SEARCHOTHERdermatology, preclinical research

other·dermatology, preclinical research, biomedical research, geriatrics, nutrition·PMC10807130

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice

Journal of Biomedical Science · 9 authors, 7 centres

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TL;DR

This preclinical study shows that hesperetin enhances CISD2 expression in human keratinocytes from an older person, improving mitochondrial function and protecting against oxidative stress in a CISD2-dependent manner, and that late-life oral hesperetin treatment in naturally aged mice (21 months old for 5 months) retards skin aging and rejuvenates aged mouse skin.

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Hesperetin was evaluated as a CISD2 activator to attenuate skin aging using HEK001 human keratinocytes from an older person and naturally aged mice. In vitro, hesperetin enhanced mitochondrial function, protected against ROS-induced oxidative stress, and suppressed UVB-induced MMP-1 expression in a CISD2-dependent manner, as confirmed by CISD2 knockdown experiments. In mouse skin, hesperetin ameliorated UVB-induced photoaging via a CISD2-dependent mechanism. Most notably, late-life hesperetin treatment starting at 21 months of age and lasting 5 months retarded skin aging and rejuvenated naturally aged mouse skin.

STUDY TYPE

other

SPECIALTY

dermatology

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AI pipeline

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ORIGINAL PAPER

PMC10807130

Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice

Journal of Biomedical Science

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ABSTRACT

Background CDGSH iron-sulfur domain-containing protein 2 (CISD2), a pro-longevity gene, mediates healthspan in mammals. CISD2 is down-regulated during aging. Furthermore, a persistently high level of CISD2 promotes longevity and ameliorates an age-related skin phenotype in transgenic mice. Here we translate the genetic evidence into a pharmaceutical application using a potent CISD2 activator, hesperetin, which enhances CISD2 expression in HEK001 human keratinocytes from an older person. We also treated naturally aged mice in order to study the activator’s anti-aging efficacy. Methods We studied the biological effects of hesperetin on aging skin using, firstly, a cell-based platform, namely a HEK001 human keratinocyte cell line established from an older person. Secondly, we used a mouse model, namely old mice at 21-month old. In the latter case, we investigate the anti-aging efficacy of hesperetin on ultraviolet B (UVB)-induced photoaging and naturally aged skin. Furthermore, to identify the underlying mechanisms and potential biological pathways involved in this process we carried out transcriptomic analysis. Finally, CISD2 knockdown HEK001 keratinocytes and Cisd2 knockout mice were used to study the Cisd2-dependent effects of hesperetin on skin aging. Results Four findings are pinpointed. Firstly , in human skin, CISD2 is mainly expressed in proliferating keratinocytes from the epidermal basal layer and, furthermore, CISD2 is down-regulated in the sun-exposed epidermis. Secondly , in HEK001 human keratinocytes from an older person, hesperetin enhances mitochondrial function and protects against reactive oxygen species-induced oxidative stress via increased CISD2 expression; this enhancement is CISD2-dependent. Additionally, hesperetin alleviates UVB-induced damage and suppresses matrix metalloproteinase-1 expression, the latter being a major indicator of UVB-induced damage in keratinocytes. Thirdly , transcriptomic analysis revealed that hesperetin modulates a panel of differentially expressed genes that are associated with mitochondrial function, redox homeostasis, keratinocyte function, and inflammation in order to attenuate senescence. Intriguingly, hesperetin activates two known longevity-associated regulators, namely FOXO3a and FOXM1, in order to suppress the senescence-associated secretory phenotype. Finally , in mouse skin, hesperetin enhances CISD2 expression to ameliorate UVB-induced photoaging and this occurs via a mechanism involving CISD2. Most strikingly, late-life treatment with hesperetin started at 21-month old and lasting for 5 months, is able to retard skin aging and rejuvenate naturally aged skin in mice. Conclusions Our results reveal that a pharmacological elevation of CISD2 expression at a late-life stage using hesperetin treatment is a feasible approach to effectively mitigating both intrinsic and extrinsic skin aging and that hesperetin could act as a functional food or as a skincare product for fighting skin aging. Supplementary Information The online version contains supplementary material available at 10.1186/s12929-024-01005-w.

CITATION EXPORT

Zhao-Qing Shen, Cheng-Yen Chang, Chi-Hsiao Yeh et al.. Hesperetin activates CISD2 to attenuate senescence in human keratinocytes from an older person and rejuvenates naturally aged skin in mice. Journal of Biomedical Science. (2024). https://doi.org/10.1186/s12929-024-01005-w

AUTHORS

9 · 7 CENTRES

Zhao-Qing Shen, Cheng-Yen Chang, Chi-Hsiao Yeh, Chung-Kuang Lu, Hao-Chih Hung, Tai-Wen Wang, Kuan-Sheng Wu, Chien-Yi Tung, Ting-Fen Tsai

1https://ror.org/00se2k293grid.260539.b0000 0001 2059 7017Department of Life Sciences and Institute of Genome Sciences, National Yang Ming Chiao Tung University, No. 155, Sec. 2, Li-Nong Street, Peitou, Taipei 112 Taiwan
2https://ror.org/02verss31grid.413801.f0000 0001 0711 0593Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan Taiwan
3grid.145695.a0000 0004 1798 0922College of Medicine, Chang Gung University, Taoyuan, Taiwan
4https://ror.org/00nnyvd56grid.419746.90000 0001 0357 4948National Research Institute of Chinese Medicine, Taipei, Taiwan
5https://ror.org/00se2k293grid.260539.b0000 0001 2059 7017Genomics Center for Clinical and Biotechnological Applications, Cancer and Immunology Research Center, National Yang Ming Chiao Tung University, Taipei, Taiwan
6https://ror.org/00se2k293grid.260539.b0000 0001 2059 7017Center for Healthy Longevity and Aging Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
7https://ror.org/02r6fpx29grid.59784.370000 0004 0622 9172Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan