Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging

The accumulation of irreparable cellular damage restricts healthy lifespan after acute stress or natural aging. Senescent cells are thought to impair tissue function and their genetic clearance can successfully delay features of aging. Identifying how senescent cells avoid apoptosis would allow for the prospective design of anti-senescence compounds to address whether homeostasis can be restored. Here, we identify FOXO4 as a pivot in the maintenance of senescent cell viability. We designed a FOXO4-based peptide which selectively competes for interaction of FOXO4 with p53. In senescent cells, this results in p53 nuclear exclusion and cell-intrinsic apoptosis. Importantly, under conditions where it was well tolerated, the FOXO4 peptide restored liver function after Doxorubicin-induced chemotoxicity. Moreover, in fast aging XpdTTD/TTD, as well as in naturally aged mice the FOXO4 peptide could counteract the loss of fitness, fur density and renal function. Thus, it is possible to therapeutically target senescent cells and thereby effectively counteract senescence-associated loss of tissue homeostasis.

不可修复的细胞损伤累积，会在急性应激或自然衰老后限制健康寿命。衰老细胞（senescent cells）被认为会损害组织功能，而通过遗传学手段清除这类细胞，可有效延缓衰老相关表型的出现。明确衰老细胞如何规避细胞凋亡（apoptosis），将有助于前瞻性设计抗衰老化合物，以探究是否能够恢复机体稳态。本研究证实FOXO4是维持衰老细胞存活的关键调控因子。我们设计了一种基于FOXO4的多肽，可竞争性特异性阻断FOXO4与p53的相互作用。在衰老细胞中，该多肽可促使p53发生核外迁移，并触发细胞内源性凋亡。值得注意的是，在耐受性良好的给药条件下，FOXO4多肽可恢复阿霉素（Doxorubicin）诱导的化学毒性损伤后的肝脏功能。此外，在快速衰老的XpdTTD/TTD模型小鼠以及自然衰老小鼠中，FOXO4多肽可逆转机体健康水平下降、毛发密度降低以及肾功能损伤的情况。综上，通过治疗性靶向衰老细胞，可有效抵消衰老相关的组织稳态失衡。