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Vol. 114. Núm. 2.
Páginas T114-T124 (febrero 2023)
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[Translated article] Oral Supplementation and Systemic Drugs for Skin Aging: A Narrative Review
Tratamiento mediante suplementación oral o fármacos sistémicos del envejecimiento cutáneo. Revisión narrativa de la literatura
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D. Morgado-Carrascoa,
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morgadodaniel8@gmail.com

Corresponding author.
, J. Gil-Lianesa, E. Jourdainb, J. Piquero-Casalsc
a Dermatology Department, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain
b Innovation and Development, ISDIN, Barcelona, Spain
c Dermik, Clínica Dermatológica Multidisciplinar, Barcelona, Spain
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D. Morgado-Carrasco, J. Gil-Lianes, E. Jourdain, J. Piquero-Casals
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Abstract

Skin aging is influenced by intrinsic and extrinsic factors and involves multiple pathogenic mechanisms. The most widely used treatments are topical products and minimally invasive procedures. Evidence on the benefits of systemic therapy is limited for several reasons: reliance on mostly small and predominantly female samples, short study durations, methodologic heterogeneity, and a lack of consensus on which outcome measures are clinically relevant. Furthermore, systemic drugs and oral supplements are not without adverse effects. Oral hydrolyzed collagen and oral hyaluronic acid are well tolerated, and numerous clinical trials show they can mitigate some signs of skin aging. Low-dose oral isotretinoin is another option, but it has a higher risk of adverse effects. Evidence is lacking on the effects of the many dietary supplements on offer, such as vitamins, flavonoids, plant extracts, and trace elements. The future of skin aging management would appear to lie in the use of senolytic and senomorphic agents targeting senescent cells in the skin.

Keywords:
Photoaging
Skin aging
Oral hydrolyzed collagen
Hyaluronic acid
Treatment
Oral
Resumen

El envejecimiento cutáneo está influido por factores intrínsecos y extrínsecos y múltiples mecanismos patogénicos están involucrados. Los tratamientos utilizados en la actualidad son sobre todo tópicos o son procedimientos mínimamente invasivos. La evidencia sobre la utilidad de la terapia sistémica es limitada: los estudios son en su mayoría de pequeño tamaño, de reducida duración, incluyen a mujeres de manera mayoritaria, la metodología de evaluación es heterogénea y no hay parámetros consensuados de respuesta clínica relevante. Además, los suplementos o fármacos sistémicos no están exentos de efectos adversos. El colágeno hidrolizado oral y el ácido hialurónico oral son bien tolerados y múltiples ensayos clínicos muestran que pueden mitigar algunos signos de envejecimiento cutáneo. La isotretinoína oral en dosis bajas es otra alternativa, pero con un mayor potencial de efectos adversos. Múltiples suplementos, como vitaminas, flavonoides, diversos extractos de plantas y oligoelementos presentan escasa evidencia clínica. El futuro del manejo del envejecimiento cutáneo parece ser el tratamiento con agentes senolíticos o senomórficos dirigidos específicamente contra células cutáneas senescentes.

Palabras clave:
Fotoenvejecimiento
Envejecimiento cutáneo
Colágeno hidrolizado oral
Ácido hialurónico
Tratamiento
Oral
Texto completo
Introduction

Skin aging is characterized by wrinkles, sun spots, an uneven skin tone, decreased elasticity, increased skin fragility and visible capillaries, impaired healing, and an increased incidence of skin cancer and infections.1 It is influenced by both intrinsic and extrinsic factors involving multiple pathogenic mechanisms (Table 1) (Fig. 1). Extrinsic aging is predominantly influenced by sun exposure (photoaging), although smoking and pollution also play a role.1 Intrinsic and extrinsic aging overlap in clinical practice.1 Demand for strategies to mitigate the signs of skin aging is high.2 Recent studies suggest that regular exercise, apart from improving quality of life and reducing the risk of mortality and chronic disease,2 might also reduce the thickness of the stratum corneum and improve dermal thickness and collagen content.3 Diet is also important, with a number of studies highlighting its role in the prevention of aging. Dietary antioxidants such as vitamin C and linoleic acid are considered important.4 Several studies have shown that calorie-restricted diets (without the loss of essential nutrients) and intermittent fasting have antioxidant and anti-inflammatory effects and associated health benefits. Animal model studies have shown that calorie restriction and fasting might reduce skin aging.5

Table 1.

