Skin Photoaging and the Biological Mechanism of the Protective Effects of Hesperidin and Derived Molecules

Abstract

The ultraviolet (UV) component of solar radiation is a major risk factor for the development of skin ailments, ranging from erythema in acute cases to premature skin aging and skin cancer in chronic reactions. While skin cells show a remarkable protective capacity against solar radiation, there is a growing interest in the use of natural substances for photoprotection purposes. This article describes the molecular and cellular mechanisms underlying UV radiation-induced skin aging, with a particular focus on the potential beneficial effects of hesperidin and its derivatives: hesperetin, hesperidin glucoside, and hesperidin methylchalcone. A review of the literature from the last 20 years reveals a substantial body of experimental evidence supporting the role of hesperidin in protecting the skin against UV radiation, and its effects on skin cells and tissue, including oxidative stress and aging processes. Moreover, flavonoids have other beneficial effects on skin cell vitality by modulating the immune system, metalloproteinases, and angiogenesis. The key mechanisms for the action of hesperidin and its derivatives involve the activation of the Nrf-2/ARE system, the expression of longevity genes CISD2, and interference with the MAP kinase and PI3PK/Akt signal transduction pathways. In murine experimental models, these derivative molecules have a protective role both systemically after dietary intake and through the topical application of dermocosmetic creams.

Keywords: UV radiation; flavonoids; hesperetin; hesperidin; longevity; skin photoaging.

Figure 1

A diagram of the epidermis and dermis, showing the penetration of UVA (315–400 nm) and UVB (280–315 nm) and several cellular and intercellular components referred to in the text. Abbreviations: L: Langerhans cells; M: melanocyte; MK: Merkel cell; F: fibroblast; HEM: hair elevator muscle; Mϕ: macrophage; MC: mast cell; PG: proteoglycan; COL: collagen; EL: elastin; FN: fibronectin.

Figure 2

An effective representation of skin aging. An AI image generated by the authors.

Figure 3

Histological features of young (A) and old (B) human skin [35]. Available via Creative Commons license BY 4.0. Scale bar: 50 mm.

Figure 4

A diagram of the electromagnetic spectrum. Adapted from a NASA image (GNU Free Documentation License).

Figure 5

A diagram of the effect of UV radiation on human DNA and consequences on the cell.

Figure 6

A diagram of cell and tissue damage caused by UV radiation. Abbreviations: MMPs: matrix metalloproteinases; ROA: reactive oxygen species; ECM: extracellular matrix; MAPKs: mitogen-activated protein kinases; PI3K: phosphatidylinositol 3-kinase; Akt: protein Aks, or protein kinase B; VEGF: vascular endothelial growth factor; HIF-1α: hypoxia-inducible factor; NF-kB: nuclear factor kappa-light-chain-enhancer of activated B cells; AP-1: activator protein transcription factor; NADPH: nicotine adenine dinucleotide phosphate. Capital letters indicate the main action points of hesperidin and related molecules, as mentioned in the text. The red arrows represent the cause-effect relationships between the various factors indicated here.

Figure 7

Structural formulas of hesperidin (C₂₈H₃₄O₁₅, MW 610.6 g/mol), hesperetin (C₁₆H₁₄O₆, MW 302.27 g/mol), alpha-glucosyl hesperidin (C₃₄H₄₄O₂₀, MW 772.7 g/mol), and hesperidin methylchalcone (C₂₉H₃₆O₁₅, MW 624.6 g/mol). A and B: Phenyl rings, C: heterocyclic ring of the flavone backbone.

Figure 8

The number of articles published and extracted from PubMed with keywords “Hesperetin” OR “Hesperidin” in the abstract and “Skin” in the title or abstract. Data through to 31 December 2024.

Figure 9

The cellular defense effects of flavonoids, which function as direct free radical scavengers and as stimulants of the Nrf2/ARE pathway. ROS: reactive oxygen species; Keap1: Kelch-like ECH-associated protein 1; Nrf2: nuclear erythroid factor 2-related factor 2. The red arrows indicate phenomena due to oxidative stress; the green arrows indicate protective actions enhanced by flavonoids.