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

Cell. 2017 Mar 23;169(1):132-147.e16. doi: 10.1016/j.cell.2017.02.031.

Abstract

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 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.

Keywords: FOXO4; IL6; LMNB1; Senescence; TP53; aging; apoptosis; cell-penetrating peptide; chemotherapy; tissue homeostasis.

Publication types

  • Comment

MeSH terms

  • Aging / drug effects
  • Aging / pathology*
  • Animals
  • Antibiotics, Antineoplastic / administration & dosage
  • Antibiotics, Antineoplastic / adverse effects*
  • Antibiotics, Antineoplastic / pharmacology
  • Apoptosis
  • Cell Cycle Proteins
  • Cell Line
  • Cell Survival
  • Cell-Penetrating Peptides / pharmacology*
  • Cellular Senescence / drug effects
  • Doxorubicin / administration & dosage
  • Doxorubicin / adverse effects*
  • Doxorubicin / pharmacology
  • Female
  • Fibroblasts / cytology
  • Forkhead Transcription Factors / chemistry
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Inclusion Bodies / drug effects
  • Inclusion Bodies / metabolism
  • Inclusion Bodies / pathology
  • Kidney / drug effects
  • Kidney / physiology
  • Liver / drug effects
  • Liver / physiology
  • Male
  • Mice
  • Trichothiodystrophy Syndromes / drug therapy
  • Tumor Suppressor Protein p53 / metabolism

Substances

  • Antibiotics, Antineoplastic
  • Cell Cycle Proteins
  • Cell-Penetrating Peptides
  • Forkhead Transcription Factors
  • FoxO4 protein, mouse
  • Tumor Suppressor Protein p53
  • Doxorubicin