Molecular Mechanisms of Skin Aging.

Molecular mechanism  Impact 
Oxidative stress  Induction of matrix metalloproteinasesIncreased production of proinflammatory cytokinesIndirect DNA damageMitochondrial damage 
Telomere shortening  Cellular senescence 
Altered micro-RNA expression and dysregulated gene expression  Dysregulation of apoptosisAltered collagen gene expression 
Increased proinflammatory state  Relative immunosuppressionAngiogenesisCell proliferation 
Apoptosis dysfunction  Cellular senescenceProtumor state 
Direct UVB radiation–induced DNA damage  Formation of mutagenic photoproducts 
Figure 1.

Skin changes induced by intrinsic and extrinsic aging (exposome). Aged skin is characterized by an atrophic epidermis, with senescent keratinocytes and melanocytes and a flattened basement membrane. Other features include a significantly reduced papillary dermis, senescent fibroblasts, significant extracellular matrix (ECM) remodeling, and subcutaneous tissue thinning.

(0,28MB).

Numerous skin aging treatments exist, and mostly consist of topical products (e.g., retinoids, α-hydroxyacids, broad-spectrum sunscreens, and antioxidant/anti-inflammatory agents, such as preparations containing vitamin C, vitamin E, and niacinamide6) and invasive or minimally invasive procedures (e.g., ablative and nonablative laser therapy, intense pulsed light therapy, radiofrequency, dermabrasion, and chemical peels). Consensus is lacking on the use of oral supplements and systemic treatments for skin aging and photoaging. In this article, we review the current evidence on the use of these treatments in the setting of skin aging and photoaging.

Material and Methods

For this narrative review, we searched for articles published in PubMed and Google Scholar between January 1, 1990 and March 2022 using the keywords oral, systemic treatment, treatment, therapy, skin aging, photoaging, oral collagen, isotretinoin, tranexamic acid, Polypodium leucotomos, niacinamide, antioxidants, metformin, hormonal replacement therapy, melatonin, flavonoids, vitamin, vitamin C, vitamin E, vitamin D, senolytics, hyaluronan, hyaluronic acid, glucosamine, coenzyme Q10, glutathione, marine complex, pine bark extract, food supplements, aloe vera, and Hydrangea serrata. We included prospective studies and randomized clinical trials (RCTs) published in English or Spanish. No limits were placed on the number of study participants. After screening the abstracts of the articles retrieved, 2 of the authors (DMC and JPC) performed a full-text review to select relevant articles.

Results

The results of the most relevant studies analyzing diverse compounds used in the treatment of skin aging are summarized below.

Oral Isotretinoin

Isotretinoin is a retinoid widely used in the treatment of acne and many other skin conditions. In addition to its comedolytic, sebum-regulating, and anti-inflammatory properties, it appears capable of inhibiting extracellular matrix metalloproteinases and increasing collagen type I and III production.7 In a prospective study, 20 individuals were administered oral isotretinoin 20mg 3 times a week for 12 weeks. Skin biopsies performed before and after treatment and 12 weeks later showed a significant increase in collagen and elastic fiber density. Sixty-five percent of the participants showed histologic improvements in the appearance and distribution of elastic fibers, while they all reported improvements in perceived skin quality.8

Two earlier studies had shown both histologic improvements (solar elastosis) and clinical improvements (reduced wrinkle depth and improved skin texture and color).9,10 No clinical or histologic differences, however, were detected in an RCT (n=32) comparing oral isotretinoin (20mg 3 times/wk) combined with sunscreen and moisturizer and sunscreen and moisturizer alone.11 The authors of a more recent systematic review of 6 studies (including 3 RCTs, Table 2) (n=251) concluded that isotretinoin might be a useful treatment for skin aging.7 There is, however, insufficient evidence to recommend oral isotretinoin over topical treatments. Potential adverse effects, such as mucocutaneous dryness, lipid and liver changes, and teratogenicity, must also be taken into account.

Table 2.

Randomized Clinical Trials Evaluating the Use of Oral Isotretinoin (ISO) in the Treatment of Skin Aging.

