Herbal Anti-Aging Creams: Pathophysiology, Molecular Mechanisms, Formulation, and Testing: A Comprehensive Review

Aging represents a natural and progressive stage of human life that arises from the interaction of several biological processes. It is associated with a gradual decline in normal physiological efficiency and a higher risk of developing age-related conditions, including osteoporosis and neurodegenerative disorders such as Alzheimer’s disease. This process originates at the cellular level and continues over time, ultimately leading to the end of life [1]. Among the various dimensions of aging, biological changes are the most apparent, followed by psychological and social alterations. These changes commonly involve weakened immune defense mechanisms, degeneration of musculoskeletal tissues, and a decline in sensory perception [2–4].The progression of aging is influenced by both internal and external determinants. Internal or intrinsic aging is largely controlled by genetic programming and metabolic alterations, such as reduced collagen biosynthesis, mitochondrial damage, hormonal imbalance, and the accumulation of senescent cells. In contrast, external or extrinsic aging, often described as photoaging, is mainly driven by environmental and lifestyle factors. Continuous exposure to ultraviolet radiation, air pollutants, poor dietary patterns, tobacco use, and prolonged mental stress accelerates the formation of reactive oxygen species (ROS). The excess generation of ROS promotes oxidative stress, lipid membrane damage, protein modification, and increased formation of advanced glycation end products (AGEs). These molecular disturbances manifest clinically as visible skin aging, including fine lines, uneven pigmentation, dryness, and loss of skin firmness and elasticity [3,5].Historically, anti-aging interventions were largely confined to the management of cutaneous aging, as the skin is the most externally exposed organ and exhibits early, visible manifestations of aging. With the advancement of pharmaceutical and cosmetic sciences, contemporary anti-aging strategies have expanded to include topical synthetic agents and procedural interventions such as chemical peeling, laser resurfacing, microdermabrasion, and invasive approaches including botulinum toxin (Botox) injections and dermal fillers [6]. Although these modalities offer rapid cosmetic benefits, their pharmacological limitations include high cost, procedure-related adverse effects, and insufficient long-term safety data. Reported complications include erythema, allergic contact dermatitis, and post-inflammatory hyperpigmentation, which may compromise skin barrier integrity. Moreover, the extensive use of synthetic excipients, preservatives, and stabilizers in conventional formulations raises toxicological and environmental safety concerns, thereby limiting their prolonged use [7]. Consequently, there is increasing interest in therapeutic approaches that provide sustained skin protection with improved safety and tolerability profiles.

The global anti-aging market has expanded substantially, attaining an estimated valuation of approximately USD 216 billion in 2021 [7]. This growth is driven by increased pharmacological awareness, demographic aging, and rising consumer demand for preventive dermatological care. While middle-aged and elderly populations remain key consumers, younger individuals—particularly Millennials and Generation Z—are increasingly adopting “pre-aging” strategies. These include early pharmacological interventions such as consistent photoprotection, antioxidant supplementation, and lifestyle modification to delay the onset of molecular and structural skin damage. In parallel, male participation in dermatological and cosmetic pharmacotherapy has increased, reflecting broader acceptance of skin health maintenance across genders. Importantly, consumer preference is shifting toward natural, plant-based, and “clean-label” formulations that align with safety, sustainability, and ethical sourcing requirements [8–9].From a pharmacological perspective, natural products derived from medicinal plants represent promising alternatives to synthetic cosmetic agents in anti-aging therapy. Herbal formulations typically incorporate plant extracts, essential oils, and micronutrients such as vitamins A, C, and E, which possess well-documented antioxidant, anti-inflammatory, and photoprotective activities [10]. The therapeutic efficacy of these botanical agents is primarily attributed to their high content of bioactive phytochemicals, including flavonoids, phenolic acids, and terpenoids. These compounds exert their effects by scavenging reactive oxygen species, enhancing collagen biosynthesis, inhibiting inflammatory mediators, and maintaining epidermal barrier function [11]. Additionally, several plant-derived actives modulate intracellular signaling pathways involved in skin regeneration, cellular repair, and extracellular matrix homeostasis. For example, green tea polyphenols, grape-derived resveratrol, and turmeric curcumin have been extensively investigated for their ability to inhibit matrix metalloproteinases (MMPs), key enzymes responsible for collagen and elastin degradation in the dermis, thereby attenuating photo-induced skin aging [12].According to the World Health Organization, more than 20,000 medicinal plant species are utilized across 91 countries, representing a vast pharmacognostic resource for cosmetic and dermatological product development. Herbal-based formulations are generally considered pharmacologically milder, more biocompatible with skin physiology, and associated with a lower incidence of adverse reactions compared to synthetic compounds. Recent pharmacological research has increasingly explored the combination of herbal and synthetic ingredients to achieve synergistic therapeutic outcomes, integrating traditional medicinal knowledge with modern formulation science. Such hybrid systems aim to enhance efficacy while maintaining acceptable safety and stability profiles [12]. Furthermore, advances in pharmaceutical formulation technologies—including nanoencapsulation, lipid-based carriers, emulsification systems, and transdermal drug delivery platforms—have significantly improved the stability, skin penetration, and bioavailability of plant-derived actives in topical preparations.

