Molecular Regulation of SASP in Cellular Senescence: Therapeutic Implications and Translational Challenges
Abstract
1. Introduction
2. Cellular Senescence: Mechanisms and Disease Implications
2.1. Accumulation of Senescent Cells and Their Role in Age-Related Diseases
2.2. Stress-Induced Premature Senescence (SIPS)
2.3. Molecular Triggers and Mechanisms
2.4. Heterogeneity of Senescent Phenotypes
2.5. Immunosenescence: Aging of the Immune System and Its Consequences
2.6. Dual Role of Senescence: Barrier and Risk Factor
3. Selected Regulators of Senescence
3.1. p53/p21 Pathway: Guardian of the Genome
3.2. p16INK4a/Rb Pathway: Cell Cycle Arrest and Tumor Suppression
3.3. Autophagy and Mitophagy in the Regulation of Cellular Senescence
4. The Dual Role of Cellular Senescence and SASP in Tissue Homeostasis and Disease
4.1. The Physiological Role of SASP
4.2. Main Regulatory Pathways of SASP
4.3. IL-6—Between Senescence and Cancer
4.4. IL-8 and TNFα in Cancer Progression and Inflammation
4.5. Pathological Microbiota and the Induction of Cellular Senescence and SASP
5. Pharmacological Strategies Targeting Senescent Cells: Senolytics, Senomorphics, and Therapeutic Challenges
5.1. Senolytics
5.2. Senomorphics
5.3. Therapeutic Challenges
6. Conclusions
- Cellular senescence acts as both a barrier to cancer and a driver of chronic diseases via the SASP.
- Senolytic and senomorphic therapies represent promising approaches, but their selectivity, clinical efficacy, and safety require further study.
- Most clinical data are still preliminary; preclinical findings should be cautiously interpreted before translation into clinical practice.
- The heterogeneity of senescent cells and lack of specific markers remain key challenges.
- Circulating SASP factors, including IL-6, may serve as valuable clinical biomarkers for predicting health status and complications in the elderly.
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Components of SASP | Factor | Effects | Reference |
---|---|---|---|
Cytokines | IL-1α | Formation and maintenance of SASP | [126] |
Promote cancer progression | [127] | ||
IL-1β | Induce angiogenesis | [114] | |
Promote tumor invasiveness | [128] | ||
Induce immunosuppression | [129] | ||
Increase vascular permeability | [130] | ||
IL-6 | Induce EMT | [106] | |
Inhibition of dendritic cells (DCs) | [131] | ||
Induce cell proliferation | [132] | ||
TNFα | Remodeling of the extracellular matrix | [114] | |
Reinforce cellular senescence | [133] | ||
Chemokines | IL-8 | Promote tumor growth and migration | [134] |
Induce cellular senescence | [135] | ||
Groα | Induce EMT | [136] | |
Promote metastasis | [137] | ||
Groβ | Promote cell proliferation | [138] | |
Promote recruitment and polarization of M2 macrophages | |||
Groγ | Inhibition of tumor cell apoptosis | [139] | |
Mediates cancer cells migration and proliferation | [140] | ||
MCP-1 | Promote tumor growth and migration | [141,142] | |
Induction of angiogenesis | [143] | ||
Activation of tumor-associated macrophages | |||
CXCL-11 | Induce tumor-suppressive cells (NKs, CTLs) | [144] | |
Promote cancer cells migration and proliferation | [145] | ||
Growth factors | IGFBP3 | Induce premature cellular senescence | [146] |
IGFBP7 | Induce cellular senescence | [147] | |
TGF-β | Promote tumor cells apoptosis | [148] | |
Induce EMT and metastasis | [149] | ||
MIC-1 | Promote cancer cells invasiveness | [150] | |
Acceleration tumor cells proliferation and invasion | [151] | ||
Others | PAI-1 | Synergistic TGF-β induced cellular senescence | [152] |
Inhibition of tumor cells apoptosis | [153] | ||
Promote polarization of M2 macrophages | [154] | ||
MMP-1 | Promote cancer cells migration and proliferation | [155] | |
Induce angiogenesis | [156] | ||
Promote cancer cells invasiveness | [157] | ||
NAMPT | Promote polarization of M1 macrophages | [158] | |