Author/y  No. of patients  Intervention  Main results 
Hernández-Pérez et al., 200087  120  Oral ISO 10–20mg 3 times/wk for 2moa  Improvement of wrinkles, pore size, and hyperpigmentation. Increased skin thickness, elasticity and tone. 
Rabello-Fonseca et al., 200910  30  Oral SO 10mg vs. 20mg 3 times/wk for 3mo  No significant differences between groups. Good/excellent subjective rating of results by patients and researchers in both groups. Microscopic findings showing an increase in collagen fibers (P<.05) and a tendency toward decreased elastosis. 
Bagatin et al., 201011  32  Oral ISO 20mg 3 times/wk and topical sunscreen for 3mo vs. topical sunscreen  No clinical or histologic differences (epidermal thickness, number of elastic fibers, and dermal collagen) between groups. Significant reduction in epidermal p53 expression in ISO group. 
Bagatin et al., 201488  24  Oral ISO 20mg/d vs. topical retinoic acid 0.05% for 6mo  Improvements in both groups for clinical, histologic (decreased stratum corneum, increased epidermal thickness, and reduced elastosis) and immunohistochemical (reduced p53, increased dermal collagen) findings. Nonsignificant differences (P>.05) 
Ianhez et al., 201989  61  ISO 10mg/d vs. tretinoin 0.05% cream every 48h for 6mo  No significant differences between groups. Both groups showed an improvement in number of actinic keratoses, histologic variables (decreased stratum corneum, increased epithelial thickness), and immunohistochemical variables (decreased expression of p53 and bax and increased expression of bcl2) 
a

Both groups of patients received other treatments for photoaging (peeling, laser, botox, liposuction), but strict control of the distribution of treatments between groups and the statistical analysis was lacking.

Oral Supplementation With Hydrolyzed Collagen

Collagen is the main structural protein in the skin, accounting for 75% of the total weight of the extracellular matrix. Hydrolyzed collagen used in oral supplements is obtained through the enzymatic hydrolysis of natural collagen from various sources, such as fish, pork, and chicken.12 When digested, it is broken down into dipeptides and tripeptides, which are absorbed into the bloodstream through the gastrointestinal tract and largely deposited in the skin. These dipeptides stimulate the metabolism, migration, and proliferation of fibroblasts and generate increased collagen and hyaluronic acid production.12–14 There is a growing interest in hydrolyzed oral collagen supplements, especially in powder forms.15 The effects of hydrolyzed collagen supplementation on skin aging were evaluated in a systematic review and meta-analysis of 19 double-blind RCTs12 involving 1125 individuals. The doses ranged from 372mg to 12g a day, and in most of the trials, the participants received a daily dose of 2.5 to 5g over a period of 8 to12 weeks. The vast majority of trials showed improved skin elasticity and a reduction in facial wrinkles following treatment. The benefits were maintained for approximately 30 days after the end of the treatment, and no adverse effects were observed. Some of the RCTs detected a reduction in skin fragility in hospitalized elderly patients after nursing procedures and improved healing after laser procedures. The meta-analysis showed significant associations between hydrolyzed collagen supplementation and an increase in skin density (z=0.48, P=.002), elasticity (z=2.31, P=.02), and hydration (z=2.58, P=.010) and a significant reduction in facial wrinkles (z=−1.11, P=009). The meta-analysis was limited by the heterogeneity of the data pertaining to the collagen supplements used (origin, composition, concentration, formulation, and vehicles [solid vs. liquid]).

A more recent RCT (n=46) (Table 3) not included in the above meta-analysis showed a significant increase in the echogenicity of the dermis in individuals treated with hydrolyzed collagen for 90 days. Confocal microscopy also showed a reduction in elastosis and improved collagen fiber appearance.16 In another double-blind RCT (n=99), daily oral supplementation with 1g or 5g of collagen was associated with a significant increase in stratum corneum water content in both groups and a reduction in transepidermal water loss in the 5-mg group.17

Table 3.

Supplementation With Hydrolyzed Collagen for the Treatment of Skin Aging: Randomized Clinical Trials Not Included in or Published After the Meta-analysis by De Miranda et al.a (2021).

