Zhang et al., 2025; Ko et al., 2020).

6.11. Urolithin

Urolithin A (UA) is a gut microbiome-derived metabolite of ellagic acid, produced from dietary ellagitannins in foods like walnuts, pomegranates, berries, and strawberries, and detected at high concentrations in blood and urine, suggesting it as the primary bioactive compound (Liu et al., 2019). UA exhibits potent antioxidant activity by scavenging ROS, inhibiting ROS-producing enzymes, and activating antioxidant systems including glutathione peroxidase (GPx), SOD, glutathione (GSH), and GST, thereby reducing oxidative stress and inflammation and maintaining skin cell integrity ((Zhao et al., 2023). UA also modulates inflammatory pathways, downregulating nitric oxide production and pro-inflammatory genes such as IL-6, TNF-α, IL-1β, iNOS, and COX-2 in both in vitro and in vivo models, and may support muscle repair, endurance, and recovery (Zhao et al., 2023; Chen et al., 2022).

D’Amico et al., 2023 conducted three randomized trials to assess topical UA on skin aging and UVB-induced photodamage. In aging study 1 (n=48), postmenopausal women applied 0.5% or 1% UA cream or placebo for 8 weeks in a split-face/arm design; 1% UA increased collagen synthesis pathways in skin biopsies and reduced wrinkle depth without affecting skin barrier. Aging study 2 (n=108) involved 1% UA in day cream, night cream, or serum in middle-aged men and women, resulting in significant wrinkle reduction and improved skin hydration (D’Amico et al., 2023). In a UVB-induced photo-damage trial, 1% UA topical application reduced erythema by ∼14%, whereas placebo and lower dose had no effect. UA also inhibited collagen-degrading and pro-inflammatory pathways while upregulating autophagy and mitophagy genes, supporting skin structure and longevity (D’Amico et al., 2023).

Liu et al., studied UA in senescent human skin fibroblasts, showing increased type I collagen, reduced MMP-1 and ROS via Nrf2-mediated antioxidative response, and induced G2/M cell cycle arrest without affecting senescence or apoptosis, confirming antiaging potential at the cellular level (Liu et al., 2019). Liu et al., demonstrated that UA protected dermal fibroblasts from UVA-induced photoaging by attenuating ROS accumulation, senescence markers, extracellular matrix breakdown, and cell cycle arrest, while activating NRF2-dependent antioxidant enzymes and mitophagy through the SIRT3-FOXO3-PINK1-PARKIN pathway (Liu et al., 2022).

Kuerec et al., systematically reviewed five human studies (n=250, 10–1000 mg/day, 28 days, & 4 months) and found UA produced dose-dependent anti-inflammatory effects, increased mitochondrial and autophagy-related gene expression, and enhanced muscle strength and endurance, without affecting ATP production, mitochondrial dynamics, gut microbiota, anthropometrics, cardiovascular outcomes, or physical function; adverse events were mild or moderate (Kuerec et al., 2024).

However, D’Amico et al. had small sample sizes (n=48 in the first trial) and short intervention durations (8 weeks), which may limit generalizability, and variability in adherence and formulations may introduce bias (D’Amico et al., 2023). Liu et al. provided mechanistic insights using in vitro fibroblasts, but these may not fully translate in vivo, and differences in UVA versus UVB protocols complicate comparisons (Liu et al., 2019, 2022). Kuerec et al. reviewed human oral UA trials, which were heterogeneous in doses (10–1000 mg/day), durations (28 days to 4 months), populations, and outcomes, limiting comparability (Kuerec et al., 2024). Some trials also lacked blinding and relied on surrogate endpoints, such as gene expression or short-term biomarkers, rather than long-term clinical outcomes, potentially affecting reliability (D’Amico et al., 2023; Liu et al., 2019, 2022; Kuerec et al., 2024).

6.12. Genistein

Genistein (4′,5,7-trihydroxyisoflavone) is a major isoflavone found in soybean seeds, with trace amounts in legumes such as garbanzo beans and chickpeas (Ganai & Farooqi, 2015). It protects skin cells against UV-induced damage by suppressing basal and UV-induced COX-2 expression in HaCaT keratinocytes, while in UVB-irradiated BJ-5ta fibroblasts it downregulates COX-2 and upregulates Gadd45, a DNA repair gene, supporting cellular repair. In human dermal fibroblasts repeatedly exposed to subcytotoxic UVB, genistein prevents senescence through antioxidant activity, inhibition of forkhead proteins, and downregulation of p66Shc (Jahan et al., 2022). Encapsulation in soybean asolectin liposomes (0–3.6 mg/mL) enhanced genistein’s antioxidant activity, reducing lipid peroxidation in 90.5% of C6 rat glioma cells. Genistein-modified polymeric hemodialysis membranes, including PES, polysulfone, and PVP, demonstrated potential therapeutic applications with superior antioxidant activity compared to mangiferin-modified formulations (Sharifi-Rad et al., 2021a). Genistein also protects red blood cells from hydrogen peroxide- or dialuric acid-induced hemolysis and inhibits Fe2+/ADP/NADPH-induced microsomal lipid peroxidation in rat liver mitochondria (Mazumder & Hongsprabhas, 2016).

