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Gil-Lianes, E. Jourdain, J. Piquero-Casals" "autores" => array:4 [ 0 => array:4 [ "nombre" => "D." "apellidos" => "Morgado-Carrasco" "email" => array:1 [ 0 => "morgadodaniel8@gmail.com" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">*</span>" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "J." "apellidos" => "Gil-Lianes" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "E." "apellidos" => "Jourdain" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] 3 => array:3 [ "nombre" => "J." "apellidos" => "Piquero-Casals" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] ] ] ] "afiliaciones" => array:3 [ 0 => array:3 [ "entidad" => "Dermatology Department, Hospital Clínic de Barcelona, Universitat de Barcelona, Spain" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Innovation and Development, ISDIN, Barcelona, Spain" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Dermik, Clínica Dermatológica Multidisciplinar, Barcelona, Spain" "etiqueta" => "c" "identificador" => "aff0015" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "Tratamiento mediante suplementación oral o fármacos sistémicos del envejecimiento cutáneo. Revisión narrativa de la literatura" ] ] "resumenGrafico" => array:2 [ "original" => 1 "multimedia" => array:5 [ "identificador" => "fig0010" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 761 "Ancho" => 1333 "Tamanyo" => 89076 ] ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">1</span></a> It is influenced by both intrinsic and extrinsic factors involving multiple pathogenic mechanisms (<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>) (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). Extrinsic aging is predominantly influenced by sun exposure (photoaging), although smoking and pollution also play a role.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">1</span></a> Intrinsic and extrinsic aging overlap in clinical practice.<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">1</span></a> Demand for strategies to mitigate the signs of skin aging is high.<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">2</span></a> Recent studies suggest that regular exercise, apart from improving quality of life and reducing the risk of mortality and chronic disease,<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">2</span></a> might also reduce the thickness of the stratum corneum and improve dermal thickness and collagen content.<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">3</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">4</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0475"><span class="elsevierStyleSup">5</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0010" class="elsevierStylePara elsevierViewall">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 niacinamide<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">6</span></a>) 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.</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Material and Methods</span><p id="par0015" class="elsevierStylePara elsevierViewall">For this narrative review, we searched for articles published in PubMed and Google Scholar between January 1, 1990 and March 2022 using the keywords <span class="elsevierStyleItalic">oral</span>, <span class="elsevierStyleItalic">systemic treatment</span>, <span class="elsevierStyleItalic">treatment</span>, <span class="elsevierStyleItalic">therapy</span>, <span class="elsevierStyleItalic">skin aging</span>, <span class="elsevierStyleItalic">photoaging</span>, <span class="elsevierStyleItalic">oral collagen</span>, <span class="elsevierStyleItalic">isotretinoin</span>, <span class="elsevierStyleItalic">tranexamic acid</span>, Polypodium leucotomos, <span class="elsevierStyleItalic">niacinamide</span>, <span class="elsevierStyleItalic">antioxidants</span>, <span class="elsevierStyleItalic">metformin</span>, <span class="elsevierStyleItalic">hormonal replacement therapy</span>, <span class="elsevierStyleItalic">melatonin</span>, <span class="elsevierStyleItalic">flavonoids</span>, <span class="elsevierStyleItalic">vitamin</span>, <span class="elsevierStyleItalic">vitamin C</span>, <span class="elsevierStyleItalic">vitamin E</span>, <span class="elsevierStyleItalic">vitamin D</span>, <span class="elsevierStyleItalic">senolytics</span>, <span class="elsevierStyleItalic">hyaluronan</span>, <span class="elsevierStyleItalic">hyaluronic acid</span>, <span class="elsevierStyleItalic">glucosamine</span>, <span class="elsevierStyleItalic">coenzyme Q10</span>, <span class="elsevierStyleItalic">glutathione</span>, <span class="elsevierStyleItalic">marine complex</span>, <span class="elsevierStyleItalic">pine bark extract</span>, <span class="elsevierStyleItalic">food supplements</span>, <span class="elsevierStyleItalic">aloe vera</span>, 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.</p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Results</span><p id="par0020" class="elsevierStylePara elsevierViewall">The results of the most relevant studies analyzing diverse compounds used in the treatment of skin aging are summarized below.</p><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Oral Isotretinoin</span><p id="par0025" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">7</span></a> In a prospective study, 20 individuals were administered oral isotretinoin 20<span class="elsevierStyleHsp" style=""></span>mg 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.<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">8</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">Two earlier studies had shown both histologic improvements (solar elastosis) and clinical improvements (reduced wrinkle depth and improved skin texture and color).