Baar Marjolein P, Brandt Renata M C, Putavet Diana A, Klein Julian D D, Derks Kasper W J, Bourgeois Benjamin R M, Stryeck Sarah, Rijksen Yvonne, van Willigenburg Hester, Feijtel Danny A, van der Pluijm Ingrid, Essers Jeroen, van Cappellen Wiggert A, van IJcken Wilfred F, Houtsmuller Adriaan B, Pothof Joris, de Bruin Ron W F, Madl Tobias, Hoeijmakers Jan H J, Campisi Judith, de Keizer Peter L J
Department of Molecular Genetics, Erasmus University Medical Center Rotterdam, Wytemaweg 80, 3015CN, Rotterdam, the Netherlands.
Institute of Molecular Biology & Biochemistry, Center of Molecular Medicine, Medical University of Graz, 8010 Graz, Austria.
Cell. 2017 Mar 23;169(1):132-147.e16. doi: 10.1016/j.cell.2017.02.031.
The accumulation of irreparable cellular damage restricts healthspan after acute stress or natural aging. Senescent cells are thought to impair tissue function, and their genetic clearance can delay features of aging. Identifying how senescent cells avoid apoptosis allows for the prospective design of anti-senescence compounds to address whether homeostasis can also be restored. Here, we identify FOXO4 as a pivot in senescent cell viability. We designed a FOXO4 peptide that perturbs the FOXO4 interaction with p53. In senescent cells, this selectively causes p53 nuclear exclusion and cell-intrinsic apoptosis. Under conditions where it was well tolerated in vivo, this FOXO4 peptide neutralized doxorubicin-induced chemotoxicity. Moreover, it restored fitness, fur density, and renal function in both fast aging Xpd and naturally aged mice. Thus, therapeutic targeting of senescent cells is feasible under conditions where loss of health has already occurred, and in doing so tissue homeostasis can effectively be restored.
急性应激或自然衰老后，不可修复的细胞损伤积累会限制健康寿命。衰老细胞被认为会损害组织功能，对其进行基因清除可延缓衰老特征。确定衰老细胞如何避免凋亡有助于前瞻性设计抗衰老化合物，以探讨是否也能恢复体内稳态。在此，我们确定FOXO4是衰老细胞存活能力的关键因素。我们设计了一种FOXO4肽，它能干扰FOXO4与p53的相互作用。在衰老细胞中，这会选择性地导致p53核排除和细胞内在凋亡。在体内耐受性良好的条件下，这种FOXO4肽可中和阿霉素诱导的化学毒性。此外，它还能恢复快速衰老的Xpd小鼠和自然衰老小鼠的健康状况、皮毛密度和肾功能。因此，在健康已经受损的情况下，对衰老细胞进行治疗性靶向是可行的，这样做可以有效地恢复组织稳态。