Genistein and 17β-estradiol mitigate oxidative stress and preserve mitochondrial function in human fibroblasts and keratinocytes by modulating ERs, GPER30, NO signaling, and kinases. Savoia et al., 2018 exposed cells to genistein or 17β-estradiol under peroxidative conditions, with or without NOS inhibitors, ERs/GPER30 blockers (fulvestrant, G15), or PI3K-Akt, p38-MAPK, & ERK1/2 inhibitors. Both agents prevented ROS accumulation, maintained mitochondrial membrane potential and cell viability, increased GSH, and promoted proliferation, effects blocked by inhibitors, confirming involvement of ERs, GPER30, and kinase pathways. To improve bioavailability and UVA photoprotection, Harwansh et al., formulated genistein nanoemulsion (GN-NE2) and nanogel (GN-NG2). Ex vivo skin permeation and in vivo rat studies showed sustained release and enhanced UVA protection compared to conventional gels (Harwansh et al., 2025.

Polito et al., evaluated systemic genistein aglycone (1 and 10 mg/kg s.c.) versus raloxifene hydrochloride (0.05 & 0.5 mg/kg s.c.) and 17-α-ethinyloestradiol (0.003 & 0.03 mg/kg s.c.) in aged ovariectomized rats treated daily for 12 weeks, with OVX and sham controls. Untreated OVX rats showed decreased TGF-β1, VEGF, MMP-2, MMP-9, TIMP-1, and TIMP-2. All treatments restored these markers; 1 mg/kg genistein significantly increased collagen thickness and skin breaking strength, demonstrating efficacy comparable to estrogen (Polito et al., 2012).

Na Takuathung et al., conducted a randomized, double-blind, placebo-controlled trial in 50 postmenopausal women who applied a genistein-based topical product twice daily for 6 weeks. GEN improved skin hydration, reduced fine pore area, enhanced redness, and in women ≥56 years, significantly reduced wrinkle parameters (Na Takuathung et al., 2023). Widodo et al., compared antioxidant and anti-collagenase activity of genistein and epicatechin from Glycine max using ABTS and collagenase inhibition assays. Both compounds were active, with epicatechin outperforming genistein (IC50 ABTS: 14.39 µg/mL vs. 43.17 µg/mL; & IC50 collagenase: 9.08±3.46 µg/mL vs. 98.74±4.25 µg/mL), indicating superior anti-aging potential (Widodo et al., 2019).

However, Polito et al. used animal models with small sample sizes and subcutaneous dosing, which may not fully translate to humans, and assessed only select molecular and mechanical markers (Polito et al., 2012). Na Takuathung et al. conducted a small, short-term (6-week) trial in older women, limiting generalizability and the ability to detect long-term effects (Na Takuathung et al., 2023). Widodo et al. relied on in vitro assays, which do not account for bioavailability or systemic effects (Widodo et al., 2019). Additionally, variability in doses, protocols, and outcome measures across studies complicates direct comparisons and may introduce bias (Polito et al., 2012; Na Takuathung et al., 2023; Widodo et al., 2019).

6.13. Ferulic Acid

Ferulic acid ([E]-3-[4-hydroxy-3-methoxy-phenyl] prop-2-enoic acid) is a phenolic compound abundant in plants such as parsley, grapes, spinach, whole grains, rhubarb, sweet corn, and cereal seeds (Srinivasan et al., 2007). It exhibits potent antioxidant activity by scavenging free radicals, chelating transition metals like copper and iron, and inhibiting ROS-producing enzymes, thereby preventing hydroxyl radical formation and lipid peroxidation. FA stabilizes AMPK, contributing to cell survival, proliferation, stress tolerance, autophagy, and homeostasis (Neopane et al., 2023). Its antioxidant efficacy is enhanced through formation of resonance-stabilized phenoxyl radicals upon UV absorption, allowing FA to terminate free radical chain reactions and protect cells from UV-induced oxidative stress (Srinivasan et al., 2007; Zduńska et al., 2018).

