The researcher carried out an electronic search on different attributes of collagen, such as the benefits of collagen supplements, types, mechanisms of action, and side effects, as well as how long it takes to produce results. Study inclusion eligibility was contingent on whether the research had focused the effects of collagen supplements on aging reversal and whether it was an original study published in English from 2010 to 2020 across both developed and developing countries. The researcher excluded secondary data, letters to the editor, case reports, and gray literature from this review.

The research was conducted by the researcher who completed a search of published articles in 2020, scanning databases such as PubMed and Google Scholar. An independent search was carried out by the author, who examined the results for potentially appropriate studies, retrieving any needed full-text articles. The researcher grouped search terms into 4 major categories by PICOS (Population, Intervention, Comparison, Outcomes and Study) design as a framework to formulate eligibility criteria. The researcher identified a combination of Medical Subject Heading (MeSH) keywords and text words. The most prevalent search terms found in abstracts and titles included the following: “collagen supplement and aging,” “collagen supplement and wrinkles,” “role of collagen supplement in skin rejuvenation, “collagen supplement and aging reversal,” “benefits of collagen supplements in reducing aging,” “types of collagen in reducing aging,” “mechanism of collagen supplements in reducing aging” and “side effects of collagen supplements used for anti-aging”.

All appropriate research studies were imported into the reference manager software (Endnote, Clarivate Analytics) file, where each study was reviewed, and titles were also screened for duplicates. The abstracts were not considered for further review, which did not explicitly explore the study objective. Finally, the full-text articles of the remaining germane articles were obtained and examined. This action was followed by abstracting and summarizing the articles that met the eligibility criteria using a proforma standard. Aside from this, the bibliography of the remaining studies was scrutinized to avoid missing any useful studies. This process of searching the articles was carried out independently by the author, and their judgments and extracted summaries were matched to identify the differences and to resolve them accordingly.

Independent reviewers filled out a standardized data extraction sheet for the eligible research articles. The reviewers compared the data extraction tables to ensure including the imperative findings of the eligible studies and pilot tested these sheets before beginning the extraction process. Besides, prevailing research articles on the chosen topic were reviewed to describe the data extraction proforma objectives. Any discrepancies between the independent reviewers were resolved by consensus between two other reviewers.

The researcher screened the identified articles initially by titles, then by abstracts, and finally, a full-text article assessment was carried out, discarding any articles not meeting the pre-defined eligibility criteria. As a result, the initial search identified 820 citations in PubMed and Google Scholar; however, 150 articles were duplicates. Of the remaining 670 unique studies, the researcher reviewed titles and abstracts, finding 150 relevant abstracts. Upon reviewing the latters, 135 articles did not meet the eligibility criteria. Hence, the researcher was able to retrieve the complete texts of 15 articles, though more than 12 articles met the necessary criteria and were included in the review, as shown in Figure 1 .

A study was conducted in Japan in which authors gave collagen peptides to patients with aging, wrinkled skin ( Table 1 ). These patients included 66 women from Japan who were more than 40 years old, about whom researchers recorded any improvements in skin parameters. These patients were given either 10 g of collagen for 56 continuous days or no treatment at all (placebo) [ 18 ] . The authors observed a statistically noteworthy dissimilarity in the moisture of the skin throughout the experiment, accompanied by a substantial increase in the moisture for the group under treatment when compared with the placebo group. Skin moisture analyzers were utilized to test skin moisture; they are portable devices that test different skin factors utilizing bioelectric impedance analysis. The level of skin moisture is ascertained by the time it takes for the current to travel across the skin. Additionally, the same study enrolled French women of more than 40 years old and followed a similar protocol for collagen treatment for about 3 continuous months. At the completion of treatment, the author found a noteworthy moisture elevation in the collagen treatment group compared with the placebo group [ 18 ] .

Moving forward, researchers undertook a randomized controlled trial (RCT) in order to evaluate the potency of collagen peptides [ 19 ] . Recruited participants were randomly assigned to ingest either oral liquid supplements containing collagen peptides (50 ml) or placebo daily for 12 weeks [ 19 ] . No noteworthy dissimilarity in skin elasticity was noticed between the 2 arms ( Table 1 ). However, in the subgroup analysis, the authors noticed that study participants who underwent cosmetic surgeries in the treatment group showed improvement in skin elasticity, as opposed to their counterparts, who showed no improvement. At the completion of the study, participants in the therapeutic arm achieved higher marks in some skin parameters like hydration and elasticity [ 19 ] .