This review critically examines plant-derived bioactive compounds employed in anti-aging cosmetic formulations from a pharmacological standpoint. It evaluates their mechanisms of action in skin hydration, pigmentation control, photoprotection, epidermal regeneration, and inflammation modulation. The review also compares the pharmacodynamic and safety profiles of natural products with conventional synthetic agents, highlighting both advantages and limitations. Emphasis is placed on the growing integration of herbal extracts into modern dermatological formulations to enhance therapeutic efficacy. Finally, the review underscores the need for rigorous pharmacological evaluation, standardization of herbal extracts, toxicological assessment, and well-designed clinical studies to support the development of safe, effective, and evidence-based natural anti-aging therapies.

PATHOPHYSIOLOGY OF SKIN AGING: A PHARMACOLOGICAL OVERVIEW

Skin aging is a gradual and complex biological phenomenon arising from the combined influence of inherent genetic mechanisms and cumulative environmental exposure. This process leads to progressive alterations in skin architecture, decline in cellular performance, and reduced regenerative efficiency. Clinically, these biological changes present as wrinkle formation, decreased elasticity, dryness, pigmentary irregularities, and impaired wound repair. At the molecular and cellular levels, skin aging is governed by interconnected mechanisms including oxidative imbalance, persistent low-grade inflammation, breakdown of the extracellular matrix, mitochondrial impairment, cellular senescence, and disruption of epidermal barrier function [13–15].

1. Intrinsic (Chronological) Skin Aging

Intrinsic aging reflects the natural, time-dependent decline in skin function that occurs irrespective of environmental influences. It is primarily regulated by genetic determinants, metabolic processes, and hormonal changes.

Within the epidermis, intrinsic aging is marked by a reduction in keratinocyte turnover, delayed cellular differentiation, and progressive epidermal thinning. Structural flattening of the dermo-epidermal junction compromises mechanical resilience and limits nutrient diffusion, thereby increasing vulnerability to mechanical stress [16]. A gradual decline in melanocyte number further contributes to irregular pigmentation patterns and reduced intrinsic photoprotection.

At the dermal level, aging is associated with diminished fibroblast viability and activity. This leads to reduced biosynthesis of structural proteins such as type I collagen and elastin, as well as decreased production of hydrophilic molecules including hyaluronic acid. The combined effect results in loss of dermal strength, elasticity, and moisture retention [17]. Reduced angiogenic capacity further restricts oxygen and nutrient supply to skin tissues.

Mitochondrial alterations are central to intrinsic aging. Accumulation of mitochondrial DNA damage enhances intracellular reactive oxygen species (ROS) generation and decreases ATP synthesis, promoting cellular senescence and programmed cell death [18]. Age-associated hormonal decline, particularly reduced estrogen levels, further accelerates collagen depletion, epidermal thinning, and delayed tissue repair [19].

2. Extrinsic Aging (Photoaging and Environmental Damage)

Extrinsic aging develops due to repeated exposure to environmental and lifestyle-related stressors and typically progresses more rapidly than intrinsic aging. Among these factors, ultraviolet (UV) radiation is the most potent accelerator of skin aging.

UV exposure induces excessive ROS formation within skin cells, exceeding endogenous antioxidant defense capacity. This oxidative burden activates redox-sensitive transcription factors, including activator protein-1 (AP-1) and nuclear factor-κB (NF-κB), which stimulate the expression of matrix metalloproteinases (MMPs) such as MMP-1, MMP-3, and MMP-9 [20]. These enzymes degrade collagen and elastin fibers in the dermal extracellular matrix, resulting in wrinkle development and structural weakening of the skin.

Additional environmental contributors—such as air pollution, tobacco smoke, inadequate nutrition, and chronic psychological stress—further intensify oxidative stress and inflammatory signaling. These exposures promote lipid peroxidation, protein modification, and DNA damage, accelerating premature aging changes. Clinically, extrinsic aging is characterized by deep wrinkles, hyperpigmentation, coarse texture, telangiectasia, and uneven skin coloration [21].

