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    "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&#44; sun spots&#44; an uneven skin tone&#44; decreased elasticity&#44; increased skin fragility and visible capillaries&#44; impaired healing&#44; and an increased incidence of skin cancer and infections&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">1</span></a> It is influenced by both intrinsic and extrinsic factors involving multiple pathogenic mechanisms &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Extrinsic aging is predominantly influenced by sun exposure &#40;photoaging&#41;&#44; although smoking and pollution also play a role&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">1</span></a> Intrinsic and extrinsic aging overlap in clinical practice&#46;<a class="elsevierStyleCrossRef" href="#bib0455"><span class="elsevierStyleSup">1</span></a> Demand for strategies to mitigate the signs of skin aging is high&#46;<a class="elsevierStyleCrossRef" href="#bib0460"><span class="elsevierStyleSup">2</span></a> Recent studies suggest that regular exercise&#44; apart from improving quality of life and reducing the risk of mortality and chronic disease&#44;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">3</span></a> Diet is also important&#44; with a number of studies highlighting its role in the prevention of aging&#46; Dietary antioxidants such as vitamin C and linoleic acid are considered important&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">4</span></a> Several studies have shown that calorie-restricted diets &#40;without the loss of essential nutrients&#41; and intermittent fasting have antioxidant and anti-inflammatory effects and associated health benefits&#46; Animal model studies have shown that calorie restriction and fasting might reduce skin aging&#46;<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&#44; and mostly consist of topical products &#40;e&#46;g&#46;&#44; retinoids&#44; &#945;-hydroxyacids&#44; broad-spectrum sunscreens&#44; and antioxidant&#47;anti-inflammatory agents&#44; such as preparations containing vitamin C&#44; vitamin E&#44; and niacinamide<a class="elsevierStyleCrossRef" href="#bib0480"><span class="elsevierStyleSup">6</span></a>&#41; and invasive or minimally invasive procedures &#40;e&#46;g&#46;&#44; ablative and nonablative laser therapy&#44; intense pulsed light therapy&#44; radiofrequency&#44; dermabrasion&#44; and chemical peels&#41;&#46; Consensus is lacking on the use of oral supplements and systemic treatments for skin aging and photoaging&#46; In this article&#44; we review the current evidence on the use of these treatments in the setting of skin aging and photoaging&#46;</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&#44; we searched for articles published in PubMed and Google Scholar between January 1&#44; 1990 and March 2022 using the keywords <span class="elsevierStyleItalic">oral</span>&#44; <span class="elsevierStyleItalic">systemic treatment</span>&#44; <span class="elsevierStyleItalic">treatment</span>&#44; <span class="elsevierStyleItalic">therapy</span>&#44; <span class="elsevierStyleItalic">skin aging</span>&#44; <span class="elsevierStyleItalic">photoaging</span>&#44; <span class="elsevierStyleItalic">oral collagen</span>&#44; <span class="elsevierStyleItalic">isotretinoin</span>&#44; <span class="elsevierStyleItalic">tranexamic acid</span>&#44; Polypodium leucotomos&#44; <span class="elsevierStyleItalic">niacinamide</span>&#44; <span class="elsevierStyleItalic">antioxidants</span>&#44; <span class="elsevierStyleItalic">metformin</span>&#44; <span class="elsevierStyleItalic">hormonal replacement therapy</span>&#44; <span class="elsevierStyleItalic">melatonin</span>&#44; <span class="elsevierStyleItalic">flavonoids</span>&#44; <span class="elsevierStyleItalic">vitamin</span>&#44; <span class="elsevierStyleItalic">vitamin C</span>&#44; <span class="elsevierStyleItalic">vitamin E</span>&#44; <span class="elsevierStyleItalic">vitamin D</span>&#44; <span class="elsevierStyleItalic">senolytics</span>&#44; <span class="elsevierStyleItalic">hyaluronan</span>&#44; <span class="elsevierStyleItalic">hyaluronic acid</span>&#44; <span class="elsevierStyleItalic">glucosamine</span>&#44; <span class="elsevierStyleItalic">coenzyme Q10</span>&#44; <span class="elsevierStyleItalic">glutathione</span>&#44; <span class="elsevierStyleItalic">marine complex</span>&#44; <span class="elsevierStyleItalic">pine bark extract</span>&#44; <span class="elsevierStyleItalic">food supplements</span>&#44; <span class="elsevierStyleItalic">aloe vera</span>&#44; and Hydrangea serrata&#46; We included prospective studies and randomized clinical trials &#40;RCTs&#41; published in English or Spanish&#46; No limits were placed on the number of study participants&#46; After screening the abstracts of the articles retrieved&#44; 2 of the authors &#40;DMC and JPC&#41; performed a full-text review to select relevant articles&#46;</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&#46;</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&#46; In addition to its comedolytic&#44; sebum-regulating&#44; and anti-inflammatory properties&#44; it appears capable of inhibiting extracellular matrix metalloproteinases and increasing collagen type I and III production&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">7</span></a> In a prospective study&#44; 20 individuals were administered oral isotretinoin 20<span class="elsevierStyleHsp" style=""></span>mg 3 times a week for 12 weeks&#46; Skin biopsies performed before and after treatment and 12 weeks later showed a significant increase in collagen and elastic fiber density&#46; Sixty-five percent of the participants showed histologic improvements in the appearance and distribution of elastic fibers&#44; while they all reported improvements in perceived skin quality&#46;<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 &#40;solar elastosis&#41; and clinical improvements &#40;reduced wrinkle depth and improved skin texture and color&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0495"><span class="elsevierStyleSup">9&#44;10</span></a> No clinical or histologic differences&#44; however&#44; were detected in an RCT &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>32&#41; comparing oral isotretinoin &#40;20<span