In human fibroblasts exposed to UVA or UVB, FA reduces ROS generation, protects DNA, modulates DNA repair genes, regulates cell cycle alterations, and preserves mitochondrial function and cell viability. FA protects key skin structures, including collagen, elastin, fibroblasts, and keratinocytes, while inhibiting tyrosinase activity to limit melanogenesis (Zduńska et al., 2018). Clinical evaluations demonstrate FA’s efficacy in improving skin parameters. Zduńska-Pęciak et al., treated 20 women aged 45–60 with 14% FA peel in 8 weekly sessions, assessing hydration, melanin, erythema, and topography at baseline, 8, and 12 weeks using MPA and photo documentation. FA peel significantly enhanced all parameters, with maximal hydration and melanin reduction immediately after treatment and greatest erythema reduction one month later. Untreated areas showed no significant change (Zduńska-Pęciak et al., 2022.

Mancuso et al., compared W/O/W multiple emulsions with simple emulsions for topical FA delivery. Multiple emulsions demonstrated superior stability, controlled release, and effective protection against UVB-induced erythema in vivo (Mancuso et al., 2021). Kamila et al., combined 14% FA peel with microneedling in 16 women aged 45–60 across 8 sessions. Measurements of hydration, elasticity, melanin, and erythema before, after the 8th session, and one-month post-treatment showed significant improvements in all parameters, with combination therapy yielding enhanced effects on skin elasticity (Kamila et al., 2020).

Roux et al. reviewed 21 studies involving 468 adults treated with topical FA (0.5–1%), alone or with 15% L-ascorbic acid and 1% α-tocopherol, once or twice daily. Consistent improvements were observed in erythema, hyperpigmentation, hydration, elasticity, texture, and skin density. FA photoprotective and anti-aging effects are attributed to restoration of the antioxidant defense system. Daily use for 1–3 months appears effective, and future studies should explore optimization of delivery vehicles (Roux et al., 2022).

However, Mancuso et al. included a limited sample size and short intervention duration, which may reduce the generalizability of their findings (Mancuso et al., 2021). Kamila et al. studied only 16 women, lacked a control group, and had a relatively short follow-up of one month, limiting the ability to draw long-term conclusions (Kamila et al., 2020). Roux et al.’s review included heterogeneous studies in terms of FA concentration, combinations with other antioxidants, application frequency, and intervention duration, making direct comparisons difficult (Roux et al., 2022). Additionally, most studies focused on short-term biomarkers, such as erythema, hydration, and elasticity, rather than long-term clinical outcomes or adverse effects (Mancuso et al., 2021; Kamila et al., 2020; Roux et al., 2022).

7. Limitations

In this study, several limitations are noted. Most evidence is derived from in vitro and animal models, which may not fully replicate human skin physiology, limiting direct translatability. Many clinical studies have small sample sizes, short durations, or lack long-term follow-up, reducing the strength of efficacy and safety conclusions. Variability in formulations, concentrations, treatment protocols, and outcome measures complicates direct comparison across studies. Additionally, bioavailability and skin penetration of many phytochemicals remain suboptimal, and optimal delivery strategies are not standardized. Potential interactions with other topical or systemic agents are underexplored. Finally, publication bias toward positive results may overestimate benefits.

8. Future Directions

The future research should focus on conducting well-powered, long-term human trials to validate the efficacy and safety of plant-derived bioactive compounds for skin anti-aging. Optimizing formulation strategies, such as nanocarriers, multiple emulsions, and combination therapies, could enhance bioavailability, skin penetration, and sustained release. Comparative studies examining dose-response relationships, synergistic effects among phytochemicals, and interactions with conventional skincare agents are warranted. Mechanistic studies integrating omics approaches, proteomics, and network pharmacology may further elucidate molecular pathways involved in photoprotection, collagen synthesis, and antioxidative defense. Standardized outcome measures, including both objective skin parameters and patient-reported outcomes, will improve comparability and clinical relevance. Additionally, evaluating safety profiles in diverse populations, including varying ages, skin types, and comorbidities, is essential.

9. Conclusions

In this study, we provided a comprehensive review of plant-derived bioactive compounds, including ferulic acid, genistein, quercetin, rutin, resveratrol, curcumin, catechins, lycopene, and sulforaphane, and their effects on skin aging. Traditionally, phytochemicals have been used in herbal medicine and functional foods to maintain skin health, slow aging, promote wound healing, and manage inflammatory and pigmentary skin conditions. Phytochemicals protect the skin by preventing oxidative stress, reducing inflammatory signaling, and enhancing collagen and elastin synthesis. They also promote cellular repair, resulting in measurable improvements in hydration, elasticity, pigmentation, and reduction of wrinkles. This review showed decreases in ROS, MDA, and pro-inflammatory cytokines, along with increases in antioxidant enzyme activity, dermal thickness, and skin barrier function. Advanced formulation strategies, such as nanoemulsions, multiple emulsions, chemical peels, and microneedling, further enhance dermal delivery and bioavailability. Preclinical and clinical findings are promising, but further research is needed to optimize dosing, delivery systems, and long-term safety.