Author, y  No. of patients  Intervention  Main results 
Kim et al., 201880  64  1g/d hydrolyzed collagen for 12wk  Improvement in skin hydration and elasticity. Reduction in periocular wrinkles. 
Evans et al., 202181  50  10g/d hydrolyzed collagen (fish) for 12wk  Decrease in wrinkles (-15%). Increased skin elasticity (+23%), hydration (+14%), and firmness (+25%). 
Lin et al., 202090  50  5–5.5g/d hydrolyzed collagen (fish)+1g Djulis extractb for 8wk  Improved skin hydration (+17.8%) and brightness (+5.4%). Reduction in periocular wrinkles (-14.9%) and pores (-9.9%). Increased dermal collagen (+22.3%). 
Miyanaga et al., 202117  99  1 vs. 5g/d hydrolyzed collagen (fish) for 90Increased stratum corneum water content and reduced transepidermal water loss. Changes maintained for up to 30 days posttreatment. 
Campos et al., 202116  46  500mg/d hydrolyzed collagen (fish) for 90Increased dermal echogenicity and reduction in facial wrinkles. Confocal microscopy showed reduction in elastosis and improved morphology of dermal collagen fibers. 
a

This systematic review analyzed 19 randomized clinical trials.

b

Chenopodium formosanum Koidz.

A recent animal model study showed that hydrolyzed collagen (tripeptide collagen) mixed with galacto-oligosaccharide at a ratio of 1:1 and 3:1 improved clinical photoaging-related parameters and inflammation secondary to UVB exposure.18

Oral Hyaluronic Acid

Hyaluronic acid (HA) is a mucopolysaccharide widely distributed in connective tissue. The skin contains 50% of all HA in the body. HA is synthesized by keratinocytes and fibroblasts, and regulates water balance and maintains the structure of the skin. HA supplements are obtained from animals or bacterial fermentation. Absorption depends on the molecular weight of the acid and can be as high as 93.6%.19 A recent double-blind RCT (n=60) showed that oral supplementation with HA 200mg/d led to significant improvements in skin hydration and elasticity and an objective reduction in transepidermal water loss and facial wrinkles.19 Sixty-three percent of participants reported a reduction in facial wrinkles and 90% an increase in elasticity. No adverse effects were reported. Another double-blind RCT evaluating the administration of HA 120mg/d for 12 weeks reported a significant reduction in wrinkles and an increase in stratum corneum water content and skin elasticity and thickness.20 Similar results had been observed in earlier RCTs (Table 4)21–23 and prospective studies.24

Table 4.

Randomized clinical trials evaluating the use of oral hyaluronic acid (HA) in the treatment of skin aging.

Author, y  No. of patients  Intervention  Main results 
Kawada et al., 201522  24  200mg/d of HA (300kDa and 800KDa) for 6wk  Increased skin hydration and decreased epithelial thickness. Increased HAS2 expression. 
Oe et al., 201721  60  120mg/d HA (2kDa or 300kDa) for 4wk  Improvement in periocular wrinkles (improvement in sulcus volume, and total wrinkle volume and area). 
Kalman et al., 202026  88  450mg/d hydrolyzed eggshella for 12wk  Reduction in periocular wrinkles. Increased hair growth and thickness. No effect on nail growth. 
Hsu et al., 202120  40  120mg/d HA for 12wk  Reduction in facial wrinkles. Increased stratum corneum water content and skin elasticity and thickness. 
Michelotti et al., 202119  60  200mg/d full-spectrum HA for 28d.  Improved skin hydration and elasticity. Reduction in transepidermal water loss and facial wrinkle volume and depth. 
a

Hydrolyzed eggshell extract contains HA and collagen peptides.

A study of the benefits of an oral eggshell supplement, which contains HA and collagen, showed an improvement in skin elasticity, a reduction in skin pigmentation, and very high patient satisfaction with facial softness, skin hydration, and hair and nail appearance.25 A double-blind RCT (n=88) with similar characteristics reported a reduction in periocular wrinkles and improved hair thickness and growth.26

Oral Tranexamic Acid

The plasmin inhibitor tranexamic acid (TA) is a potent anti-inflammatory and depigmenting agent. Numerous RCTs have demonstrated the efficacy of oral TA in the treatment of melasma.27 Melasma has several features suggestive of a photoaging disorder, such as neovascularization, basement membrane damage, and solar elastosis.28 TA appears to indirectly decrease metalloproteinase 1 activation and reduce the expression of proinflammatory cytokines, such as interleukin 6 and tumor necrosis factor. It has also been linked to reduced expression of metalloproteinase 9, generation of reactive oxygen species,29 and increased HA synthesis.30 It also appears to increase fibroblast proliferation and collagen generation.31

Several animal studies of TA have shown a reduction in wrinkles31 and skin30 and photoaging32 signs. Another study found that TA may even be capable of improving the lifespan of mice not exposed to UV radiation.29

Oral TA has a good safety profile.33 In our review of the literature, we found no prospective clinical studies evaluating its effects on skin aging.