class="elsevierStyleHsp" style=""></span>mg 3 times&#47;wk&#41; combined with sunscreen and moisturizer and sunscreen and moisturizer alone&#46;<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">11</span></a> The authors of a more recent systematic review of 6 studies &#40;including 3 RCTs&#44; <a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41; &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>251&#41; concluded that isotretinoin might be a useful treatment for skin aging&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">7</span></a> There is&#44; however&#44; insufficient evidence to recommend oral isotretinoin over topical treatments&#46; Potential adverse effects&#44; such as mucocutaneous dryness&#44; lipid and liver changes&#44; and teratogenicity&#44; must also be taken into account&#46;</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&#44; accounting for 75&#37; of the total weight of the extracellular matrix&#46; Hydrolyzed collagen used in oral supplements is obtained through the enzymatic hydrolysis of natural collagen from various sources&#44; such as fish&#44; pork&#44; and chicken&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">12</span></a> When digested&#44; it is broken down into dipeptides and tripeptides&#44; which are absorbed into the bloodstream through the gastrointestinal tract and largely deposited in the skin&#46; These dipeptides stimulate the metabolism&#44; migration&#44; and proliferation of fibroblasts and generate increased collagen and hyaluronic acid production&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">12&#8211;14</span></a> There is a growing interest in hydrolyzed oral collagen supplements&#44; especially in powder forms&#46;<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&#46; The doses ranged from 372<span class="elsevierStyleHsp" style=""></span>mg to 12<span class="elsevierStyleHsp" style=""></span>g a day&#44; and in most of the trials&#44; the participants received a daily dose of 2&#46;5 to 5<span class="elsevierStyleHsp" style=""></span>g over a period of 8 to12 weeks&#46; The vast majority of trials showed improved skin elasticity and a reduction in facial wrinkles following treatment&#46; The benefits were maintained for approximately 30 days after the end of the treatment&#44; and no adverse effects were observed&#46; Some of the RCTs detected a reduction in skin fragility in hospitalized elderly patients after nursing procedures and improved healing after laser procedures&#46; The meta-analysis showed significant associations between hydrolyzed collagen supplementation and an increase in skin density &#40;<span class="elsevierStyleItalic">z</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;48&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;002&#41;&#44; elasticity &#40;<span class="elsevierStyleItalic">z</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;31&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;02&#41;&#44; and hydration &#40;<span class="elsevierStyleItalic">z</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>2&#46;58&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#46;010&#41; and a significant reduction in facial wrinkles &#40;<span class="elsevierStyleItalic">z</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#8722;1&#46;11&#44; <span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>009&#41;&#46; The meta-analysis was limited by the heterogeneity of the data pertaining to the collagen supplements used &#40;origin&#44; composition&#44; concentration&#44; formulation&#44; and vehicles &#91;solid vs&#46; liquid&#93;&#41;&#46;</p><p id="par0040" class="elsevierStylePara elsevierViewall">A more recent RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>46&#41; &#40;<a class="elsevierStyleCrossRef" href="#tbl0015">Table 3</a>&#41; 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&#46; Confocal microscopy also showed a reduction in elastosis and improved collagen fiber appearance&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">16</span></a> In another double-blind RCT &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>99&#41;&#44; 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&#46;<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 &#40;tripeptide collagen&#41; mixed with galacto-oligosaccharide at a ratio of 1&#58;1 and 3&#58;1 improved clinical photoaging-related parameters and inflammation secondary to UVB exposure&#46;<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 &#40;HA&#41; is a mucopolysaccharide widely distributed in connective tissue&#46; The skin contains 50&#37; of all HA in the body&#46; HA is synthesized by keratinocytes and fibroblasts&#44; and regulates water balance and maintains the structure of the skin&#46; HA supplements are obtained from animals or bacterial fermentation&#46; Absorption depends on the molecular weight of the acid and can be as high as 93&#46;6&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">19</span></a> A recent double-blind RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>60&#41; showed that oral supplementation with HA 200<span class="elsevierStyleHsp" style=""></span>mg&#47;d led to significant improvements in skin hydration and elasticity and an objective reduction in transepidermal water loss and facial wrinkles&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">19</span></a> Sixty-three percent of participants reported a reduction in facial wrinkles and 90&#37; an increase in elasticity&#46; No adverse effects were reported&#46; Another double-blind RCT evaluating the administration of HA 120<span class="elsevierStyleHsp" style=""></span>mg&#47;d for 12 weeks reported a significant reduction in wrinkles and an increase in stratum corneum water content and skin elasticity and thickness&#46;<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">20</span></a> Similar results had been observed in earlier RCTs &#40;<a class="elsevierStyleCrossRef" href="#tbl0020">Table 4</a>&#41;<a class="elsevierStyleCrossRefs" href="#bib0555"><span class="elsevierStyleSup">21&#8211;23</span></a> and prospective studies&#46;<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&#44; which contains HA and collagen&#44; showed an improvement in skin elasticity&#44; a reduction in skin pigmentation&#44; and very high patient satisfaction with facial