<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">9,10</span></a> No clinical or histologic differences, however, were detected in an RCT (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>32) comparing oral isotretinoin (20<span class="elsevierStyleHsp" style=""></span>mg 3 times/wk) combined with sunscreen and moisturizer and sunscreen and moisturizer alone.<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">11</span></a> The authors of a more recent systematic review of 6 studies (including 3 RCTs, <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>) (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>251) concluded that isotretinoin might be a useful treatment for skin aging.<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">7</span></a> 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.</p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Oral Supplementation With Hydrolyzed Collagen</span><p id="par0035" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">12</span></a> 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.<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">12–14</span></a> There is a growing interest in hydrolyzed oral collagen supplements, especially in powder forms.<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">15</span></a> The effects of hydrolyzed collagen supplementation on skin aging were evaluated in a systematic review and meta-analysis of 19 double-blind RCTs<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">12</span></a> involving 1125 individuals. The doses ranged from 372<span class="elsevierStyleHsp" style=""></span>mg to 12<span class="elsevierStyleHsp" style=""></span>g a day, and in most of the trials, the participants received a daily dose of 2.5 to 5<span class="elsevierStyleHsp" style=""></span>g 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 (<span class="elsevierStyleItalic">z</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>0.48, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.002), elasticity (<span class="elsevierStyleItalic">z</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2.31, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.02), and hydration (<span class="elsevierStyleItalic">z</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>2.58, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>.010) and a significant reduction in facial wrinkles (<span class="elsevierStyleItalic">z</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>−1.11, <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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]).</p><p id="par0040" class="elsevierStylePara elsevierViewall">A more recent RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>46) (<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>) 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.<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">16</span></a> In another double-blind RCT (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>99), daily oral supplementation with 1<span class="elsevierStyleHsp" style=""></span>g or 5<span class="elsevierStyleHsp" style=""></span>g 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.<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">17</span></a></p><elsevierMultimedia ident="tbl0015"></elsevierMultimedia><p id="par0045" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Oral Hyaluronic Acid</span><p id="par0050" class="elsevierStylePara elsevierViewall">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%.<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">19</span></a> A recent double-blind RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>60) showed that oral supplementation with HA 200<span class="elsevierStyleHsp" style=""></span>mg/d led to significant improvements in skin hydration and elasticity and an objective reduction in transepidermal water loss and facial wrinkles.<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">19</span></a> 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 120<span class="elsevierStyleHsp" style=""></span>mg/d for 12 weeks reported a significant reduction in wrinkles and an increase in stratum corneum water content and skin elasticity and thickness.<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">20</span></a> Similar results had been observed in earlier RCTs (<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>)<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">21–23</span></a> and prospective studies.<a class="elsevierStyleCrossRef" href="#bib0570"><span class="elsevierStyleSup">24</span></a></p><elsevierMultimedia ident="tbl0020"></elsevierMultimedia><p id="par0055" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">25</span></a> A double-blind RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>88) with similar characteristics reported a reduction in periocular wrinkles and improved hair thickness and growth.<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">26</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Oral Tranexamic Acid</span><p id="par0060" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">27</span></a> Melasma has several features suggestive of a photoaging disorder, such as neovascularization, basement membrane damage, and solar elastosis.<a class="elsevierStyleCrossRef" href="#bib0590"><span class="elsevierStyleSup">28</span></a> 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,<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">29</span></a> and increased HA synthesis.