3. Oxidative Stress and Free Radical–Mediated Injury

Oxidative stress represents a unifying mechanism linking intrinsic and extrinsic aging pathways. Excessive ROS, including superoxide radicals, hydrogen peroxide, and hydroxyl ions, cause structural and functional damage to cellular membranes, proteins, and nucleic acids.

In aging skin, endogenous antioxidant defenses—such as superoxide dismutase, catalase, and glutathione peroxidase—are markedly diminished, leading to sustained redox imbalance [22]. Persistent oxidative stress not only induces direct molecular damage but also accelerates inflammatory responses, extracellular matrix degradation, and cellular senescence.

4. Advanced Glycation End Products (AGEs)

Advanced glycation end products arise from non-enzymatic reactions between reducing sugars and proteins or lipids. These compounds progressively accumulate in aging skin and form irreversible cross-links within collagen fibers, increasing tissue rigidity and reducing elasticity [23]. Binding of AGEs to their cellular receptor (RAGE) further stimulates ROS production and pro-inflammatory signaling, exacerbating skin aging and impairing tissue remodeling.

5. Chronic Inflammation and Inflammaging

Low-grade, persistent inflammation—referred to as inflammaging—is a defining feature of aged skin. Elevated expression of inflammatory mediators such as interleukin-1β, interleukin-6, and tumor necrosis factor-α has been consistently observed in aging tissues [24]. These cytokines enhance MMP activity while suppressing collagen synthesis, resulting in continuous degradation of the dermal matrix.

Sustained inflammation also compromises immune surveillance mechanisms, increasing susceptibility to infections and delaying wound healing.

6. Cellular Senescence and Stem Cell Decline

Cellular senescence is characterized by irreversible growth arrest accompanied by profound metabolic and secretory alterations. Senescent skin cells release a range of cytokines, proteolytic enzymes, and growth factors collectively termed the senescence-associated secretory phenotype (SASP) [25]. SASP amplifies local inflammation, disrupts extracellular matrix integrity, and negatively affects neighboring cells.

Concurrently, depletion and functional impairment of epidermal stem cells reduce regenerative capacity, contributing to epidermal thinning and delayed tissue repair.

7. Disruption of Skin Barrier Integrity

Aging significantly alters the lipid architecture of the stratum corneum, particularly levels of ceramides, cholesterol, and free fatty acids. These changes result in increased transepidermal water loss (TEWL), reduced hydration, and compromised barrier function [26]. Barrier impairment heightens skin sensitivity and predisposes aged skin to irritants, allergens, and microbial invasion.

8. Pharmacological Significance in Anti-Aging Herbal Creams

The complex and interconnected nature of skin aging underscores the need for multitargeted therapeutic strategies. Herbal anti-aging creams are pharmacologically relevant due to their ability to influence multiple aging mechanisms simultaneously. Medicinal plant extracts are rich in flavonoids, phenolic compounds, terpenoids, vitamins, and antioxidants that neutralize ROS, suppress inflammatory mediators, inhibit MMP activity, and stimulate collagen biosynthesis [27].

Many plant-derived bioactives modulate key intracellular pathways, including MAPK, NF-κB, and TGF-β signaling, thereby supporting skin regeneration and preservation of extracellular matrix structure. Furthermore, herbal formulations enhance barrier repair and hydration while demonstrating improved safety and tolerability profiles compared with synthetic agents, making them suitable for long-term anti-aging interventions [28].

“The interconnected biological mechanisms underlying skin aging and their modulation by herbal bioactives are summarized schematically below.”

MOLECULAR MECHANISMS OF SKIN AGING AND THEIR PHARMACOLOGICAL MODULATION BY HERBAL ANTI-AGING AGENTS

Skin aging is controlled by an intricate interplay of molecular processes that gradually disturb cellular equilibrium, intracellular signaling, and extracellular matrix (ECM) stability. These alterations develop over time as a consequence of both genetically programmed changes and continuous environmental exposure, ultimately leading to progressive loss of skin structure and function. A detailed understanding of these molecular events is fundamental for the development of effective anti-aging strategies, particularly herbal-based therapies that exert therapeutic effects through multiple biological targets rather than a single pathway.