softness&#44; skin hydration&#44; and hair and nail appearance&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">25</span></a> A double-blind RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>88&#41; with similar characteristics reported a reduction in periocular wrinkles and improved hair thickness and growth&#46;<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 &#40;TA&#41; is a potent anti-inflammatory and depigmenting agent&#46; Numerous RCTs have demonstrated the efficacy of oral TA in the treatment of melasma&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">27</span></a> Melasma has several features suggestive of a photoaging disorder&#44; such as neovascularization&#44; basement membrane damage&#44; and solar elastosis&#46;<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&#44; such as interleukin 6 and tumor necrosis factor&#46; It has also been linked to reduced expression of metalloproteinase 9&#44; generation of reactive oxygen species&#44;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">29</span></a> and increased HA synthesis&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">30</span></a> It also appears to increase fibroblast proliferation and collagen generation&#46;<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&#46; Another study found that TA may even be capable of improving the lifespan of mice not exposed to UV radiation&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">33</span></a> In our review of the literature&#44; we found no prospective clinical studies evaluating its effects on skin aging&#46;</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&#37; 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&#46;55&#37; loss of skin elasticity each year&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">35</span></a> A double-blind RCT evaluating the effects of hormone replacement therapy &#40;HRT&#41; &#40;2<span class="elsevierStyleHsp" style=""></span>mg 17B estradiol&#47;10<span class="elsevierStyleHsp" style=""></span>mg dydrogesterone&#41; on the skin of 40 postmenopausal women found an increase in skin thickness&#44; hydration&#44; and elasticity after 7 months of treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0630"><span class="elsevierStyleSup">36</span></a> Another study &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>55&#41; showed that postmenopausal women on HRT with estrogen and testosterone had 48&#37; higher collagen content in the skin&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">37</span></a> A similar study &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>25&#41; reported significantly higher type III collagen content in women treated with estradiol and testosterone implants&#46;<a class="elsevierStyleCrossRef" href="#bib0640"><span class="elsevierStyleSup">38</span></a> Likewise&#44; a large prospective study involving 176 women found a 5&#46;2&#37; increase in skin elasticity after 12 months of HRT&#46;<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 &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>200&#41; in women on HRT&#46;<a class="elsevierStyleCrossRef" href="#bib0645"><span class="elsevierStyleSup">39</span></a> Nonetheless&#44; a large RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>485&#41; detected no differences in facial wrinkles or skin laxity between postmenopausal women treated with HRT and those treated with placebo&#46;<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&#46;<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&#46;<a class="elsevierStyleCrossRefs" href="#bib0655"><span class="elsevierStyleSup">41&#44;42</span></a> Potential adverse effects include gynecomastia and carpal tunnel syndrome&#46;</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&#46; 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&#44; such as vitiligo and melasma&#46;<a class="elsevierStyleCrossRefs" href="#bib0665"><span class="elsevierStyleSup">43&#44;44</span></a> It has an excellent safety profile&#46; The findings of numerous in vitro studies using animal and human models suggest that <span class="elsevierStyleItalic">P&#46; leucotomos</span> might be able to mitigate photoaging induced by UV radiation and visible light&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">43</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">A recent double-blind RCT &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>30&#41; found a significant increase in minimal erythema dose and skin antioxidant capacity and skin hydration&#44; in addition to improvements in skin appearance and elasticity following oral supplementation with a dietary product containing <span class="elsevierStyleItalic">P&#46; leucotomos</span>&#44; green tea&#44; and other antioxidants&#46;<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&#46; A double-blind RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>33&#41; evaluating the effects of oral coenzyme Q10 on the skin found improvements in wrinkles and skin smoothness&#44; but no changes in skin hydration&#44; dermal thickness&#44; or minimal erythema dose&#46;<a class="elsevierStyleCrossRef" href="#bib0680"><span class="elsevierStyleSup">46</span></a> Another double-blind RCT &#40;<span class="elsevierStyleItalic">n</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>34&#41; found that a dietary supplement containing coenzyme Q10&#44; oral collagen&#44; vitamin C&#44; vitamin A&#44; and biotin for 12 weeks reduced facial wrinkles and increased dermal density&#44; but had no impact on skin hydration or thickness&#46;<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&#46; It is essential for the synthesis of glycoproteins&#44; glycolipids&#44; glycosaminoglycans&#44; and proteoglycans&#46; 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&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">48</span></a> In a blinded RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>53&#41;&#44; a dietary supplement containing glucosamine&#44; minerals&#44; and antioxidants significantly decreased the number of facial wrinkles and fine lines&#46;<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&#44; antitumor&#44; antiviral&#44; and antimelanogenic properties&#46;<a class="elsevierStyleCrossRef" href="#bib0700"><span class="elsevierStyleSup">50</span></a> Oral and