<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">30</span></a> It also appears to increase fibroblast proliferation and collagen generation.<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">31</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Several animal studies of TA have shown a reduction in wrinkles<a class="elsevierStyleCrossRef" href="#bib0605"><span class="elsevierStyleSup">31</span></a> and skin<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">30</span></a> and photoaging<a class="elsevierStyleCrossRef" href="#bib0610"><span class="elsevierStyleSup">32</span></a> signs. Another study found that TA may even be capable of improving the lifespan of mice not exposed to UV radiation.<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">29</span></a></p><p id="par0070" class="elsevierStylePara elsevierViewall">Oral TA has a good safety profile.<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">33</span></a> In our review of the literature, we found no prospective clinical studies evaluating its effects on skin aging.</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Hormone Replacement Therapy</span><p id="par0075" class="elsevierStylePara elsevierViewall">Women can lose up to 30% of skin collagen in the first 5 years of menopause<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">34</span></a> and may also experience a 0.55% loss of skin elasticity each year.<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">35</span></a> A double-blind RCT evaluating the effects of hormone replacement therapy (HRT) (2<span class="elsevierStyleHsp" style=""></span>mg 17B estradiol/10<span class="elsevierStyleHsp" style=""></span>mg dydrogesterone) on the skin of 40 postmenopausal women found an increase in skin thickness, hydration, and elasticity after 7 months of treatment.<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">36</span></a> Another study (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>55) showed that postmenopausal women on HRT with estrogen and testosterone had 48% higher collagen content in the skin.<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">37</span></a> A similar study (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>25) reported significantly higher type III collagen content in women treated with estradiol and testosterone implants.<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">38</span></a> Likewise, a large prospective study involving 176 women found a 5.2% increase in skin elasticity after 12 months of HRT.<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">35</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Other authors have also reported a significant increase in skin viscoelasticity (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>200) in women on HRT.<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">39</span></a> Nonetheless, a large RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>485) detected no differences in facial wrinkles or skin laxity between postmenopausal women treated with HRT and those treated with placebo.<a class="elsevierStyleCrossRef" href="#bib0650"><span class="elsevierStyleSup">40</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall">Elderly individuals may show low levels of growth hormones and also experience a dramatic decrease in skin thickness.<a class="elsevierStyleCrossRef" href="#bib0655"><span class="elsevierStyleSup">41</span></a> Two studies have reported increased epidermal and dermal thickness in individuals with deficient growth hormone levels treated with growth hormone therapy.<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">41,42</span></a> Potential adverse effects include gynecomastia and carpal tunnel syndrome.</p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Oral Polypodium Leucotomos</span><p id="par0090" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Polipodium leucotomos</span> 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.<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">43,44</span></a> It has an excellent safety profile. The findings of numerous in vitro studies using animal and human models suggest that <span class="elsevierStyleItalic">P. leucotomos</span> might be able to mitigate photoaging induced by UV radiation and visible light.<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">43</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">A recent double-blind RCT (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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 <span class="elsevierStyleItalic">P. leucotomos</span>, green tea, and other antioxidants.<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">45</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Oral Coenzyme Q10</span><p id="par0100" class="elsevierStylePara elsevierViewall">Coenzyme Q10 has both antioxidative and anti-inflammatory properties. A double-blind RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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.<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">46</span></a> Another double-blind RCT (<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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.<a class="elsevierStyleCrossRef" href="#bib0685"><span class="elsevierStyleSup">47</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Oral Glucosamine</span><p id="par0105" class="elsevierStylePara elsevierViewall">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 250<span class="elsevierStyleHsp" style=""></span>mg of glucosamine administered for 8 weeks increased the expression of type I and III collagen and hyaluronan synthase.