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.

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

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

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

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

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.

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.

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

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 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

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

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.

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 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.

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

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.