intravenous formulations have been used to decrease skin pigmentation and photoaging&#44; but 2 recent systematic reviews of the literature&#44; including 3 RCTs&#44; did not find sufficient evidence to recommend their use in this setting&#46;<a class="elsevierStyleCrossRefs" href="#bib0700"><span class="elsevierStyleSup">50&#44;51</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">A more recent RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>124&#41;&#44; not included in the above systematic reviews&#44; 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&#46; Glutathione 250<span class="elsevierStyleHsp" style=""></span>mg alone&#44; however&#44; was not significantly superior to placebo&#46;<a class="elsevierStyleCrossRef" href="#bib0710"><span class="elsevierStyleSup">52</span></a> Another recent RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>46&#41; reported decreased skin pigmentation following an 8-week regimen of 600<span class="elsevierStyleHsp" style=""></span>mg of glutathione&#44; 50<span class="elsevierStyleHsp" style=""></span>mg of &#945;-lipoic acid&#44; and 4<span class="elsevierStyleHsp" style=""></span>mg of zinc&#46;<a class="elsevierStyleCrossRef" href="#bib0715"><span class="elsevierStyleSup">53</span></a> Even better results were observed for oral glutathione combined with topical 2&#37; glutathione&#46; A multicenter RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>83&#41;&#44; however&#44; found no significant differences between glutathione supplementation and placebo&#46;<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&#44; but it is also synthesized and metabolized in the skin&#46; It has powerful antioxidant&#44; anti-inflammatory&#44; immunomodulatory&#44; and antitumor properties&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0725"><span class="elsevierStyleSup">55</span></a> In our review of the literature&#44; we found no clinical studies analyzing its effect on skin aging&#46;</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&#46; Multiple studies have shown that it can reduce the incidence of age-related diseases&#44; such as cardiovascular and neurological diseases and cancer&#44; as well as overall mortality<a class="elsevierStyleCrossRef" href="#bib0730"><span class="elsevierStyleSup">56</span></a> in both diabetic and nondiabetic individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0735"><span class="elsevierStyleSup">57</span></a> Animal studies have also shown an increase in lifespan&#46;<a class="elsevierStyleCrossRef" href="#bib0740"><span class="elsevierStyleSup">58</span></a> The ongoing Targeting Aging with Metformin &#40;TAME&#41; trial is a large multicenter trial evaluating the effects of metformin on human aging&#46;<a class="elsevierStyleCrossRef" href="#bib0745"><span class="elsevierStyleSup">59</span></a> We did not find any clinical studies analyzing its use in skin aging&#46;</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&#44; which are powerful antioxidants and anti-inflammatory agents&#46; Clinical studies have shown that it has several antiaging and cardio- and neuro-protective properties&#44; and can also alleviate osteoarticular&#44; urologic&#44; and menopause-related discomfort&#46;<a class="elsevierStyleCrossRef" href="#bib0750"><span class="elsevierStyleSup">60</span></a> The extract has also been found to have a photoprotective&#44; modulating effect on skin pigmentation&#46;<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&#44; such as wrinkles and solar lentigines&#44;<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">62&#44;63</span></a> and increased levels of hyaluronan synthase and type I collagen&#46;<a class="elsevierStyleCrossRef" href="#bib0770"><span class="elsevierStyleSup">64</span></a> Another RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>76&#41; showed increased skin elasticity and hydration and decreased skin darkening in Asians working in highly polluted areas after treatment for 12 weeks&#46;<a class="elsevierStyleCrossRef" href="#bib0775"><span class="elsevierStyleSup">65</span></a> No relevant adverse effects were reported&#46;</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&#44; zinc&#44; and other antioxidants led to improved facial appearance in 2 RCTs led by the same group of authors &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>152<a class="elsevierStyleCrossRef" href="#bib0780"><span class="elsevierStyleSup">66</span></a> and n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>72<a class="elsevierStyleCrossRef" href="#bib0785"><span class="elsevierStyleSup">67</span></a>&#41;&#46; Similar findings were reported in prospective clinical studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0790"><span class="elsevierStyleSup">68&#44;69</span></a> A large multicenter RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>194&#41;&#44; however&#44; found no significant differences with placebo&#46;<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&#46;<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&#44; such as vitamins A&#44; C&#44; D&#44; and E&#44; green tea polyphenols&#44; niacinamide&#44; and trace elements such as zinc may help mitigate signs of skin aging&#46; Many of the studies evaluating different combinations of antioxidants&#44; however&#44; have used different methodologies&#44; impeding replication&#46;<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&#44; and some authors urge caution when it comes to recommending vitamins or dietary supplements to well-nourished individuals&#46;<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>&#44; <span class="elsevierStyleItalic">Citrus paradisi</span>&#44; <span class="elsevierStyleItalic">Rosmarinus officinalis</span>&#44; <span class="elsevierStyleItalic">Cyclopia intermedia</span>&#44; and <span class="elsevierStyleItalic">Hydrangea serrata</span>&#44;<a class="elsevierStyleCrossRef" href="#bib0815"><span class="elsevierStyleSup">73</span></a> but clinical evidence is lacking&#46;</p><p id="par0145" class="elsevierStylePara elsevierViewall">Almonds contain high levels of vitamin E&#46; Two RCTs &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>91 and n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>31&#41; showed that participants who consumed almonds as 20&#37; of their daily energy