Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.
Laboratory of Cutaneous Physiopathology and Integrated Center for Metabolomics Research, San Gallicano Dermatological Institute, IRCCS, Rome, Italy.
Ageing Res Rev. 2020 Jan;57:100981. doi: 10.1016/j.arr.2019.100981. Epub 2019 Nov 14.
Although senescence was originally described as an in vitro acquired cellular characteristic, it was recently recognized that senescence is physiologically and pathologically involved in aging and age-related diseases in vivo. The definition of cellular senescence has expanded to include the growth arrest caused by various cellular stresses, including DNA damage, inadequate mitochondria function, activated oncogene or tumor suppressor genes and oxidative stress. While senescence in normal aging involves various tissues over time and contributes to a decline in tissue function even with healthy aging, disease-induced premature senescence may be restricted to one or a few organs triggering a prolonged and more intense rate of accumulation of senescent cells than in normal aging. Organ-specific high senescence rate could lead to chronic diseases, especially in post-mitotic rich tissue. Recently, two opposite acquired pathological conditions related to skin pigmentation were described to be associated with premature senescence: vitiligo and melasma. In both cases, it was demonstrated that pathological dysfunctions are not restricted to melanocytes, the cell type responsible for melanin production and transport to surrounding keratinocytes. Similar to physiological melanogenesis, dermal and epidermal cells contribute directly and indirectly to deregulate skin pigmentation as a result of complex intercellular communication. Thus, despite senescence usually being reported as a uniform phenotype sharing the expression of characteristic markers, skin senescence involving mainly the dermal compartment and its paracrine function could be associated with the disappearance of melanocytes in vitiligo lesions and with the exacerbated activity of melanocytes in the hyperpigmentation spots of melasma. This suggests that the difference may arise in melanocyte intrinsic differences and/or in highly defined microenvironment peculiarities poorly explored at the current state of the art. A similar dualistic phenotype has been attributed to intratumoral stromal cells as cancer-associated fibroblasts presenting a senescent-like phenotype which influence the behavior of neoplastic cells in either a tumor-promoting or tumor-inhibiting manner. Here, we present a framework dissecting senescent-related molecular alterations shared by vitiligo and melasma patients and we also discuss disease-specific differences representing new challenges for treatment.
虽然衰老最初被描述为体外获得的细胞特征，但最近人们认识到衰老在体内与衰老和与年龄相关的疾病在生理和病理上有关。细胞衰老的定义已经扩大到包括各种细胞应激引起的生长停滞，包括 DNA 损伤、线粒体功能不足、激活的癌基因或抑癌基因以及氧化应激。虽然正常衰老过程中涉及各种组织的衰老，并随着健康衰老导致组织功能下降，但疾病诱导的过早衰老可能仅限于一个或几个器官，引发比正常衰老更快、更强烈的衰老细胞积累速度。组织特异性高衰老率可能导致慢性疾病，尤其是在后有丝分裂丰富的组织中。最近，两种与皮肤色素沉着有关的相反获得性病理状况被描述为与过早衰老有关：白癜风和黄褐斑。在这两种情况下，都证明了病理性功能障碍不仅限于黑色素细胞，即负责黑色素产生和向周围角质形成细胞运输的细胞类型。与生理黑色素生成一样，真皮和表皮细胞直接和间接地有助于由于复杂的细胞间通讯而使皮肤色素沉着失调。因此，尽管衰老通常被报道为具有共享特征标志物表达的单一表型，但主要涉及真皮区及其旁分泌功能的皮肤衰老可能与白癜风病变中黑色素细胞的消失以及黄褐斑中黑色素细胞活性的加剧有关。这表明，这种差异可能源于黑色素细胞内在差异和/或在目前的技术水平下尚未充分探索的高度定义的微环境特异性。类似的二元表型归因于肿瘤基质细胞中的肿瘤相关成纤维细胞，它们呈现出衰老样表型，以促进或抑制肿瘤细胞的行为。在这里，我们提出了一个框架来剖析白癜风和黄褐斑患者共享的与衰老相关的分子改变，并讨论了代表新的治疗挑战的疾病特异性差异。
