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

By M. Baar, Renata M. C. Brandt, D. Putavet, Julian D. D. Klein, K. Derks, Benjamin Bourgeois, Sarah Stryeck, Y. Rijksen, Hester van Willigenburg, D. Feijtel and 11 more. Cell, 2017

1,276 citations recorded by the source corpus.

Summary 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 which 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 XpdTTD/TTD 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.

Subfields: Aging, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/2f6504a99c31a1f45f2924724c6eb602b5769066

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Aging

In Molecular Biology

In Physiology

Citations in the corpus

Cellular Senescence: Aging, Cancer, and Injury. (2019, background): “The FOXO4-DRI peptide neutralized doxorubicin-induced accelerated aging and restored fitness, fur density, and renal function in treated mice (19).”
A proteomic atlas of senescence-associated secretomes for aging biomarker development (2019, background): “Data from several laboratories, including our own, 52 strongly support the idea that senescent cells and the SASP drive multiple age-related 53 phenotypes and pathologies, including atherosclerosis [10], osteoarthritis [11], cancer 54 metastasis and cardiac dysfunction [12,13], myeloid skewing [14,1”
Hallmarks of Cellular Senescence. (2018, positive): “FOXO4 is overexpressed at the mRNA and protein levels in senescent cells, and prevents cell death by sequestering p53 in the nucleus [86].”
Cellular Senescence: A Translational Perspective (2017, methodology): “…example, using the strategy of targeting SCAPs, a FOXO4-related peptide that inhibits the PI3K/AKT/p53/p21/ serpine SCAP originally described in 2015 (Zhu et al., 2015b) was recently noted to be senolytic, at least in certain humanfibroblast-like culture-habituated cell strains (Baar et al., 2017).”
Kidney fibrosis: from mechanisms to therapeutic medicines (2023, background): “Recently, several creative studies validated the efficacy and safety of senescent cell clearances, applying transgenic mice with selectively sensitive pharmacological agents,(92,93) or the mice access to antiapoptotic drugs.(92,94,95) Moreover, various strategies are being tested to prevent the form”
DNA methylation aging clocks: challenges and recommendations (2019, background): “An important example in the context of aging is sporadic senescent cells that occur in aging tissues, with accumulating evidence that these cells may be a driver in deteriorating organ function [174].”