intake experienced a significant reduction in wrinkles and facial pigmentation&#46;<a class="elsevierStyleCrossRefs" href="#bib0820"><span class="elsevierStyleSup">74&#44;75</span></a> Another RCT &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>36&#41; found that eating 85<span class="elsevierStyleHsp" style=""></span>g of mango a day reduced the depth of facial wrinkles&#46; Consumption&#44; however&#44; of 250<span class="elsevierStyleHsp" style=""></span>g a day was associated with an increase in wrinkle length and depth&#46;<a class="elsevierStyleCrossRef" href="#bib0830"><span class="elsevierStyleSup">76</span></a> In a large cohort study &#40;n<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>4025&#41;&#44; beneficial effects were observed for a higher intake of vitamin C &#40;decreased likelihood of facial wrinkles and dry skin&#41; and consumption of linoleic acid &#40;less atrophy and dry skin&#41;&#46; By contrast&#44; 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&#46;<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&#46;<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&#44; as it would eliminate or reduce the need for topical treatments or invasive or minimally invasive procedures&#44; which can be costly and are not without adverse effects&#46; Multivitamin and dietary supplements have many uses and are popular among the general population&#44; and demand for antiaging supplements is on the rise&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">15</span></a> It is estimated that more than 50&#37; of adults in the United States take vitamin supplements&#44; and this percentage is expected to increase in coming years&#46;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">77</span></a> Vitamins and other supplements are perceived as natural and safe&#44;<a class="elsevierStyleCrossRef" href="#bib0835"><span class="elsevierStyleSup">77</span></a> but the evidence supporting their effectiveness is weak&#46; According to a recent systematic review&#44; supplementation with vitamin A&#44; C&#44; B<span class="elsevierStyleInf">12</span>&#44; B<span class="elsevierStyleInf">3</span>&#44; B<span class="elsevierStyleInf">6</span>&#44; and D &#40;with or without calcium&#41;&#44; multivitamins&#44; selenium&#44; and calcium does not reduce the risk of overall or cardiovascular mortality&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0840"><span class="elsevierStyleSup">78</span></a> Indeed&#44; it advises against beta-carotene supplementation&#44; as there is evidence that it might increase the risk of lung cancer and overall and cardiovascular mortality&#46; It also advises against vitamin E for the prevention of cardiovascular disease and cancer&#44; and warns of the potential risks of vitamin or mineral supplementation in general&#44; recommending instead a healthy&#44; balanced diet&#46;<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&#44; as their purpose is to reverse or slow down a natural process rather than treat a particular disease&#46; 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&#44; as most of the evidence is based on small&#44; single-center studies with short follow-up periods &#40;mostly 2&#8211;4 months&#41;&#44; predominantly female samples&#44; and use of heterogeneous methodologies and evaluation criteria&#46; In addition&#44; some of the confirmatory studies have been performed by the same researchers&#46; Agreement on clinically relevant outcome measures is also lacking&#44;<a class="elsevierStyleCrossRef" href="#bib0805"><span class="elsevierStyleSup">71</span></a> and many studies have clear conflicts of interest&#46;</p><p id="par0160" class="elsevierStylePara elsevierViewall">In our review of the literature&#44; we did not find any prospective clinical studies with sufficient evidence to support the use of metformin&#44; melatonin&#44; tranexamic acid&#44; vitamins A&#44; C&#44; D&#44; E&#44; niacinamide&#44; or zinc in the treatment of skin aging&#46; Evidence on isotretinoin is also lacking&#44; and caution must be exerted before recommending its use due to potential safety issues&#46; More evidence is also needed on the effects of HRT on skin aging&#44; and careful consideration must be given to the risk of cardiovascular disease and breast cancer before prescribing this treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0845"><span class="elsevierStyleSup">79</span></a> We also found insufficient evidence to recommend glucosamine&#44; glutathione&#44; or coenzyme Q10&#46;</p><p id="par0165" class="elsevierStylePara elsevierViewall">Oral supplementation with hydrolyzed collagen&#44; analyzed by 24 RCTs&#44; has the strongest evidence in favor of its use for the mitigation of skin aging&#46;<a class="elsevierStyleCrossRefs" href="#bib0510"><span class="elsevierStyleSup">12&#44;16&#44;17&#44;26&#44;80&#44;81</span></a> It is inexpensive&#44; has a good safety profile&#44; and may also work in synergy with other antioxidants and anti-inflammatory agents&#46; Oral HA is another novel&#44; well-tolerated treatment that could help mitigate the effects of skin aging&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">19&#8211;22&#44;26</span></a> Optimal doses&#44; molecular weights&#44; and duration of treatment remain to be determined for both collagen and HA supplements&#46; Other promising compounds are French maritime pine bark extract<a class="elsevierStyleCrossRefs" href="#bib0760"><span class="elsevierStyleSup">62&#44;63</span></a> and marine complexes&#46;<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&#44; which is characterized by cell cycle arrest and changes in the epigenome&#44; transcriptome&#44; proteome&#44; and secretome&#44; is attracting increasing attention in the setting of skin aging&#46; Markers of cellular senescence include increased intracellular levels of damaged and fragmented double-stranded DNA&#44; lipofuscin&#44; cell cycle inhibitors such as p16 and p21&#44; and a proinflammatory secretory phenotype&#46; The long-term presence of senescent cells has been linked to aging and skin diseases&#46;<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&#46;<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&#46; Questions&#44; however&#44; remain about potential adverse effects&#44; as&#44; paradoxically&#44; the transient presence