Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging
Open accessAbstract
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 TTD/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.
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In senescent cells, FOXO4 binds p53 and keeps it in the nucleus; disrupting this interaction with an inverse peptide causes p53 to leave the nucleus, triggering cytochrome c release from mitochondria and apoptosis.
“In senescent cells, FOXO4 binds to p53 to localize it to the nucleus. If this interaction is disrupted by the administration of an inverse peptide, p53 is excluded from the nucleus, initiating cytochrome c release from the mitochondria and apoptosis206.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [206]
The Results section on FOXO4-DRI reports that the peptide competes with FOXO4 for p53 binding, excludes active p53 from the nucleus, and induces apoptosis in senescent cells (page unavailable). The paper reports mitochondrial cytochrome c release after FOXO4 inhibition by shRNA, not specifically after administration of FOXO4-DRI; that step in the claimed peptide-induced sequence is not established by our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredThe peptide proxofim induces senolysis by disrupting the interaction between p53 and FOXO4.
“Administration of proxofim (a peptide) promotes senolysis by interfering with the binding of p53 to forkhead box protein O4 (FOXO4)206.”
From Cellular senescence in ageing: from mechanisms to therapeutic opportunities (2021) · cites this paper as [206]
The Results section reports that the peptide FOXO4-DRI competes with FOXO4 for p53 binding and selectively induces apoptosis in senescent cells. Our copy does not name the peptide proxofim or establish that proxofim is FOXO4-DRI, so it does not verify that part of the claim. (LLM, conf=0.84)
Experimental — accuracy not yet measuredIn Xpd TTD/TTD mice, treatment with FOXO4-DRI peptide disrupted FOXO4 interaction with p53, documenting a role for senescence in driving aging.
“the role of senescence in driving aging in the Xpd TTD/TTD was clearly documented by the fact that treatment with a D-retro inverso (DRI-)isoform peptide of FOXO4 was able to disrupt FOXO4 interaction with p53”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Baar et al., 2017
The Results section on FOXO4–p53 reports that FOXO4-DRI competes with FOXO4 for p53 binding. The Results section on XpdTTD/TTD mice reports reduced senescence and improved features of frailty after treatment. The copy does not show that the interaction was measured in those mice, so the sentence joins a demonstrated peptide mechanism to the mouse findings more directly than the paper does. (LLM, conf=0.82)
Experimental — accuracy not yet measuredFOXO4 retains p53 in the nucleus, so peptides that interfere with this interaction can cause p53-mediated apoptosis in some senescent cells.
“forkhead box O4 (FOXO4) retains p53 in the nucleus, so peptides interfering with this interaction can lead to p53-mediated apoptosis in some types of senescent cells87.”
From Cellular senescence and senolytics: the path to the clinic (2022) · cites this paper as [87]
A peptide that blocks the p53-FOXO4 interaction causes apoptosis of senescent cells in vitro and in vivo and improves fitness, hair growth, and renal function in progeroid and aged mice.
“In addition, a peptide that blocks the interaction of p53 with FOXO4 (a forkhead transcription factor family member that binds p53 to induce cellular senescence) induces apoptosis of Sncs in vitro and in vivo, improving fitness, hair growth, and renal function in progeroid and aged mice (29).”
From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [29]
Treatment with FOXO4-DRI peptide reduced lethargy and improved fur density, running wheel activity, and physical responses to stimuli in Xpd TTD/TTD mice.
“Treatment with the FOXO4-DRI peptide-reduced lethargy in Xpd TTD/TTD mice and improved fur density, running wheelactivity, and physical responsestostimuli”
From Cellular Senescence: Defining a Path Forward (2019) · cites this paper as Baar et al., 2017
FOXO4-DRI selectively induces apoptosis in senescent cells by disrupting the p53-FOXO4 interaction; removal of senescent cells using FOXO4-DRI neutralized doxorubicin-induced toxicity in vivo and restored general fitness and renal function in aged animals.
“FOXO4- DRI is a peptide designed to disrupt the p53-FOXO4 interaction, thereby selectively inducing apoptosis in senescent cells. Removal of senescent cells using FOXO4- DRI neutralized doxorubicin- induced toxicity invivo and restored general fitness as well as renal function in aged animals 218 .”
From Senescence and cancer — role and therapeutic opportunities (2022) · cites this paper as [218]
Interaction of p53 with FOXO4 during cellular senescence plays a crucial role in regulating its transcriptional activity and localization.
“Interaction of p53 with FOXO4 during cellular senescence plays a crucial role in regulating its transcriptional activity and localization (Baar et al., 2017).”
From Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021) · cites this paper as Baar et al., 2017
SASP is involved in immunological clearance of senescent cells and affects neighboring cells with intact proliferative potential.
“Although such a senescence-associated secretory phenotype (SASP) appears to be involved in the immunological clearance of senescent cells, it also affects the biology of neighboring cells with an intact proliferative potential (and this has major implications for senescence-inducing anticancer agents) [941–945].”
From Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. (2018) · cites this paper as [945]
Senolytic drugs are more effective against particular senescent cell types in vitro, and less effective against others, for unclear reasons.
“Senolytic drugs were known to be more effective against particular senescent cell types in vitro, and less effective against others, for unclear reasons.42,174–185”
From Senescence-induced inflammation: an important player and key therapeutic target in atherosclerosis (2020) · cites this paper as [181]
A FOXO4 peptide that perturbs the FOXO4 interaction with p53 clears senescent cells and improves healthspan in aged and progeroid mice.
“Recently, a FOXO4 peptide that perturbs the FOXO4 interaction with p53 was shown to clear senescent cells and improve healthspan in aged and progeroid mice (Baar et al., 2017).”
From Stress, cell senescence and organismal ageing (2018) · cites this paper as Baar et al., 2017
FOXO4-DRI (5 mg/kg injected every 2 days for 6 days) triggers selective apoptosis in senescent cells induced by ageing and by chemotherapy, resulting in improvement in mouse health, including protection of renal structure and function.
“The most important contribution came from Baar and colleagues, 17 who designed the interfering peptide, FOXO4-DRI (5 mg/kg injected every 2 days for 6 days), which was shown to trigger selective apoptosis in senescent cells induced by ageing and by chemotherapy, resulting in an improvement in mouse health, including protection of renal structure and function.”
From The costs and benefits of senotherapeutics for human health (2022) · cites this paper as [17]
Senolytic drugs identified to date were not discovered by a truly unbiased high-throughput screening method and appear to have limitations in clinical applications.
“However, the senolytic drugs identified to date were not discovered by a truly unbiased high-throughput screening (HTS) method, and thus appear to have limitations in clinical applications15,17–19.”
From A BET family protein degrader provokes senolysis by targeting NHEJ and autophagy in senescent cells (2020) · cites this paper as [18]
Senolytic drugs have significant limitations in killing senescent cells in terms of specificity and broad-spectrum activity because of the dynamic and highly heterogeneous nature of the senescence program.
“However, senolytic drugs have significant limitations in killing senescent cells in terms of specificity and broad-spectrum activity because of the dynamic and highly heterogeneous nature of the senescence program, which leads to the varying sensitivity of different types of senescent cells to current senolytic drugs.6,16,17”
From Elimination of senescent cells by β-galactosidase-targeted prodrug attenuates inflammation and restores physical function in aged mice (2020) · cites this paper as [16]
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Relevance of the p53–MDM2 axis to aging
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- Authors
- Baar, M. P., Brandt, R. M. C., Putavet, D. A., Klein, J. D. D., Derks, K. W. J., Bourgeois, B. R. M., Stryeck, S., Rijksen, Y., van Willigenburg, H., Feijtel, D. A., van der Pluijm, I., Essers, J., van Cappellen, W. A., van IJcken, W. F., Houtsmuller, A. B., Pothof, J., de Bruin, R. W. F., Madl, T., Hoeijmakers, J. H. J., Campisi, J., & de Keizer, P. L. J.
- Affiliations
- Erasmus MC (NL)
- Medical University of Graz (AT)
- Buck Institute for Research on Aging (US)
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2017-03
- Volume
- 169
- Issue
- 1
- Pages
- 132-147.e16
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC5556182
- OpenAlex
- W2599353531
- Cited by
- 1,454
- References
- 61
- Citations by year
- 2026: 109 · 2025: 149 · 2024: 173 · 2023: 145 · 2022: 177 · 2021: 169 · 2020: 184 · 2019: 160 · 2018: 124 · 2017: 62 · 2013: 1
- FWCI
- 107.28
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (publishedVersion)
- PubMed Central (acceptedVersion)
- EUR Research Repository (Erasmus University Rotterdam) (submittedVersion)
- RePub (Erasmus University Rotterdam) (submittedVersion, other-oa)
- eScholarship (California Digital Library) (submittedVersion)
- Funders
- KWF Kankerbestrijding (EMCR 2014-7141)
- National Institutes of Health (R37-AG009909)
- Erasmus Universitair Medisch Centrum Rotterdam
- National Institute on Aging (PPG AG-17242-02)
- Koninklijke Nederlandse Akademie van Wetenschappen
- Nierstichting (15OP11)
- Austrian Science Fund (DK-MCD W1226, FWF P28854)
- Topics
- Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Keywords
- senescent cells, apoptosis, FOXO4, p53, senolytics, tissue homeostasis, aging, chemotherapy toxicity, doxorubicin, healthspan, renal function
- MeSH terms
- Aging, Animals, Antibiotics, Antineoplastic, Cell Line, Cell Survival, Inclusion Bodies, Doxorubicin, Female, Fibroblasts, Humans, Kidney, Liver, Male, Tumor Suppressor Protein p53, Cellular Senescence, Apoptosis, Cell Cycle Proteins, Mice, Forkhead Transcription Factors, Trichothiodystrophy Syndromes, Cell-Penetrating Peptides
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