<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">48</span></a> In a blinded RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>53), a dietary supplement containing glucosamine, minerals, and antioxidants significantly decreased the number of facial wrinkles and fine lines.<a class="elsevierStyleCrossRef" href="#bib0695"><span class="elsevierStyleSup">49</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Systemic Glutathione</span><p id="par0110" class="elsevierStylePara elsevierViewall">Glutathione has antioxidative, antitumor, antiviral, and antimelanogenic properties.<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">50</span></a> 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.<a class="elsevierStyleCrossRefs" href="#bib0700"><span class="elsevierStyleSup">50,51</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">A more recent RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>124), not included in the above systematic reviews, showed that 250<span class="elsevierStyleHsp" style=""></span>mg of glutathione combined with 500<span class="elsevierStyleHsp" style=""></span>mg of <span class="elsevierStyleSmallCaps">l</span>-cystine for 12 weeks significantly reduced solar lentigines and hyperpigmented macules in Asian women. Glutathione 250<span class="elsevierStyleHsp" style=""></span>mg alone, however, was not significantly superior to placebo.<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">52</span></a> Another recent RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>46) reported decreased skin pigmentation following an 8-week regimen of 600<span class="elsevierStyleHsp" style=""></span>mg of glutathione, 50<span class="elsevierStyleHsp" style=""></span>mg of α-lipoic acid, and 4<span class="elsevierStyleHsp" style=""></span>mg of zinc.<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">53</span></a> Even better results were observed for oral glutathione combined with topical 2% glutathione. A multicenter RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>83), however, found no significant differences between glutathione supplementation and placebo.<a class="elsevierStyleCrossRef" href="#bib0720"><span class="elsevierStyleSup">54</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Oral Melatonin</span><p id="par0120" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">55</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">55</span></a> In our review of the literature, we found no clinical studies analyzing its effect on skin aging.</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Oral Metformin</span><p id="par0125" class="elsevierStylePara elsevierViewall">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 mortality<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">56</span></a> in both diabetic and nondiabetic individuals.<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">57</span></a> Animal studies have also shown an increase in lifespan.<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">58</span></a> The ongoing Targeting Aging with Metformin (TAME) trial is a large multicenter trial evaluating the effects of metformin on human aging.<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">59</span></a> We did not find any clinical studies analyzing its use in skin aging.</p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">French Maritime Pine Bark Extract</span><p id="par0130" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">60</span></a> The extract has also been found to have a photoprotective, modulating effect on skin pigmentation.<a class="elsevierStyleCrossRef" href="#bib0755"><span class="elsevierStyleSup">61</span></a> 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,<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">62,63</span></a> and increased levels of hyaluronan synthase and type I collagen.<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">64</span></a> Another RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>76) showed increased skin elasticity and hydration and decreased skin darkening in Asians working in highly polluted areas after treatment for 12 weeks.<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">65</span></a> No relevant adverse effects were reported.</p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Other Agents</span><p id="par0135" class="elsevierStylePara elsevierViewall">Administration of 210<span class="elsevierStyleHsp" style=""></span>mg 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<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>152<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">66</span></a> and n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>72<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">67</span></a>). Similar findings were reported in prospective clinical studies.<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">68,69</span></a> A large multicenter RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>194), however, found no significant differences with placebo.<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">70</span></a> A meta-analysis of the above findings for a total of 480 patients showed a favorable effect on facial appearance.<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">70</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">71</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0810"><span class="elsevierStyleSup">72</span></a> Promising results have been observed with extracts from plants such as <span class="elsevierStyleItalic">Aloe vera</span>, <span class="elsevierStyleItalic">Citrus paradisi</span>, <span class="elsevierStyleItalic">Rosmarinus officinalis</span>, <span class="elsevierStyleItalic">Cyclopia intermedia</span>, and <span class="elsevierStyleItalic">Hydrangea serrata</span>,<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">73</span></a> but clinical evidence is lacking.