Impact of Senolytics on Aged Vaccine Responses

项目总结 尽管广泛接种疫苗，流感(流感)仍然是老年人死亡的主要原因。 接种疫苗是预防传染病最有效的方法。然而，年长的成年人有不规范的行为 降低疫苗效力并使其面临严重感染和死亡风险的免疫反应。更老的 成人流感后T细胞增殖减少，B细胞反应受损，抗体效价下降 接种疫苗。目前提高老年人疫苗效力的方法针对的是单一的免疫缺陷 回应，但未能完全救援回应。接种疫苗需要复杂的协调 细胞类型和组织；因此，这是一种与老年科学相一致的针对整体衰老生物学的方法 假说，可能更适合于改善老年人的疫苗保护和免疫反应。 衰老的细胞堆积是衰老的标志，随着年龄的增长，在各种组织中都很明显。尽管这些 细胞的特征是几乎不可逆的细胞周期停滞状态，它们保持新陈代谢活跃和 重要的是，分泌一种不同种类的炎性细胞因子和趋化因子的鸡尾酒，这有助于 组织功能障碍和损伤称为衰老相关分泌表型(SASP)。 衰老细胞和SASP的积累创造了促炎环境，并在 许多与年龄相关的疾病。CD4T细胞和B细胞，负责强效疫苗接种的主要细胞 对它们的微环境极为敏感。因此，我们建议，积累 随着年龄的增长，衰老的细胞和它们的SASP会导致疫苗接种反应减弱。 重要的是，专门杀死衰老细胞的药物，称为感觉剂，已经开发出来，需要 仅间歇给药以消除衰老细胞，减轻SASP。安全性和有效性 小鼠的研究表明，一系列的抗衰老药物可以缓解一系列与年龄相关的疾病。人类 初步研究已经证实了它们在某些病理上的安全性和临床实用性。然而， 老年人群中的增感剂对疫苗接种反应的影响尚未得到检验。总体假设 在这项提案中，衰老细胞和SASP在受损的流感疫苗接种中起着因果作用 衰老反应和衰老细胞的药理清除将改善疫苗接种 回应。我们将通过对幼鼠和老年鼠进行治疗来检验这一假说， 接种疫苗。我们将使用两种不同的疫苗接种方法，重组流感核蛋白来诱导 保护性免疫和佐剂灭活流感诱导中和免疫，然后感染流感小鼠 询问细胞介导性和体液免疫反应。此外，我们还将检验我们的假设 通过确定衰老的细胞条件培养液如何影响人类T和B细胞的反应 文化。这些方法将使我们能够检查细胞衰老在受损疫苗接种中的作用。 对衰老的反应，并调查促衰老药物作为疫苗接种前佐剂的翻译效用。

PROJECT SUMMARY Despite widespread vaccination, influenza (flu) remains a leading cause of death among older adults. Vaccination is the most effective way to prevent infectious disease. However, older adults have dysregulated immune responses that reduce vaccine efficacy and leave them at risk for severe infection and death. Older adults have reduced T cell proliferation, impaired B cell responses, and decreased antibody titers following flu vaccination. Current methods to improve vaccine efficacy in older adults target singular deficits in immune responses and fail to completely rescue responses. Vaccination requires a complex coordination of multiple cell types and tissues; thus an approach that targets the overall biology of aging, in line with the geroscience hypothesis, may be more appropriate for improving vaccine protection and immune responses in older adults. Senescent cell accumulation is a hallmark of aging and evident in various tissues with age. Although these cells are characterized by a mostly irreversible state of cell cycle arrest, they remain metabolically active and importantly, secrete a heterogeneous cocktail of inflammatory cytokines and chemokines that contribute to tissue dysfunction and damage that is coined senescence associate secretory phenotype (SASP). Accumulation of senescent cells and SASP create pro-inflammatory environments and have a causal role in many age-related disorders. CD4 T cells and B cells, the main cells responsible for robust vaccination responses, are extremely sensitive to their microenvironments. Thus, we propose that accumulation of senescent cells and their SASP drive diminished vaccination responses with aging. Importantly, drugs that specifically kill senescent cells, termed senolytics, have been developed and require only intermittent administration to eliminate senescence cells and mitigate the SASP. The safety and efficacy of senolytics have been shown in mouse studies and can alleviate a range of age-related diseases. Human pilot studies have supported their safety and clinical utility in certain pathologies. However, the impact of senolytics on vaccination responses in aged populations has not yet been examined. The overall hypothesis in this proposal is that senescent cells and the SASP play a causal role in impaired flu vaccination responses with aging and that pharmacological clearance of senescent cells will improve vaccination responses. We will test this hypothesis by treating young and aged mice with senolytic drugs prior to vaccination. We will utilize two different vaccination methods, recombinant flu nucleoprotein to induce protective immunity and adjuvanted inactivated flu to induce neutralizing immunity, and then infect mice with flu to interrogate both cell-mediated and humoral vaccination responses. Additionally, we will test our hypothesis in human cells by determining how senescent cell conditioned media impact human T and B cells responses in culture. These approaches will allow us to examine the role of cellular senescence in impaired vaccination responses with aging and investigate the translational utility of senolytic drugs as a pre-vaccination adjuvant.