Hormone Replacement Therapy

Women can lose up to 30% of skin collagen in the first 5 years of menopause34 and may also experience a 0.55% loss of skin elasticity each year.35 A double-blind RCT evaluating the effects of hormone replacement therapy (HRT) (2mg 17B estradiol/10mg dydrogesterone) on the skin of 40 postmenopausal women found an increase in skin thickness, hydration, and elasticity after 7 months of treatment.36 Another study (n=55) showed that postmenopausal women on HRT with estrogen and testosterone had 48% higher collagen content in the skin.37 A similar study (n=25) reported significantly higher type III collagen content in women treated with estradiol and testosterone implants.38 Likewise, a large prospective study involving 176 women found a 5.2% increase in skin elasticity after 12 months of HRT.35

Other authors have also reported a significant increase in skin viscoelasticity (n=200) in women on HRT.39 Nonetheless, a large RCT (n=485) detected no differences in facial wrinkles or skin laxity between postmenopausal women treated with HRT and those treated with placebo.40

Elderly individuals may show low levels of growth hormones and also experience a dramatic decrease in skin thickness.41 Two studies have reported increased epidermal and dermal thickness in individuals with deficient growth hormone levels treated with growth hormone therapy.41,42 Potential adverse effects include gynecomastia and carpal tunnel syndrome.

Oral Polypodium Leucotomos

Polipodium leucotomos is a fern with anti-inflammatory and antioxidant properties native to Central and South America. Clinical studies have shown that it can reduce erythema induced by UV radiation and DNA damage and is also a useful adjuvant in the treatment of photoinduced and photoaggravated skin conditions and pigmentation disorders, such as vitiligo and melasma.43,44 It has an excellent safety profile. The findings of numerous in vitro studies using animal and human models suggest that P. leucotomos might be able to mitigate photoaging induced by UV radiation and visible light.43

A recent double-blind RCT (n=30) found a significant increase in minimal erythema dose and skin antioxidant capacity and skin hydration, in addition to improvements in skin appearance and elasticity following oral supplementation with a dietary product containing P. leucotomos, green tea, and other antioxidants.45

Oral Coenzyme Q10

Coenzyme Q10 has both antioxidative and anti-inflammatory properties. A double-blind RCT (n=33) evaluating the effects of oral coenzyme Q10 on the skin found improvements in wrinkles and skin smoothness, but no changes in skin hydration, dermal thickness, or minimal erythema dose.46 Another double-blind RCT (n=34) found that a dietary supplement containing coenzyme Q10, oral collagen, vitamin C, vitamin A, and biotin for 12 weeks reduced facial wrinkles and increased dermal density, but had no impact on skin hydration or thickness.47

Oral Glucosamine

Oral glucosamine sulfate is widely used in osteoarthritis. It is essential for the synthesis of glycoproteins, glycolipids, glycosaminoglycans, and proteoglycans. A clinical study involving 8 participants showed that 250mg of glucosamine administered for 8 weeks increased the expression of type I and III collagen and hyaluronan synthase.48 In a blinded RCT (n=53), a dietary supplement containing glucosamine, minerals, and antioxidants significantly decreased the number of facial wrinkles and fine lines.49

Systemic Glutathione

Glutathione has antioxidative, antitumor, antiviral, and antimelanogenic properties.50 Oral and intravenous formulations have been used to decrease skin pigmentation and photoaging, but 2 recent systematic reviews of the literature, including 3 RCTs, did not find sufficient evidence to recommend their use in this setting.50,51

A more recent RCT (n=124), not included in the above systematic reviews, showed that 250mg of glutathione combined with 500mg of l-cystine for 12 weeks significantly reduced solar lentigines and hyperpigmented macules in Asian women. Glutathione 250mg alone, however, was not significantly superior to placebo.52 Another recent RCT (n=46) reported decreased skin pigmentation following an 8-week regimen of 600mg of glutathione, 50mg of α-lipoic acid, and 4mg of zinc.53 Even better results were observed for oral glutathione combined with topical 2% glutathione. A multicenter RCT (n=83), however, found no significant differences between glutathione supplementation and placebo.54

Oral Melatonin

Melatonin is a hormone secreted by the pineal gland, but it is also synthesized and metabolized in the skin. It has powerful antioxidant, anti-inflammatory, immunomodulatory, and antitumor properties.55 In vivo and in vitro studies have shown that it can attenuate the deleterious effects of UV radiation and increase the antioxidant capacity of the skin.55 In our review of the literature, we found no clinical studies analyzing its effect on skin aging.