</p><p id="par0145" class="elsevierStylePara elsevierViewall">Almonds contain high levels of vitamin E. Two RCTs (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>91 and n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>31) showed that participants who consumed almonds as 20% of their daily energy intake experienced a significant reduction in wrinkles and facial pigmentation.<a class="elsevierStyleCrossRefs" href="#bib0820"><span class="elsevierStyleSup">74,75</span></a> Another RCT (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>36) found that eating 85<span class="elsevierStyleHsp" style=""></span>g of mango a day reduced the depth of facial wrinkles. Consumption, however, of 250<span class="elsevierStyleHsp" style=""></span>g a day was associated with an increase in wrinkle length and depth.<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">76</span></a> In a large cohort study (n<span class="elsevierStyleHsp" style=""></span>=<span class="elsevierStyleHsp" style=""></span>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.<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">4</span></a></p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Discussion</span><p id="par0150" class="elsevierStylePara elsevierViewall">Demand for skin antiaging therapies is high and expected to increase.<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">15</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">15</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">77</span></a> Vitamins and other supplements are perceived as natural and safe,<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">77</span></a> but the evidence supporting their effectiveness is weak. According to a recent systematic review, supplementation with vitamin A, C, B<span class="elsevierStyleInf">12</span>, B<span class="elsevierStyleInf">3</span>, B<span class="elsevierStyleInf">6</span>, and D (with or without calcium), multivitamins, selenium, and calcium does not reduce the risk of overall or cardiovascular mortality.<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">78</span></a> The US Preventive Services Task Force does not recommend the use of vitamins or multivitamins to prevent cardiovascular disease or cancer.<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">78</span></a> 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.<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">78</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall">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,<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">71</span></a> and many studies have clear conflicts of interest.</p><p id="par0160" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">79</span></a> We also found insufficient evidence to recommend glucosamine, glutathione, or coenzyme Q10.</p><p id="par0165" class="elsevierStylePara elsevierViewall">Oral supplementation with hydrolyzed collagen, analyzed by 24 RCTs, has the strongest evidence in favor of its use for the mitigation of skin aging.<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">12,16,17,26,80,81</span></a> 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.<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">19–22,26</span></a> 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 extract<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">62,63</span></a> and marine complexes.<a class="elsevierStyleCrossRef" href="#bib0800"><span class="elsevierStyleSup">70</span></a></p><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">The Future of Systemic Treatments for Skin Aging</span><p id="par0170" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">82</span></a> Animal studies have shown that the destruction of senescent cells may prolong survival and reduce carcinogenesis and the incidence of age-related diseases.<a class="elsevierStyleCrossRef" href="#bib0865"><span class="elsevierStyleSup">83</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">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.<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">82</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">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,<a class="elsevierStyleCrossRef" href="#bib0870"><span class="elsevierStyleSup">84</span></a> protect against UV radiation damage,<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">85</span></a> and reinitiate fibroblast proliferation.<a class="elsevierStyleCrossRef" href="#bib0870"><span class="elsevierStyleSup">84</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">Metformin has also shown senomorphic effects in lung fibroblasts.<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">86</span></a> Flavonoids and plant extracts such as <span class="elsevierStyleItalic">Solidago virgaurea</span> extracts, are capable of modulating cellular senescence.<a class="elsevierStyleCrossRef" href="#bib0860"><span class="elsevierStyleSup">82</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">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.</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Limitations</span><p id="par0195" class="elsevierStylePara elsevierViewall">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.</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Conclusions</span><p id="par0200" class="elsevierStylePara elsevierViewall">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.