In another RCT, women were allocated to 4 different arms [ 20 ] . The first arm received 2.5 grams of collagen hydrolysate, the second arm was given 5.0 grams of collagen hydrolysate, the third arm received 2.5 grams of a placebo, and the fourth arm was given 5.0 grams of placebo [ 20 ] . Participants were followed for around 60 days, and it was found that each treatment arm with a different dose of collagen hydrolysate showed a statistically noteworthy rise in the elasticity of the skin when juxtaposed with their counterparts in 2 placebo groups. Improvement in elasticity was noticed among elderly women relatively earlier (ie, at 1-month follow-up) [ 20 ] . Furthermore, a positive correlation was observed between treatment with collagen hydrolysate and skin moisture and evaporation, with statistically insignificant results [ 20 ] .

Another double-blinded RCT was undertaken to assess the collagen (with low molecular weight) effects on the elasticity of the skin elasticity, hydration, and finally wrinkling [ 21 ] . This study was conducted with Korean women at least 40 years old (n = 64) who were randomized to 1000 mg of collagen or to placebo every day for 3 months [ 21 ] . The authors found noteworthy elevations in skin hydration in the treatment arm even at 6 weeks of follow-up when compared to the placebo group. Furthermore, different parameters of skin wrinkling (all 3 parameters) and skin elasticity (1/3 parameters) were notably elevated in the treatment arm when compared with the placebo group, as shown in Table 1 [ 21 ] .

In the same vein, 1 more RCT was conducted to find out the effects of collagen hydrolysate constituted of the bioactive dipeptides, prolylhydroxyproline, and hydroxypropylglycine on Chinese women (n = 85) of at least 35 years of age [ 22 ] . The study was comprised of 3 main groups: 1 was randomized to receive collagen peptides (higher content), 1 was randomized to collagen peptides (lower content), and the last group received placebo [ 22 ] . The total duration of the study was roughly 2 months, and participants took their respective treatments daily. Both intervention arms demonstrated substantial improvement in skin moisture, especially around the cheek and canthus, as opposed to the placebo group, which displayed no such improvements. Moreover, the findings also showed a substantial increase in the moisture and elasticity of the skin, as well as a reduction in wrinkling and roughness in the first treatment group, unlike either the second or the placebo groups, as shown in Table 1 [ 22 ] .

Apart from studies conducted on human beings, animals have been examined as well to assess the effect of collagen [ 23 ] . In animal models, the authors have used clinical and histological appearance, along with gene expression, to study the necessary outcomes. One research was carried out to assess the consequences of collagen hydrolysates on 9-month-old mice for 24 weeks. The results of the study revealed a significant increase in both distribution and density of said collagen and ratio between type I and type III collagen, with a particular dose-response relationship [ 23 ] .

In another study, collagen peptides were given to mice for one and a half months [ 24 ] . The authors found a higher expression of genes, along with their upregulation in the skin [ 24 ] . One more study was conducted on mice, in which they were fed a diet containing collagen hydrolysate for roughly 3 months. The study revealed improvements in the water content of their skin and an increase in elasticity, as opposed to the mice in the control group, who experienced no such benefits [ 25 ] . Lastly, mice were observed on a diet rich in prolylhydroxyproline and hydroxypropylglycine for around 5 weeks in one more study. The mice that received collagen hydrolysates showed increased skin hydration [ 26 ] .

Generally, there have been fewer studies assessing the effect of topical collagen on the aging process when compared with the studies conducted for oral collagen supplements. For instance, one conducted by Sanz et al in 2015 revealed that those women who were asked to apply a product containing collagen performed better than those in the control group [ 27 ] . More specifically, around three quarters of the treated women showed anti-wrinkling effects and substantial increases in the dermal density and elasticity of their skin after 7 days of treatment [ 27 ] . Similarly, Matthias et al conducted a retrospective study in Germany and South Africa on 480 patients with wrinkles, lax skin, scarring, and stretch marks [ 28 ] . These patients were administered percutaneous collagen after preparing their skin with necessary vitamins and creams for at least 1 month [ 28 ] . The findings demonstrated that patients were found to have skin 60% to 80% improved from before the treatment. Furthermore, researchers carried out a histologic examination on a subset of patients that demonstrated a substantial upsurge in collagen and elastin deposition. There was around 40% thickening of the epidermis, mainly stratum spinosum, 1 year after treatment [ 28 ] .

