Comparative Analysis of Retinoid Generations in the Management of Skin Photoaging

Aytakin Mammadova^1* , Oktay Aliyev² , Aybaniz Taghizade² , Narmin Taghiyeva²

Abstract. Retinoids constitute the most thoroughly researched group of topical agents in dermatological anti-aging treatments due to their significant effects on epidermal cell proliferation, differentiation, and dermal extracellular matrix remodeling. This review comprehensively evaluates the pharmacological classification, mechanisms of action, clinical efficacy, safety profiles, and formulation-related issues of natural and synthetic retinoids used in the management of skin aging. Tretinoin, a first-generation retinoid, is still considered the gold standard, particularly in the improvement of photo-aged skin, thanks to strong clinical evidence; however, its use is often limited due to dose-dependent irritation. Although metabolic precursors such as retinol and retinaldehyde offer higher tolerability, their clinical success largely depends on enzymatic conversion capacity and formulation stability. Retinyl esters, frequently used in cosmetic products, show limited and variable clinical results and also raise additional concerns regarding photodegradation and potential pro-oxidant effects. While second-generation retinoids are not currently widely preferred in topical anti-aging applications, third-generation retinoids such as adapalene and tazarotene demonstrate similar efficacy to tretinoin but offer more selective receptor interaction and, in some cases, faster clinical responses. Although fourth-generation retinoids such as tripharotene and seletinoid G have shown promising results in preclinical studies, clinical data on their effects on photoaging are still insufficient. One of the key factors determining the effectiveness of retinoids is formulation technology; stability problems and limitations in skin penetration significantly affect treatment outcomes. While newly developed nanoformulation systems have the potential to increase efficacy and reduce irritation, clinical evidence in this area is still limited. Consequently, while tretinoin remains the reference standard, new generation retinoids and advanced delivery systems may offer more advantageous therapeutic profiles. However, more extensive controlled clinical trials are needed to clarify the long-term efficacy, safety, and comparative superiority of these agents.

Keywords: retinoids, skin aging, photoaging, topical anti-aging therapy, nanoformulations