</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflicts of Interest</span><p id="par0205" class="elsevierStylePara elsevierViewall">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.</p></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:13 [ 0 => array:3 [ "identificador" => "xres1852184" "titulo" => "Graphical abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0005" ] ] ] 1 => array:3 [ "identificador" => "xres1852186" "titulo" => "Abstract" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0010" ] ] ] 2 => array:2 [ "identificador" => "xpalclavsec1610373" "titulo" => "Keywords" ] 3 => array:3 [ "identificador" => "xres1852185" "titulo" => "Resumen" "secciones" => array:1 [ 0 => array:1 [ "identificador" => "abst0015" ] ] ] 4 => array:2 [ "identificador" => "xpalclavsec1610374" "titulo" => "Palabras clave" ] 5 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 6 => array:2 [ "identificador" => "sec0010" "titulo" => "Material and Methods" ] 7 => array:3 [ "identificador" => "sec0015" "titulo" => "Results" "secciones" => array:13 [ 0 => array:2 [ "identificador" => "sec0020" "titulo" => "Oral Isotretinoin" ] 1 => array:2 [ "identificador" => "sec0025" "titulo" => "Oral Supplementation With Hydrolyzed Collagen" ] 2 => array:2 [ "identificador" => "sec0030" "titulo" => "Oral Hyaluronic Acid" ] 3 => array:2 [ "identificador" => "sec0035" "titulo" => "Oral Tranexamic Acid" ] 4 => array:2 [ "identificador" => "sec0040" "titulo" => "Hormone Replacement Therapy" ] 5 => array:2 [ "identificador" => "sec0045" "titulo" => "Oral Polypodium Leucotomos" ] 6 => array:2 [ "identificador" => "sec0050" "titulo" => "Oral Coenzyme Q10" ] 7 => array:2 [ "identificador" => "sec0055" "titulo" => "Oral Glucosamine" ] 8 => array:2 [ "identificador" => "sec0060" "titulo" => "Systemic Glutathione" ] 9 => array:2 [ "identificador" => "sec0065" "titulo" => "Oral Melatonin" ] 10 => array:2 [ "identificador" => "sec0070" "titulo" => "Oral Metformin" ] 11 => array:2 [ "identificador" => "sec0075" "titulo" => "French Maritime Pine Bark Extract" ] 12 => array:2 [ "identificador" => "sec0080" "titulo" => "Other Agents" ] ] ] 8 => array:3 [ "identificador" => "sec0085" "titulo" => "Discussion" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "sec0090" "titulo" => "The Future of Systemic Treatments for Skin Aging" ] ] ] 9 => array:2 [ "identificador" => "sec0095" "titulo" => "Limitations" ] 10 => array:2 [ "identificador" => "sec0100" "titulo" => "Conclusions" ] 11 => array:2 [ "identificador" => "sec0105" "titulo" => "Conflicts of Interest" ] 12 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2022-05-12" "fechaAceptado" => "2022-09-20" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec1610373" "palabras" => array:6 [ 0 => "Photoaging" 1 => "Skin aging" 2 => "Oral hydrolyzed collagen" 3 => "Hyaluronic acid" 4 => "Treatment" 5 => "Oral" ] ] ] "es" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palabras clave" "identificador" => "xpalclavsec1610374" "palabras" => array:6 [ 0 => "Fotoenvejecimiento" 1 => "Envejecimiento cutáneo" 2 => "Colágeno hidrolizado oral" 3 => "Ácido hialurónico" 4 => "Tratamiento" 5 => "Oral" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">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.</p></span>" ] "es" => array:2 [ "titulo" => "Resumen" "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">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.</p></span>" ] ] "multimedia" => array:6 [ 0 => array:7 [ "identificador" => "fig0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1403 "Ancho" => 2458 "Tamanyo" => 289923 ] ] "descripcion" => array:1 [ "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">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.</p>" ] ] 1 => array:8 [ "identificador" => "tbl0005" "etiqueta" => "Table 1" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at1" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:1 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Molecular mechanism \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Impact \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oxidative stress \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Induction of matrix metalloproteinasesIncreased production of proinflammatory cytokinesIndirect DNA damageMitochondrial damage \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Telomere shortening \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cellular senescence \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Altered micro-RNA expression and dysregulated gene expression \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Dysregulation of apoptosisAltered collagen gene expression \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increased proinflammatory state \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Relative immunosuppressionAngiogenesisCell proliferation \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Apoptosis dysfunction \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Cellular senescenceProtumor state \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Direct UVB radiation–induced DNA damage \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Formation of mutagenic photoproducts \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">Molecular Mechanisms of Skin Aging.</p>" ] ] 2 => array:8 [ "identificador" => "tbl0010" "etiqueta" => "Table 2" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at2" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author/y \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. of patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Main results \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hernández-Pérez et al., 2000<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">87</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">120 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral ISO 10–20<span class="elsevierStyleHsp" style=""></span>mg 3 times/wk for 2<span class="elsevierStyleHsp" style=""></span>mo<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Improvement of wrinkles, pore size, and hyperpigmentation. Increased skin thickness, elasticity and tone. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Rabello-Fonseca et al., 2009<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">10</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">30 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral SO 10<span class="elsevierStyleHsp" style=""></span>mg vs. 20<span class="elsevierStyleHsp" style=""></span>mg 3 times/wk for 3<span class="elsevierStyleHsp" style=""></span>mo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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 (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span><<span class="elsevierStyleHsp" style=""></span>.05) and a tendency toward decreased elastosis. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bagatin et al., 2010<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">11</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">32 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral ISO 20<span class="elsevierStyleHsp" style=""></span>mg 3 times/wk and topical sunscreen for 3<span class="elsevierStyleHsp" style=""></span>mo vs. topical sunscreen \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Bagatin et al., 2014<a class="elsevierStyleCrossRef" href="#bib0890"><span class="elsevierStyleSup">88</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oral ISO 20<span class="elsevierStyleHsp" style=""></span>mg/d vs. topical retinoic acid 0.05% for 6<span class="elsevierStyleHsp" style=""></span>mo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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 (<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>><span class="elsevierStyleHsp" style=""></span>.05) \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Ianhez et al., 2019<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">89</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">61 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">ISO 10<span class="elsevierStyleHsp" style=""></span>mg/d vs. tretinoin 0.05% cream every 48<span class="elsevierStyleHsp" style=""></span>h for 6<span class="elsevierStyleHsp" style=""></span>mo \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">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) \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0005" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0005">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.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Randomized Clinical Trials Evaluating the Use of Oral Isotretinoin (ISO) in the Treatment of Skin Aging.</p>" ] ] 3 => array:8 [ "identificador" => "tbl0015" "etiqueta" => "Table 3" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at3" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author, y \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. of patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Main results \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Kim et al., 2018<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">80</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">64 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1<span class="elsevierStyleHsp" style=""></span>g/d hydrolyzed collagen for 12<span class="elsevierStyleHsp" style=""></span>wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Improvement in skin hydration and elasticity. Reduction in periocular wrinkles. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Evans et al., 2021<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">81</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">10<span class="elsevierStyleHsp" style=""></span>g/d hydrolyzed collagen (fish) for 12<span class="elsevierStyleHsp" style=""></span>wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Decrease in wrinkles (-15%). Increased skin elasticity (+23%), hydration (+14%), and firmness (+25%). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Lin et al., 2020<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">90</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">50 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">5–5.5<span class="elsevierStyleHsp" style=""></span>g/d hydrolyzed collagen (fish)<span class="elsevierStyleHsp" style=""></span>+<span class="elsevierStyleHsp" style=""></span>1<span class="elsevierStyleHsp" style=""></span>g Djulis extract<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">b</span></a> for 8<span class="elsevierStyleHsp" style=""></span>wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Improved skin hydration (+17.8%) and brightness (+5.4%). Reduction in periocular wrinkles (-14.9%) and pores (-9.9%). Increased dermal collagen (+22.3%). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Miyanaga et al., 2021<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">17</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">99 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">1 vs. 5<span class="elsevierStyleHsp" style=""></span>g/d hydrolyzed collagen (fish) for 90<span class="elsevierStyleHsp" style=""></span>d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increased stratum corneum water content and reduced transepidermal water loss. Changes maintained for up to 30 days posttreatment. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Campos et al., 2021<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">16</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">46 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">500<span class="elsevierStyleHsp" style=""></span>mg/d hydrolyzed collagen (fish) for 90<span class="elsevierStyleHsp" style=""></span>d \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increased dermal echogenicity and reduction in facial wrinkles. Confocal microscopy showed reduction in elastosis and improved morphology of dermal collagen fibers. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:2 [ 0 => array:3 [ "identificador" => "tblfn0010" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0010">This systematic review analyzed 19 randomized clinical trials.</p>" ] 1 => array:3 [ "identificador" => "tblfn0015" "etiqueta" => "b" "nota" => "<p class="elsevierStyleNotepara" id="npar0015"><span class="elsevierStyleItalic">Chenopodium formosanum</span> Koidz.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">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 class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a> (2021).</p>" ] ] 4 => array:8 [ "identificador" => "tbl0020" "etiqueta" => "Table 4" "tipo" => "MULTIMEDIATABLA" "mostrarFloat" => true "mostrarDisplay" => false "detalles" => array:1 [ 0 => array:3 [ "identificador" => "at4" "detalle" => "Table " "rol" => "short" ] ] "tabla" => array:2 [ "tablatextoimagen" => array:1 [ 0 => array:1 [ "tabla" => array:1 [ 0 => """ <table border="0" frame="\n \t\t\t\t\tvoid\n \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author, y \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No. of patients \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Intervention \t\t\t\t\t\t\n \t\t\t\t\t\t</th><th class="td" title="\n \t\t\t\t\ttable-head\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Main results \t\t\t\t\t\t\n \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Kawada et al., 2015<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">22</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">24 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">200<span class="elsevierStyleHsp" style=""></span>mg/d of HA (300<span class="elsevierStyleHsp" style=""></span>kDa and 800<span class="elsevierStyleHsp" style=""></span>KDa) for 6<span class="elsevierStyleHsp" style=""></span>wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Increased skin hydration and decreased epithelial thickness. Increased <span class="elsevierStyleItalic">HAS2</span> expression. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Oe et al., 2017<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">21</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">120<span class="elsevierStyleHsp" style=""></span>mg/d HA (2<span class="elsevierStyleHsp" style=""></span>kDa or 300<span class="elsevierStyleHsp" style=""></span>kDa) for 4<span class="elsevierStyleHsp" style=""></span>wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Improvement in periocular wrinkles (improvement in sulcus volume, and total wrinkle volume and area). \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Kalman et al., 2020<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">26</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">88 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">450<span class="elsevierStyleHsp" style=""></span>mg/d hydrolyzed eggshell<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a> for 12<span class="elsevierStyleHsp" style=""></span>wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reduction in periocular wrinkles. Increased hair growth and thickness. No effect on nail growth. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Hsu et al., 2021<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">20</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">40 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">120<span class="elsevierStyleHsp" style=""></span>mg/d HA for 12<span class="elsevierStyleHsp" style=""></span>wk \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Reduction in facial wrinkles. Increased stratum corneum water content and skin elasticity and thickness. \t\t\t\t\t\t\n \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Michelotti et al., 2021<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">19</span></a> \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="char" valign="\n \t\t\t\t\ttop\n \t\t\t\t">60 \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">200<span class="elsevierStyleHsp" style=""></span>mg/d full-spectrum HA for 28<span class="elsevierStyleHsp" style=""></span>d. \t\t\t\t\t\t\n \t\t\t\t</td><td class="td" title="\n \t\t\t\t\ttable-entry\n \t\t\t\t " align="left" valign="\n \t\t\t\t\ttop\n \t\t\t\t">Improved skin hydration and elasticity. Reduction in transepidermal water loss and facial wrinkle volume and depth. \t\t\t\t\t\t\n \t\t\t\t</td></tr></tbody></table> """ ] ] ] "notaPie" => array:1 [ 0 => array:3 [ "identificador" => "tblfn0020" "etiqueta" => "a" "nota" => "<p class="elsevierStyleNotepara" id="npar0020">Hydrolyzed eggshell extract contains HA and collagen peptides.</p>" ] ] ] "descripcion" => array:1 [ "en" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Randomized clinical trials evaluating the use of oral hyaluronic acid (HA) in the treatment of skin aging.</p>" ] ] 5 => array:5 [ "identificador" => "fig0010" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 761 "Ancho" => 1333 "Tamanyo" => 89076 ] ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0015" "bibliografiaReferencia" => array:90 [ 0 => array:3 [ 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