of senescent cells could be beneficial during embryogenesis and wound healing&#46;<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&#46; One such molecule is rapamycin&#44; an mTOR inhibitor&#46; Acute use of this drug in animal models has been seen to reverse several characteristics of senescent fibroblasts&#44;<a class="elsevierStyleCrossRef" href="#bib0870"><span class="elsevierStyleSup">84</span></a> protect against UV radiation damage&#44;<a class="elsevierStyleCrossRef" href="#bib0875"><span class="elsevierStyleSup">85</span></a> and reinitiate fibroblast proliferation&#46;<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&#46;<a class="elsevierStyleCrossRef" href="#bib0880"><span class="elsevierStyleSup">86</span></a> Flavonoids and plant extracts such as <span class="elsevierStyleItalic">Solidago virgaurea</span> extracts&#44; are capable of modulating cellular senescence&#46;<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&#44; but clinical studies are needed to evaluate their true effectiveness and safety&#46;</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&#46; In addition&#44; most of the studies analyzed were small prospective studies or clinical trials with heterogeneous methodologies&#46;</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&#46; Clinical evidence&#44; however&#44; is largely lacking&#46; Potential risks and benefits must be carefully weighed up before recommending any treatments&#46; Oral supplementation with hydrolyzed collagen and HA has a good safety profile and is supported by the strongest evidence&#46;</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&#44; in the collection&#44; analysis&#44; or interpretation of data&#44; or in the preparation&#44; review&#44; or approval of this manuscript&#46;</p></span></span>"
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          "titulo" => "Introduction"
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        "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&#46; The most widely used treatments are topical products and minimally invasive procedures&#46; Evidence on the benefits of systemic therapy is limited for several reasons&#58; reliance on mostly small and predominantly female samples&#44; short study durations&#44; methodologic heterogeneity&#44; and a lack of consensus on which outcome measures are clinically relevant&#46; Furthermore&#44; systemic drugs and oral supplements are not without adverse effects&#46; Oral hydrolyzed collagen and oral hyaluronic acid are well tolerated&#44; and numerous clinical trials show they can mitigate some signs of skin aging&#46; Low-dose oral isotretinoin is another option&#44; but it has a higher risk of adverse effects&#46; Evidence is lacking on the effects of the many dietary supplements on offer&#44; such as vitamins&#44; flavonoids&#44; plant extracts&#44; and trace elements&#46; The future of skin aging management would appear to lie in the use of senolytic and senomorphic agents targeting senescent cells in the skin&#46;</p></span>"
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        "resumen" => "<span id="abst0015" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">El envejecimiento cut&#225;neo est&#225; influido por factores intr&#237;nsecos y extr&#237;nsecos y m&#250;ltiples mecanismos patog&#233;nicos est&#225;n involucrados&#46; Los tratamientos utilizados en la actualidad son sobre todo t&#243;picos o son procedimientos m&#237;nimamente invasivos&#46; La evidencia sobre la utilidad de la terapia sist&#233;mica es limitada&#58; los estudios son en su mayor&#237;a de peque&#241;o tama&#241;o&#44; de reducida duraci&#243;n&#44; incluyen a mujeres de manera mayoritaria&#44; la metodolog&#237;a de evaluaci&#243;n es heterog&#233;nea y no hay par&#225;metros consensuados de respuesta cl&#237;nica relevante&#46; Adem&#225;s&#44; los suplementos o f&#225;rmacos sist&#233;micos no est&#225;n exentos de efectos adversos&#46; El col&#225;geno hidrolizado oral y el &#225;cido hialur&#243;nico oral son bien tolerados y m&#250;ltiples ensayos cl&#237;nicos muestran que pueden mitigar algunos signos de envejecimiento cut&#225;neo&#46; La isotretino&#237;na oral en dosis bajas es otra alternativa&#44; pero con un mayor potencial de efectos adversos&#46; M&#250;ltiples suplementos&#44; como vitaminas&#44; flavonoides&#44; diversos extractos de plantas y oligoelementos presentan escasa evidencia cl&#237;nica&#46; El futuro del manejo del envejecimiento cut&#225;neo parece ser el tratamiento con agentes senol&#237;ticos o senom&#243;rficos dirigidos espec&#237;ficamente contra c&#233;lulas cut&#225;neas senescentes&#46;</p></span>"
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          "en" => "<p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Skin changes induced by intrinsic and extrinsic aging &#40;exposome&#41;&#46; Aged skin is characterized by an atrophic epidermis&#44; with senescent keratinocytes and melanocytes and a flattened basement membrane&#46; Other features include a significantly reduced papillary dermis&#44; senescent fibroblasts&#44; significant extracellular matrix &#40;ECM&#41; remodeling&#44; and subcutaneous tissue thinning&#46;</p>"
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                  <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&nbsp;\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&nbsp;\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&nbsp;\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
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                  \t\t\t\t">Induction of matrix metalloproteinasesIncreased production of proinflammatory cytokinesIndirect DNA damageMitochondrial damage&nbsp;\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&nbsp;\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&nbsp;\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
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                  \t\t\t\t">Altered micro-RNA expression and dysregulated gene expression&nbsp;\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