1. Oxidative Stress–Induced Molecular Injury

Oxidative stress represents one of the earliest and most influential molecular triggers of skin aging. Excess production of reactive oxygen species (ROS), such as superoxide radicals, hydroxyl radicals, and hydrogen peroxide, disrupts intracellular redox balance and compromises normal cellular function [29]. These highly reactive molecules interact with essential biomolecules, including lipids, proteins, and nucleic acids, resulting in cumulative molecular damage.

Peroxidation of membrane lipids reduces membrane stability and interferes with receptor-mediated signaling, while oxidative modification of proteins leads to loss of enzymatic activity and structural integrity. Damage to nuclear and mitochondrial DNA activates repair pathways which, when persistently overstimulated or insufficient, drive cells toward senescence or programmed cell death [30]. In aged skin, the decline in endogenous antioxidant defenses—such as superoxide dismutase, catalase, and glutathione peroxidase—further intensifies oxidative injury and accelerates aging-related degeneration.

2. Activation of MAPK Signaling Cascades

Mitogen-activated protein kinase (MAPK) pathways are key molecular mediators that convert oxidative and ultraviolet-induced stress into cellular responses. ROS activate MAPK family members, including extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 MAPK, initiating downstream transcriptional changes [31].

JNK and p38 signaling promotes phosphorylation of activator protein-1 (AP-1), a transcription factor that simultaneously suppresses collagen gene transcription and enhances expression of matrix metalloproteinases (MMPs). This combined effect accelerates breakdown of the dermal matrix while impairing its repair, positioning MAPK signaling as a central contributor to molecular skin aging [32].

3. NF-κB–Driven Inflammatory Signaling

Nuclear factor-κB (NF-κB) functions as a master regulator of inflammatory gene expression and exhibits sustained activation in chronologically aged and photo-damaged skin. Environmental stressors and oxidative imbalance trigger NF-κB translocation into the nucleus, resulting in enhanced production of inflammatory cytokines such as interleukin-1β, interleukin-6, and tumor necrosis factor-α [33].

Persistent activation of this pathway creates a pro-inflammatory tissue environment that increases MMP synthesis, inhibits collagen production, and weakens immune regulation. This prolonged, low-grade inflammatory state—commonly described as inflammaging—plays a substantial role in the gradual deterioration of skin structure and function [34].

4. Matrix Metalloproteinase Overactivity and ECM Breakdown

Matrix metalloproteinases are zinc-dependent proteolytic enzymes responsible for physiological ECM remodeling. During skin aging, MMP-1, MMP-3, and MMP-9 are excessively expressed as a consequence of AP-1 and NF-κB activation [35].

Uncontrolled MMP activity causes fragmentation of collagen and elastin fibers, leading to loss of dermal strength and elasticity. Moreover, degraded collagen fragments impair fibroblast attachment and signaling, further reducing new matrix synthesis and creating a self-sustaining cycle of ECM deterioration [36].

5. Inhibition of Transforming Growth Factor-β (TGF-β) Signaling

Transforming growth factor-β (TGF-β) plays a pivotal role in maintaining dermal homeostasis by stimulating fibroblast proliferation and collagen production through Smad-dependent signaling. In youthful skin, this pathway supports tissue repair and matrix renewal. However, during aging, oxidative stress and inflammatory mediators downregulate TGF-β receptor expression and disrupt Smad activation [37].

As a result, collagen synthesis declines and wound healing capacity is reduced. Restoration or enhancement of TGF-β signaling is therefore considered an important pharmacological target in anti-aging interventions.

6. Mitochondrial Impairment and Energy Depletion

Mitochondria act as both generators and victims of oxidative stress. With advancing age, accumulation of mitochondrial DNA mutations compromises the efficiency of the electron transport chain, leading to elevated ROS production and diminished ATP synthesis [38].

Insufficient cellular energy supply weakens repair mechanisms, promotes apoptotic signaling, and accelerates senescence in keratinocytes and fibroblasts. Consequently, mitochondrial dysfunction serves as a key amplifier that links oxidative stress to multiple downstream aging pathways.

7. Cellular Senescence and SASP Development

Cellular senescence is defined by irreversible growth arrest accompanied by profound changes in gene expression and secretory behavior. Senescent skin cells release a mixture of cytokines, proteases, and growth factors collectively termed the senescence-associated secretory phenotype (SASP) [39].

SASP factors intensify inflammation, enhance ECM degradation, and impair the function of surrounding healthy cells. Progressive accumulation of senescent keratinocytes and fibroblasts markedly reduces the regenerative potential of aging skin.

