Effective Topical and Oral Treatments for Skin Aging: Review

The utilization of both systemic and topical treatments in dermatology with the expectation that their combination will enhance attributed benefits and provide preventive dermatology has gained interest. In order to identify effective combined treatments for skin aging, a systematic review was conducted, which comprehensively searched the Capes Journal Portal of E-Journals. Out of the 4543 articles evaluated, only 24 were deemed eligible for final analysis. The findings were characterized as clinical studies that evaluated various combinations of treatments. It was concluded that the efficacy of collagen peptides, antioxidants, moisturizers, and lifestyle changes in mitigating skin aging resulted in improvements in the firmness, elasticity, hydration, and antioxidant protection of human skin.


INTRODUCTION
The utilization of systemic and topical treatments in dermatology has been in practice for decades, though there are still controversies regarding the efficacy of this strategy in preventing aging. The most common practice is to use these treatments separately, either via oral or topical dermatological route. An example of separate and proven effective use is the use of oral isotretinoin or topical retinoic acid for treating acne vulgaris. These treatments not only control the disease but also provide anti-aging benefits 1 . Oral vitamin D has been indicated for patients with psoriasis who need this supplementation 2 and consumption of fatty acids has been shown to improve the barrier function of the skin of menopausal women 3 .
Nutritionists, dermatologists and pharmacists are the main prescribers of nutricosmetics, nutraceuticals, and cosmeceuticals 4 for the prevention and treatment of skin aging. Nutricosmetics, nutraceuticals, and cosmeceuticals can be used in isolation or in combination, when the combination is performed, it is called "in-out" treatment (inside and out), with the expectation that the combination enhances the benefits attributed and thus have a preventive dermatology.
This knowledge extends to the prevention of skin aging, which can be increased when there is the combined use of specific nutrients, such as vitamins A, E and C, in addition to minerals such as zinc, copper and selenium, among others, which increase the antioxidant defenses of the skin and consequently its resistance to ultraviolet radiation 5,6 .
Certain functional foods, also called nutricosmetics, containing polyphenols, antioxidant vitamins, peptides and other substances can promote skin improvement 7 .
Antioxidants have been widely used in dermatology and are indicated for photoaging, melasma, psoriasis, alopecia and skin cancer prevention 8,9 . They are important for the redox balance of the skin and preventing damage caused by free radicals arising from exposure to ultraviolet radiation and pollution 10

DISCUSSION
Our systematic review identified 24 articles reporting on clinical studies examining the effectiveness of oral and/or topical active substances for skin disorders or skin aging ( Figure 1 and Table 1).
We have specifically focused on those studies which were conducted on human participants, regardless of the type or number of active substances used. The studies examined collagen peptides, vitamins, minerals, antioxidants, and herbal compounds,

Collagen Peptides
The biomechanical properties of the dermis are primarily determined by its structural components, which include collagen, elastin, and ground substance. Collagen, in particular, is essential for skin firmness 14 , which may explain why numerous studies have examined the cutaneous effects of oral collagen supplementation. Collagen peptides are classified as nutraceuticals and are believed to contribute to increased skin firmness, thereby making them suitable for use in anti-aging treatments 15 .
Hydrolyzed collagen is commonly used in cosmetic applications due to its high biocompatibility, ease of biodegradability, and low antigenicity. It is a safe biomaterial that possesses antioxidant properties and has been shown to effectively moisturize the skin 16 .
In this context, a study examined the clinical efficacy of a dermocosmetic formulation containing di and tripeptides, as well as the effects of an oral supplementation based on hydrolyzed collagen in women aged 40 to 50 years old 17 . The topical formulation produced a significant increase in the stratum corneum water content and skin elasticity after 28 days, while oral supplementation improved skin elasticity and had a more pronounced effect on the echogenicity of the dermis, resulting in reduced skin pores after 90 days. The authors of this study considered the results of oral supplementation and topical application to be complementary in improving the overall condition of the skin, acting on different mechanisms.
A similar outcome was observed in a randomized, placebo-controlled study involving women over 35 years of age. The study revealed that oral supplementation of collagen peptides, along with other nutrients, improved skin hydration and elasticity, reduced wrinkles, and increased skin density for at least three months. In this doubleblind, randomized, placebo-controlled trial, a mixture of 2.5g of collagen peptides, acerola fruit extract, vitamin C, zinc, biotin, and a vitamin E complex was administered, resulting in increased skin hydration, improved elasticity, wrinkle reduction, and increased skin densit 18 . Another double-blind, randomized, placebo-controlled study evaluated the effect of low-molecular-weight collagen peptides on 64 participants who were administered the supplement daily for three months. The study concluded that these peptides can be used as a functional ingredient to improve skin hydration, elasticity, and wrinkles in humans 19. The randomized, double-blind, placebo-controlled crossover trial conducted on 59 female volunteers who received amino acid supplementation for six weeks, allowed for the conclusion that there was a significant increase in the improvement of skin texture