Similarly, Campos et al evaluated the consequences of topical and oral collagen additions in the skin enhancement of 60 healthy female subjects. The findings showed that females who were given a topical product demonstrated a substantial rise in skin hydration and elasticity at the end of 1 month. On the other hand, the group with oral supplementation showed more noticeable results in dermal echogenicity and decreasing pore size at the end of 3 months without any adverse effects [ 29 ] . Another study demonstrated that those patients who received topical treatment showed a noteworthy depletion in the total wrinkle surface, number of wrinkles, and average wrinkle length and depth were observed in comparison with those who underwent placebo.

In addition, the anti-wrinkle activity of the topical triple peptide complex (3%) has been reported by a clinical research conducted by Byrne et al in 2010. Their findings suggested that topical application significantly improves the photo-damaged skin by the end of 1 month when compared with the placebo group [ 30 ] . These studies revealed noteworthy relative depletions in the number of wrinkles and total wrinkle surface -in conjunction with increase in their mean depth and length -at the end of 1 month, ranging from 10% to 28% [ 30 ] .

One of the proteins found in abundance in human beings is collagen, and it helps to maintain the structure, stability, and strength of the dermal layers [ 31 ] . The studies have shown antioxidant and established reparative actions of collagen in wrinkled or damaged skin. Skin experiences the double action of collagen: first, it provides the skin essential components for both elastin and collagen, and second, it is attached to the fibroblast receptors in the dermis to initiate the production of elastin and hyaluronic acid [ 32 ] . So far, oral collagen has been studied to a greater extent than topical collagen. The available literature suggests that the topical application of collagen improves both skin elasticity and texture. However, topical collagen does not infiltrate the skin completely owning to its high molecular weight [ 33 ] . In contrast, oral collagen ingestion has been found to improve mechanical properties by increasing both the density and the diameter of collagen fibrils [ 34 ] . Orally consumed collagen bioactive peptides are absorbed relatively quickly because such collagen products have lower molecular weights, distributing these peptides easily across several tissues [ 35 ] . Additionally, evidence from the animal models suggested that oral administration of collagen reduces the intensity of skin hydration caused by UV radiation and also reduces hyperplasia of the epidermis caused by UV rays [ 36 ] . Furthermore, oral intake of collagen enhances the moisture content of the skin, especially the stratum corneum, as well as the elasticity of the skin, reducing wrinkling and roughness [ 37 ] . Overall, collagen causes an increase in fibroblasts and extracellular matrix proteins and a decrease in metalloproteinase. These rising fibroblasts found in the various layers of the human dermis produce a plethora of extracellular matrix proteins that enhance skin health and thus slow skin aging [ 38 ] .

Generally, no adverse effects of oral and topical collagen have been observed in any of these studies [ 39 ] . There have been no side effects such as vomiting, diarrhea, nausea, or constipation reported in the treatment or control groups of any of the studies [ 40 ] . For example, trials conducted in 2019 and 2020 found no adverse effects of collagen until they observed their participants [ 39 , 41 ] . These findings were also confirmed by a research by Inoue et al in 2017, where they conducted a RCT to assess the effect of high versus low doses of collagen and placebo [ 22 ] . Likewise, Genovese et al had shown analogous findings concerning the side effects during the period of study while comparing the effect of supplements on skin elasticity, wrinkling, and roughness with the placebo [ 19 ] . Besides, these findings were further endorsed by a study conducted in 2013 by Proksch et al: the authors found no side effects in any of the 4 groups that were assigned to high-dose collagen, low-dose collagen, a high-dose placebo, or a low-dose placebo [ 20 ] . One more double-blinded RCT conducted on Korean women showed no adverse events related to the treatment or intervention throughout the study period [ 21 ] . Similarly, there were no adverse effects of topical collagen in various studies [ 28 – 30 ] .