Translating Senotherapeutic Interventions into the Clinic with Emerging Proteomic Technologies.
Translating Senotherapeutic Interventions into the Clinic with Emerging Proteomic Technologies.
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衰老细胞的积累现在被广泛认为是衰老和许多与年龄相关的病理学的驱动因素，例如神经变性和2型糖尿病等。靶向衰老细胞以选择性去除或改变它们释放的蛋白质是对抗年龄相关疾病的有希望的治疗策略。然而，衰老细胞的生物学是复杂的、动态的和异质的。为了更好地识别病理驱动衰老细胞并开发改变其复杂生物学或驱动其走向细胞死亡的疗法，需要对衰老相关蛋白和使衰老细胞逃避细胞死亡的机制进行详细而全面的了解。在过去的十年中，蛋白质组学工作流程的主要发展使得越来越全面，定量和特定的分子分析和细胞机制的询问成为可能。在这篇综述中，我们讨论了翻译衰老研究的现状，以及现代蛋白质组学技术，特别是基于质谱的蛋白质组学，可以加速我们对驱动衰老的基本机制的理解，并有力地探测衰老细胞异质群体的蛋白质组表型。我们将专注于这些基本的生物学见解将如何最终加速衰老靶向疗法或senotherapeutics的发展。细胞衰老是一种不可逆的生长停滞状态，具有深刻的表型变化，包括衰老相关分泌表型（SASP）。衰老细胞积累导致衰老和许多病理学，包括慢性炎症、2型糖尿病、癌症和神经变性。在临床前模型中靶向去除衰老细胞可促进健康和长寿，这表明选择性消除衰老细胞是一种有前途的治疗方法，可减轻人类中无数与年龄相关的病理。然而，将衰老靶向药物（senotherapeutics）转移到临床将需要治疗靶点和生物标志物，通过对衰老细胞群体及其分子特征的复杂和动态生物学的更好理解，以及衰老细胞和SASP的出现和维持的机制。基于质谱的蛋白质组学技术和工作流程的进步有可能满足这些需求。在这里，我们回顾了翻译衰老研究的状态，以及蛋白质组学方法如何增加我们对衰老生物学的认识。此外，我们通过新兴蛋白质组学技术的开发和应用，包括靶向和非靶向蛋白质组学方法，自下而上和自上而下的方法，稳定性蛋白质组学和表面组学，制定了从基础生物学发现到临床翻译的路线图。这些技术对于探测衰老细胞的细胞组成和动力学以及最终开发衰老型特异性生物标志物和senotherapeutics（senolytics和senomorphics）是不可或缺的。这篇综述旨在强调蛋白质组学的新兴领域和应用，这将有助于探索新的衰老细胞生物学和未来的senotherapeutics翻译。
The accumulation of senescent cells is now widely known to be a driver of aging and many age-related pathologies, such as neurodegeneration and type 2 diabetes, among others. Targeting senescent cells for selective removal or altering the proteins they release are promising therapeutic strategies against age-related diseases. However, the biology of senescent cells is complex, dynamic, and heterogeneous. In order to better identify pathology-driving senescent cells and develop therapies to alter their complex biology or drive them toward cell death, a detailed and comprehensive understanding of senescence-associated proteins and the mechanisms that enable senescent cells to evade cell death is required. Major developments in proteomic workflows over the past decade have enabled an increasingly comprehensive, quantitative, and specific molecular profiling and interrogation of cellular mechanisms. In this review, we discuss the current state of translational senescence research and how modern proteomic technologies, particularly mass spectrometry-based proteomics, can accelerate our understanding of the fundamental mechanisms that drive senescence and robustly probe the proteomic phenotypes of heterogenous populations of senescent cells. We will focus on how these fundamental biological insights will ultimately accelerate the development of senescence-targeting therapies, or senotherapeutics. Cellular senescence is a state of irreversible growth arrest with profound phenotypic changes, including the senescence-associated secretory phenotype (SASP). Senescent cell accumulation contributes to aging and many pathologies including chronic inflammation, type 2 diabetes, cancer, and neurodegeneration. Targeted removal of senescent cells in preclinical models promotes health and longevity, suggesting that the selective elimination of senescent cells is a promising therapeutic approach for mitigating a myriad of age-related pathologies in humans. However, moving senescence-targeting drugs (senotherapeutics) into the clinic will require therapeutic targets and biomarkers, fueled by an improved understanding of the complex and dynamic biology of senescent cell populations and their molecular profiles, as well as the mechanisms underlying the emergence and maintenance of senescence cells and the SASP. Advances in mass spectrometry-based proteomic technologies and workflows have the potential to address these needs. Here, we review the state of translational senescence research and how proteomic approaches have added to our knowledge of senescence biology to date. Further, we lay out a roadmap from fundamental biological discovery to the clinical translation of senotherapeutic approaches through the development and application of emerging proteomic technologies, including targeted and untargeted proteomic approaches, bottom-up and top-down methods, stability proteomics, and surfaceomics. These technologies are integral for probing the cellular composition and dynamics of senescent cells and, ultimately, the development of senotype-specific biomarkers and senotherapeutics (senolytics and senomorphics). This review aims to highlight emerging areas and applications of proteomics that will aid in exploring new senescent cell biology and the future translation of senotherapeutics.
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DOI：
10.1073/pnas.1808790115
发表时间：
2018-11-13
影响因子：
11.1
作者：
Bausch-Fluck D;Goldmann U;Müller S;van Oostrum M;Müller M;Schubert OT;Wollscheid B
通讯作者：
Wollscheid B
影响因子：
3.8
作者：
Bracun, Valentina;van Essen, Bart;Voors, Adriaan A.;van Veldhuisen, Dirk J.;Dickstein, Kenneth;Zannad, Faiez;Metra, Marco;Anker, Stefan;Samani, Nilesh J.;Ponikowski, Piotr;Filippatos, Gerasimos;Cleland, John G. F.;Lang, Chim C.;Ng, Leong L.;Shi, Canxia;de Wit, Sanne;Msallem, Joseph P. About;Meijers, Wouter C.;Klip, IJsbrand T.;van der Meer, Peter;de Boer, Rudolf A.
通讯作者：
de Boer, Rudolf A.
影响因子：
82.9
作者：
Chaib, Selim;Tchkonia, Tamar;Kirkland, James L.
通讯作者：
Kirkland, James L.
影响因子：
9
作者：
通讯作者：
--
影响因子：
16.6
作者：
Blume, John E.;Manning, William C.;Farokhzad, Omid C.
通讯作者：
Farokhzad, Omid C.