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                  \t\t\t\t">Dysregulation of apoptosisAltered collagen gene expression&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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&nbsp;\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&#8211;induced DNA damage&nbsp;\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&nbsp;\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&#46;</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&#47;y&nbsp;\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&#46; of patients&nbsp;\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&nbsp;\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&nbsp;\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">Hern&#225;ndez-P&#233;rez et al&#46;&#44; 2000<a class="elsevierStyleCrossRef" href="#bib0885"><span class="elsevierStyleSup">87</span></a>&nbsp;\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&nbsp;\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&#8211;20<span class="elsevierStyleHsp" style=""></span>mg 3 times&#47;wk for 2<span class="elsevierStyleHsp" style=""></span>mo<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a>&nbsp;\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&#44; pore size&#44; and hyperpigmentation&#46; Increased skin thickness&#44; elasticity and tone&#46;&nbsp;\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&#46;&#44; 2009<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">10</span></a>&nbsp;\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&nbsp;\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&#46; 20<span class="elsevierStyleHsp" style=""></span>mg 3 times&#47;wk for 3<span class="elsevierStyleHsp" style=""></span>mo&nbsp;\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&#46; Good&#47;excellent subjective rating of results by patients and researchers in both groups&#46; Microscopic findings showing an increase in collagen fibers &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#60;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41; and a tendency toward decreased elastosis&#46;&nbsp;\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&#46;&#44; 2010<a class="elsevierStyleCrossRef" href="#bib0505"><span class="elsevierStyleSup">11</span></a>&nbsp;\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&nbsp;\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&#47;wk and topical sunscreen for 3<span class="elsevierStyleHsp" style=""></span>mo vs&#46; topical sunscreen&nbsp;\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 &#40;epidermal thickness&#44; number of elastic fibers&#44; and dermal collagen&#41; between groups&#46; Significant reduction in epidermal p53 expression in ISO group&#46;&nbsp;\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&#46;&#44; 2014<a class="elsevierStyleCrossRef" href="#bib0890"><span class="elsevierStyleSup">88</span></a>&nbsp;\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&nbsp;\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&#47;d vs&#46; topical retinoic acid 0&#46;05&#37; for 6<span class="elsevierStyleHsp" style=""></span>mo&nbsp;\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&#44; histologic &#40;decreased stratum corneum&#44; increased epidermal thickness&#44; and reduced elastosis&#41; and immunohistochemical &#40;reduced p53&#44; increased dermal collagen&#41; findings&#46; Nonsignificant differences &#40;<span class="elsevierStyleItalic">P</span><span class="elsevierStyleHsp" style=""></span>&#62;<span class="elsevierStyleHsp" style=""></span>&#46;05&#41;&nbsp;\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&#46;&#44; 2019<a class="elsevierStyleCrossRef" href="#bib0895"><span class="elsevierStyleSup">89</span></a>&nbsp;\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&nbsp;\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&#47;d vs&#46; tretinoin 0&#46;05&#37; cream every 48<span class="elsevierStyleHsp" style=""></span>h for 6<span class="elsevierStyleHsp" style=""></span>mo&nbsp;\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&#46; Both groups showed an improvement in number of actinic keratoses&#44; histologic variables &#40;decreased stratum corneum&#44; increased epithelial thickness&#41;&#44; and immunohistochemical variables &#40;decreased expression of p53 and bax and increased expression of bcl2&#41;&nbsp;\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 &#40;peeling&#44; laser&#44; botox&#44; liposuction&#41;&#44; but strict control of the distribution of treatments between groups and the statistical analysis was lacking&#46;</p>"
            ]
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Randomized Clinical Trials Evaluating the Use of Oral Isotretinoin &#40;ISO&#41; in the Treatment of Skin Aging&#46;</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&#44; y&nbsp;\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&#46; of patients&nbsp;\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&nbsp;\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&nbsp;\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&#46;&#44; 2018<a class="elsevierStyleCrossRef" href="#bib0850"><span class="elsevierStyleSup">80</span></a>&nbsp;\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&nbsp;\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&#47;d hydrolyzed collagen for 12<span class="elsevierStyleHsp" style=""></span>wk&nbsp;\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&#46; Reduction in periocular wrinkles&#46;&nbsp;\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&#46;&#44; 2021<a class="elsevierStyleCrossRef" href="#bib0855"><span class="elsevierStyleSup">81</span></a>&nbsp;\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&nbsp;\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&#47;d hydrolyzed collagen &#40;fish&#41; for 12<span class="elsevierStyleHsp" style=""></span>wk&nbsp;\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 &#40;-15&#37;&#41;&#46; Increased skin elasticity &#40;&#43;23&#37;&#41;&#44; hydration &#40;&#43;14&#37;&#41;&#44; and firmness &#40;&#43;25&#37;&#41;&#46;&nbsp;\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&#46;&#44; 2020<a class="elsevierStyleCrossRef" href="#bib0900"><span class="elsevierStyleSup">90</span></a>&nbsp;\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&nbsp;\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&#8211;5&#46;5<span class="elsevierStyleHsp" style=""></span>g&#47;d hydrolyzed collagen &#40;fish&#41;<span class="elsevierStyleHsp" style=""></span>&#43;<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&nbsp;\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 &#40;&#43;17&#46;8&#37;&#41; and brightness &#40;&#43;5&#46;4&#37;&#41;&#46; Reduction in periocular wrinkles &#40;-14&#46;9&#37;&#41; and pores &#40;-9&#46;9&#37;&#41;&#46; Increased dermal collagen &#40;&#43;22&#46;3&#37;&#41;&#46;&nbsp;\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&#46;&#44; 2021<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">17</span></a>&nbsp;\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&nbsp;\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&#46; 5<span class="elsevierStyleHsp" style=""></span>g&#47;d hydrolyzed collagen &#40;fish&#41; for 90<span class="elsevierStyleHsp" style=""></span>d&nbsp;\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&#46; Changes maintained for up to 30 days posttreatment&#46;&nbsp;\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&#46;&#44; 2021<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">16</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="char" valign="\n
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                  \t\t\t\t">46&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">500<span class="elsevierStyleHsp" style=""></span>mg&#47;d hydrolyzed collagen &#40;fish&#41; for 90<span class="elsevierStyleHsp" style=""></span>d&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t  " align="left" valign="\n
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                  \t\t\t\t">Increased dermal echogenicity and reduction in facial wrinkles&#46; Confocal microscopy showed reduction in elastosis and improved morphology of dermal collagen fibers&#46;&nbsp;\t\t\t\t\t\t\n
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">Supplementation With Hydrolyzed Collagen for the Treatment of Skin Aging&#58; Randomized Clinical Trials Not Included in or Published After the Meta-analysis by De Miranda et al&#46;<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">a</span></a> &#40;2021&#41;&#46;</p>"
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Author&#44; y&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">No&#46; of patients&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Main results&nbsp;\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
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                  \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&#46;&#44; 2015<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">22</span></a>&nbsp;\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&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">200<span class="elsevierStyleHsp" style=""></span>mg&#47;d of HA &#40;300<span class="elsevierStyleHsp" style=""></span>kDa and 800<span class="elsevierStyleHsp" style=""></span>KDa&#41; for 6<span class="elsevierStyleHsp" style=""></span>wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Increased skin hydration and decreased epithelial thickness&#46; Increased <span class="elsevierStyleItalic">HAS2</span> expression&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Oe et al&#46;&#44; 2017<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">21</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">60&nbsp;\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&#47;d HA &#40;2<span class="elsevierStyleHsp" style=""></span>kDa or 300<span class="elsevierStyleHsp" style=""></span>kDa&#41; for 4<span class="elsevierStyleHsp" style=""></span>wk&nbsp;\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
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                  \t\t\t\t">Improvement in periocular wrinkles &#40;improvement in sulcus volume&#44; and total wrinkle volume and area&#41;&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Kalman et al&#46;&#44; 2020<a class="elsevierStyleCrossRef" href="#bib0580"><span class="elsevierStyleSup">26</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">88&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">450<span class="elsevierStyleHsp" style=""></span>mg&#47;d hydrolyzed eggshell<a class="elsevierStyleCrossRef" href="#tblfn0020"><span class="elsevierStyleSup">a</span></a> for 12<span class="elsevierStyleHsp" style=""></span>wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
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                  \t\t\t\t">Reduction in periocular wrinkles&#46; Increased hair growth and thickness&#46; No effect on nail growth&#46;&nbsp;\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
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                  \t\t\t\t">Hsu et al&#46;&#44; 2021<a class="elsevierStyleCrossRef" href="#bib0550"><span class="elsevierStyleSup">20</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">40&nbsp;\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
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                  \t\t\t\t">120<span class="elsevierStyleHsp" style=""></span>mg&#47;d HA for 12<span class="elsevierStyleHsp" style=""></span>wk&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
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                  \t\t\t\t">Reduction in facial wrinkles&#46; Increased stratum corneum water content and skin elasticity and thickness&#46;&nbsp;\t\t\t\t\t\t\n
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                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
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                  \t\t\t\t">Michelotti et al&#46;&#44; 2021<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">19</span></a>&nbsp;\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
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                  \t\t\t\t">60&nbsp;\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
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                  \t\t\t\t">200<span class="elsevierStyleHsp" style=""></span>mg&#47;d full-spectrum HA for 28<span class="elsevierStyleHsp" style=""></span>d&#46;&nbsp;\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&#46; Reduction in transepidermal water loss and facial wrinkle volume and depth&#46;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                        "volumen" => "7"
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