Department 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.
Department of Thoracic and Cardiovascular Surgery, Chang Gung Memorial Hospital, Linkou, Taoyuan, Taiwan.
J Biomed Sci. 2024 Jan 23;31(1):15. doi: 10.1186/s12929-024-01005-w.
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.
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.
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.
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.
CDGSH 铁硫域蛋白 2（CISD2）是一种长寿基因，可调节哺乳动物的健康寿命。CISD2 在衰老过程中下调。此外，持续高水平的 CISD2 可促进长寿并改善转基因小鼠的与年龄相关的皮肤表型。在这里，我们使用一种有效的 CISD2 激活剂橙皮素将遗传证据转化为药物应用，该激活剂可增强来自老年人的 HEK001 人角质形成细胞中的 CISD2 表达。我们还对自然衰老的小鼠进行了处理，以研究该激活剂的抗衰老功效。
我们首先使用基于细胞的平台，即源自老年人的 HEK001 人角质形成细胞系，研究了橙皮素对衰老皮肤的生物学影响。其次，我们使用了一种小鼠模型，即 21 个月大的老年小鼠。在后一种情况下，我们研究了橙皮素对紫外线 B（UVB）诱导的光老化和自然衰老皮肤的抗衰老功效。此外，为了鉴定该过程中涉及的潜在生物学途径和潜在生物学途径，我们进行了转录组分析。最后，使用 CISD2 敲低的 HEK001 角质形成细胞和 Cisd2 敲除小鼠研究了橙皮素对皮肤衰老的 Cisd2 依赖性影响。
确定了四项发现。首先，在人类皮肤中，CISD2 主要在表皮基底层的增殖角质形成细胞中表达，此外，CISD2 在暴露于阳光的表皮中下调。其次，在源自老年人的 HEK001 人角质形成细胞中，橙皮素通过增加 CISD2 表达来增强线粒体功能并抵御活性氧诱导的氧化应激；这种增强作用是 CISD2 依赖性的。此外，橙皮素减轻了 UVB 诱导的损伤并抑制了基质金属蛋白酶-1 的表达，后者是角质形成细胞中 UVB 诱导损伤的主要指标。第三，转录组分析表明，橙皮素调节了一组差异表达的基因，这些基因与线粒体功能、氧化还原稳态、角质形成细胞功能和炎症有关，以减轻衰老。有趣的是，橙皮素激活了两种已知的与长寿相关的调节剂，即 FOXO3a 和 FOXM1，以抑制衰老相关的分泌表型。最后，在小鼠皮肤中，橙皮素通过 CISD2 来增强 CISD2 的表达，以改善 UVB 诱导的光老化，而这种作用是通过 CISD2 介导的。最引人注目的是，在 21 个月大时开始并持续 5 个月的老年期使用橙皮素治疗可提高 CISD2 表达，从而有效减轻内在和外在的皮肤衰老，并使自然衰老的皮肤恢复活力。
我们的研究结果表明，使用橙皮素治疗在老年期通过药理升高 CISD2 表达是一种可行的方法，可以有效减轻内在和外在的皮肤衰老，并且橙皮素可以作为功能性食品或护肤品来抵抗皮肤衰老。