Oral Metformin

Metformin is a promising drug widely used in the treatment of type 2 diabetes mellitus. Multiple studies have shown that it can reduce the incidence of age-related diseases, such as cardiovascular and neurological diseases and cancer, as well as overall mortality56 in both diabetic and nondiabetic individuals.57 Animal studies have also shown an increase in lifespan.58 The ongoing Targeting Aging with Metformin (TAME) trial is a large multicenter trial evaluating the effects of metformin on human aging.59 We did not find any clinical studies analyzing its use in skin aging.

French Maritime Pine Bark Extract

French maritime pine bark extract is a blend of bioflavonoids, which are powerful antioxidants and anti-inflammatory agents. Clinical studies have shown that it has several antiaging and cardio- and neuro-protective properties, and can also alleviate osteoarticular, urologic, and menopause-related discomfort.60 The extract has also been found to have a photoprotective, modulating effect on skin pigmentation.61 Several RCTs evaluating the use of French maritime pine bark extract have shown a significant reduction in signs of facial aging, such as wrinkles and solar lentigines,62,63 and increased levels of hyaluronan synthase and type I collagen.64 Another RCT (n=76) showed increased skin elasticity and hydration and decreased skin darkening in Asians working in highly polluted areas after treatment for 12 weeks.65 No relevant adverse effects were reported.

Other Agents

Administration of 210mg of a marine complex combined with vitamin C, zinc, and other antioxidants led to improved facial appearance in 2 RCTs led by the same group of authors (n=15266 and n=7267). Similar findings were reported in prospective clinical studies.68,69 A large multicenter RCT (n=194), however, found no significant differences with placebo.70 A meta-analysis of the above findings for a total of 480 patients showed a favorable effect on facial appearance.70

Multiple oral antioxidants and anti-inflammatory agents, such as vitamins A, C, D, and E, green tea polyphenols, niacinamide, and trace elements such as zinc may help mitigate signs of skin aging. Many of the studies evaluating different combinations of antioxidants, however, have used different methodologies, impeding replication.71 There is insufficient clinical evidence to recommend the use of dietary supplements in the management of skin aging, and some authors urge caution when it comes to recommending vitamins or dietary supplements to well-nourished individuals.72 Promising results have been observed with extracts from plants such as Aloe vera, Citrus paradisi, Rosmarinus officinalis, Cyclopia intermedia, and Hydrangea serrata,73 but clinical evidence is lacking.

Almonds contain high levels of vitamin E. Two RCTs (n=91 and n=31) showed that participants who consumed almonds as 20% of their daily energy intake experienced a significant reduction in wrinkles and facial pigmentation.74,75 Another RCT (n=36) found that eating 85g of mango a day reduced the depth of facial wrinkles. Consumption, however, of 250g a day was associated with an increase in wrinkle length and depth.76 In a large cohort study (n=4025), beneficial effects were observed for a higher intake of vitamin C (decreased likelihood of facial wrinkles and dry skin) and consumption of linoleic acid (less atrophy and dry skin). By contrast, a 17-g increase in fat intake and a 50-g increase in carbohydrate intake was associated with a higher likelihood of wrinkles and skin atrophy.4

Discussion

Demand for skin antiaging therapies is high and expected to increase.15 The use of oral supplements and systemic drugs to fight skin aging is an attractive option, as it would eliminate or reduce the need for topical treatments or invasive or minimally invasive procedures, which can be costly and are not without adverse effects. Multivitamin and dietary supplements have many uses and are popular among the general population, and demand for antiaging supplements is on the rise.15 It is estimated that more than 50% of adults in the United States take vitamin supplements, and this percentage is expected to increase in coming years.77 Vitamins and other supplements are perceived as natural and safe,77 but the evidence supporting their effectiveness is weak. According to a recent systematic review, supplementation with vitamin A, C, B12, B3, B6, and D (with or without calcium), multivitamins, selenium, and calcium does not reduce the risk of overall or cardiovascular mortality.78 The US Preventive Services Task Force does not recommend the use of vitamins or multivitamins to prevent cardiovascular disease or cancer.78 Indeed, it advises against beta-carotene supplementation, as there is evidence that it might increase the risk of lung cancer and overall and cardiovascular mortality. It also advises against vitamin E for the prevention of cardiovascular disease and cancer, and warns of the potential risks of vitamin or mineral supplementation in general, recommending instead a healthy, balanced diet.78