Antioxidants
Antioxidant compounds were also prominent in the eligible studies for this review.
One randomized clinical trial evaluated the oral supplementation of superoxide dismutase, an essential enzyme in antioxidant defense, for a period of 60 days. The study found a significant increase in total antioxidant status, a reduction in transepidermal water loss (TEWL), and an improvement in skin with reduced dryness 23 .
Oral antioxidant supplementation has been shown to have skin benefits, particularly in terms of increased photoprotection, with botanical compounds and vitamins demonstrating photoprotective effects 24 . In a study of Caucasian individuals aged 18 to 50 years, the effects of oral supplementation and topical administration of a concentrate obtained from melon were evaluated, and it was found that the use of this Carotenoids, such as beta-carotene, lycopene, astaxanthin, and lutein, have been found to have free radical scavenging effects that are crucial for combating skin aging.
They can be utilized as nutraceuticals, cosmeceuticals, and photoprotectors due to their antioxidant, anti-inflammatory, and immunomodulatory properties, which increase protection against ultraviolet radiation and contribute to the skin's youthful and healthy appearance. A diet rich in fruits and vegetables provides numerous benefits to public health, including disease prevention, and the use of nanotechnology to deliver these active compounds in the body is a critical area for developing new delivery systems that should be extensively explored in the future 28 .
Authors have also evaluated the effects of vitamin C derivatives such as Trisodium Thus, this topical treatment can be a beneficial strategy to deliver ascorbic acid and improve the physiology of damaged skin 29 . An oral antioxidant supplement containing marine protein, vitamin C, grape seed extract, zinc, and tomato extract was evaluated in another study. This 210-day study involved 47 volunteers. The results showed an increase in dermis density, facial hydration, and a reduction in pH, as well as an increase in collagen and elastin fibers, indicating excellent results for skin anti-aging 34 .

Effective Topical and Oral Treatments for Skin
In addition to antioxidants, protecting mitochondrial DNA is important in preventing skin aging. Substances such as vitamins C and E, coenzyme Q10, as well as antiinflammatory ingredients like argan oil, caffeine, chamomile, feverfew, green tea, licorice extract, aloe, linoleic acid, and niacinamide have shown significant effects against ultraviolet radiation 35 . Oral administration of glutathione at a dose of 250mg/day for 12 weeks has also been shown to reduce wrinkles and increase skin elasticity 36 .
Ghafarzadeha and Eatemadi 37  In summary, prescribed treatments target the physiological processes of skin aging and have been clinically proven to effectively modify the skin's structure and appearance 39 .

Skin Hydration
Supplementing with hyaluronic acid has been shown to be useful for skin hydration 40 . In one clinical study, a supplement containing hyaluronic acid, biotin, vitamin C, copper, and zinc was administered to women aged 45 to 60 with healthy skin once daily for 40 days. Results showed a significant increase in skin elasticity and hydration, as well as a significant decrease in roughness and depth of wrinkles. The supplement was well-tolerated with no observed side effects throughout the study 41 .
Another study evaluated a combination of 200mg hyaluronic acid, 500mg L-carnosine, and 400mg methylsulfonylmethane, or a placebo, in 50 women aged 40 to 65 with photoaging for 60 days. The combination supplement showed significant improvement in reducing the periocular region 42 . centenarians. The foundations for a long life are multifactorial, and while genetics play a strong role, they are not the only factors 47 . Microbial changes in the gut have also been linked to age-related diseases and immune response, emphasizing the importance of ingesting probiotics and maintaining a healthy diet for the gut microbiota. Nutrition plays a crucial role in healthy aging and can impact the prevention of aging-related diseases, including sarcopenia and cognitive decline 48 .
Upon conducting a comprehensive evaluation of the results obtained in the reviewed studies, it is evident that the majority of them demonstrate a high level of scientific evidence as they are randomized, double-blind, and placebo-controlled.
Furthermore, these studies involved middle-aged and elderly adults, who are the population groups that would benefit the most from the proposed interventions. As a result, the combination of topical treatments containing antioxidant compounds, along with oral administration of collagen peptides, diverse antioxidants, and botanical compounds may be a promising approach for improving the structure of human skin.
These interventions may also have a positive impact on self-esteem and quality of life.

FINAL CONSIDERATIONS
Several clinical studies have demonstrated the effectiveness of both topical and oral treatments in preventing skin aging and improving skin conditions. Collagen peptides and various antioxidants, administered topically and orally, have been extensively studied and their efficacy in improving human skin has been proven, with increased firmness, elasticity, skin hydration, and antioxidant protection. As such, young adults can benefit from their use to maintain healthy skin and slow the aging process, particularly if they combine these treatments with a healthy lifestyle.

Conflicts of Interest:
The authors declare no conflict of interest.