8. AGE–RAGE Signaling Axis

Advanced glycation end products (AGEs) are formed through non-enzymatic reactions between sugars and proteins or lipids and accumulate steadily with age. In the skin, AGEs form irreversible cross-links within collagen fibers, increasing tissue rigidity and reducing elasticity [40].

Interaction of AGEs with their receptor (RAGE) activates intracellular ROS production and NF-κB signaling, thereby amplifying inflammation and matrix degradation. The AGE–RAGE pathway represents a crucial molecular connection between metabolic dysregulation and skin aging.

9. Pharmacological Actions of Herbal Anti-Aging Agents

Herbal anti-aging agents demonstrate pharmacological efficacy by simultaneously modulating multiple molecular targets involved in skin aging. Bioactive plant constituents such as polyphenols, flavonoids, terpenoids, and vitamins exhibit strong antioxidant activity, directly neutralizing ROS and restoring redox balance [41].

Many phytochemicals suppress MAPK and NF-κB signaling, resulting in decreased MMP expression and reduced inflammatory mediator release. Certain herbal compounds enhance TGF-β signaling, promoting collagen synthesis and fibroblast proliferation. Additionally, plant-derived bioactives support mitochondrial function and limit cellular senescence, thereby contributing to sustained skin regeneration [42].

The ability of herbal formulations to act on diverse molecular pathways, coupled with their favorable safety profiles, supports their suitability for long-term topical use in anti-aging pharmacotherapy.

“A simplified schematic summarizing the key molecular mechanisms of skin aging and their pharmacological modulation by herbal anti-aging agents is represented below.”

Mechanistic Schematic: Molecular Pathways of Skin Aging and Herbal Pharmacological Modulation

Pharmacological Intervention by Herbal Anti-Aging Agents

FORMULATION OF ANTI-AGING HERBAL CREAM

Rationale for formulation design

The formulation of an anti-aging herbal cream requires integration of pharmacological principles with pharmaceutical formulation science. Skin aging is associated with enhanced oxidative stress, persistent low-grade inflammation, degradation of extracellular matrix components, reduced fibroblast function, and impairment of the skin barrier. These biological changes collectively contribute to wrinkle formation, loss of elasticity, and uneven skin texture. Therefore, an effective formulation should deliver herbal bioactive constituents in a stable and bioavailable form while maintaining skin compatibility and long-term safety (43,44).

Herbal anti-aging formulations offer a multi-targeted therapeutic approach by combining antioxidants, anti-inflammatory agents, collagen-protective compounds, and skin-repairing phytoconstituents. An oil-in-water (O/W) emulsion system is commonly preferred because it supports incorporation of both hydrophilic and lipophilic herbal extracts, provides good spreadability, and ensures patient acceptability for prolonged topical use (45).

Selection of herbal active ingredients

Herbal plants incorporated into anti-aging creams are selected based on traditional medicinal use and supported by experimental pharmacological evidence. Antioxidant-rich plants such as green tea, grape seed, pomegranate, turmeric, amla, and holy basil are widely used to counteract oxidative damage caused by reactive oxygen species. These plants have been reported to reduce lipid peroxidation and protect collagen and elastin fibers from oxidative degradation (43,46–48).

Anti-inflammatory and soothing herbs, including aloe vera, calendula, chamomile, licorice, and neem, are frequently included to suppress inflammatory mediators, reduce skin irritation, and promote tissue repair. Their ability to improve skin barrier function further contributes to delaying visible signs of aging (44,45).

Collagen-supportive and regenerative herbs such as Centella asiatica, ginseng, rosehip, papaya leaf, and marigold flower are known to enhance fibroblast activity, inhibit matrix metalloproteinases, and promote dermal remodeling. These properties make them valuable components of anti-aging herbal creams aimed at improving skin firmness and elasticity (43–45).

Medicinal Plants Commonly Incorporated in Anti-Aging Herbal Creams and Their Pharmacological Significance

Standardization and concentration of herbal extracts

For pharmacological relevance and reproducibility, herbal extracts used in anti-aging creams should be standardized using appropriate markers such as total phenolic content, flavonoid content, or specific phytoconstituents. Hydroalcoholic extraction is commonly preferred, as it allows efficient extraction of both polar and moderately lipophilic compounds. Standardization ensures consistency in biological activity and strengthens the scientific validity of the formulation (45).

In polyherbal formulations, individual extracts are typically incorporated at concentrations ranging from 0.2–2% w/w, while the total herbal content is maintained between 2–5% w/w to minimize the risk of irritation, instability, and formulation incompatibility (45).

Typical composition of an anti-aging herbal cream (O/W type)