The risks and benefits of systemic skin aging treatments must be carefully weighed up, as their purpose is to reverse or slow down a natural process rather than treat a particular disease. It is very difficult to make recommendations or draw valid conclusions on the effectiveness of oral supplements and systemic drugs in the treatment of skin aging, as most of the evidence is based on small, single-center studies with short follow-up periods (mostly 2–4 months), predominantly female samples, and use of heterogeneous methodologies and evaluation criteria. In addition, some of the confirmatory studies have been performed by the same researchers. Agreement on clinically relevant outcome measures is also lacking,71 and many studies have clear conflicts of interest.

In our review of the literature, we did not find any prospective clinical studies with sufficient evidence to support the use of metformin, melatonin, tranexamic acid, vitamins A, C, D, E, niacinamide, or zinc in the treatment of skin aging. Evidence on isotretinoin is also lacking, and caution must be exerted before recommending its use due to potential safety issues. More evidence is also needed on the effects of HRT on skin aging, and careful consideration must be given to the risk of cardiovascular disease and breast cancer before prescribing this treatment.79 We also found insufficient evidence to recommend glucosamine, glutathione, or coenzyme Q10.

Oral supplementation with hydrolyzed collagen, analyzed by 24 RCTs, has the strongest evidence in favor of its use for the mitigation of skin aging.12,16,17,26,80,81 It is inexpensive, has a good safety profile, and may also work in synergy with other antioxidants and anti-inflammatory agents. Oral HA is another novel, well-tolerated treatment that could help mitigate the effects of skin aging.19–22,26 Optimal doses, molecular weights, and duration of treatment remain to be determined for both collagen and HA supplements. Other promising compounds are French maritime pine bark extract62,63 and marine complexes.70

The Future of Systemic Treatments for Skin Aging

Cellular senescence, which is characterized by cell cycle arrest and changes in the epigenome, transcriptome, proteome, and secretome, is attracting increasing attention in the setting of skin aging. Markers of cellular senescence include increased intracellular levels of damaged and fragmented double-stranded DNA, lipofuscin, cell cycle inhibitors such as p16 and p21, and a proinflammatory secretory phenotype. The long-term presence of senescent cells has been linked to aging and skin diseases.82 Animal studies have shown that the destruction of senescent cells may prolong survival and reduce carcinogenesis and the incidence of age-related diseases.83

Selective agents targeting senescent cells in the dermis hold promise as a treatment for aging. Questions, however, remain about potential adverse effects, as, paradoxically, the transient presence of senescent cells could be beneficial during embryogenesis and wound healing.82

A more conservative approach involves the use of molecules with senomorphic effects capable of modulating the counterproductive nature of senescent cells and restarting cell proliferation. One such molecule is rapamycin, an mTOR inhibitor. Acute use of this drug in animal models has been seen to reverse several characteristics of senescent fibroblasts,84 protect against UV radiation damage,85 and reinitiate fibroblast proliferation.84

Metformin has also shown senomorphic effects in lung fibroblasts.86 Flavonoids and plant extracts such as Solidago virgaurea extracts, are capable of modulating cellular senescence.82

Senolytics and senomorphics are promising new agents in the field of human aging, but clinical studies are needed to evaluate their true effectiveness and safety.

Limitations

One limitation of this study is that it is a narrative rather than a systematic review. In addition, most of the studies analyzed were small prospective studies or clinical trials with heterogeneous methodologies.

Conclusions

A number of systemic drugs and dietary supplements may be useful for the treatment of skin aging. Clinical evidence, however, is largely lacking. Potential risks and benefits must be carefully weighed up before recommending any treatments. Oral supplementation with hydrolyzed collagen and HA has a good safety profile and is supported by the strongest evidence.

Conflicts of Interest

Industry groups had no role in the design or conduct of this study, in the collection, analysis, or interpretation of data, or in the preparation, review, or approval of this manuscript.

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