Induce inflammation | [159] | ||
STC1 | Inhibition of tumor migration and invasion | [160] | |
Promote tumorigenesis | [161] |
Compound/Class | Mechanism of Action | Cell Type/Model | Clinical Status | Gen. | Main Findings/Conclusions | Adverse Effects/Risks (Reported) | Ref. |
---|---|---|---|---|---|---|---|
Navitoclax (ABT-263/737) | BCL-2 family inhibition | IMR-90 (in vitro) MEFs (in vitro) HUVECs (in vitro) mouse lung tissue (in vivo) mouse skin (in vivo) irradiated mice (in vivo) | No clinical trials | I | Effectively clears senescent cells, particularly after irradiation or stress-induced senescence; promotes apoptosis by inhibiting BCL-2 | thrombocytopenia | [169,171,172] |
Navitoclax + Ruxolitinib | BCL-2 inhibition (navitoclax), selective JAK1/JAK2 inhibition (ruxolitinib) | Human myelofibrosis patients (in vivo) | Yes, Phase II NCT03222609 | I | Improved spleen volume, reduced symptoms, and bone marrow fibrosis in myelofibrosis patients | Thrombocytopenia (88%), anemia, fatigue | [173] |
Navitoclax + Venetoclax + Decitabine | BCL-2 family inhibition (navitoclax), selective BCL-2 inhibition (venetoclax), DNA hypomethylation (decitabine) | Human refractory acute myeloid leukemia (AML) patients (in vivo) | Yes, Phase Ib NCT05222984 | I | 20% achieved complete remission with incomplete/partial hematologic recovery (CRi/CRh), 60% had reduction in bone marrow blasts, 20% proceeded to allogeneic stem cell transplantation | Thrombocytopenia, neutropenia, anemia, febrile neutropenia, gastrointestinal symptoms (nausea, diarrhea) | [174] |
Venetoclax (ABT-199) | Selective BCL-2 inhibition | Human sarcoma cell lines STS93, STS109, STS117 (in vitro) | No clinical trials | I | Induces apoptosis in irradiated, senescent sarcoma cells. | Not applicable | [175] |
Quercetin | BCL-2/Bcl-xL inhibition Axl/STAT3/IL-6 pathway suppression, EMT blockade | Jurkat T cells (in vitro) U87MG, U373MG, glioblastoma cells (in vitro) glioblastoma PANC-1 (in vitro) PATU-8988 pancreatic cancer cells (in vitro) | No clinical trials | I | Induces apoptosis in cancer cells, suppresses EMT and invasiveness, reduces STAT3/IL-6 signaling | Not applicable | [176,177,178] |
Dasatinib + Quercetin (D + Q) | Multi-kinase inhibition (dasatinib) BCL-2/Bcl-xL inhibition (quercetin) | Postmenopausal women aged 55–80 with osteopenia or generally healthy (in vivo) | Yes, Phase II NCT04313634 | I | In exploratory analyses, women with higher baseline levels of T cell senescence markers showed improvements in bone formation, reduced bone resorption, and increased radial bone mineral density after treatment | No significant adverse effects reported | [179] |
Adults with diabetic kidney disease (in vivo) | Yes, Phase II NCT02848131 | I | Short-term D + Q treatment reduced the burden of senescent cells (p16INK4A, p21CIP1, and SA-β-gal positive cells) in adipose tissue and skin, decreased SASP factors and inflammatory markers | Mild to moderate gastrointestinal symptoms, transient chills, or headache observed. | [180] | ||
Piperlongumine | OXR1 protein degradation | Human peripheral blood mononuclear cells (PBMCs) (in vitro) | No clinical trials | I | Senolytic compounds reduced the epigenetic age of blood samples in vitro; supports rejuvenation potential of senolytic treatment in human cells | Not applicable | [181] |
Curcumin | Nrf2 and NF-κB inhibition | Human intervertebral disc cells (in vitro) | No clinical trials | I | Induces apoptosis in senescent cells | Not applicable | [182] |
PPARγ/p53 activation | Rat hepatic stellate cells (in vivo) | No clinical trials | I | Induction of senescence in rat HSCs; increased expression of p16 and p21 | No significant adverse effects reported | [183] | |
Ouabain | Na+/K+-ATPase inhibition | Senescent IMR-90 human fibroblasts (in vitro) | No clinical trials | I | Selectively induces apoptosis in senescent cells by upregulating NOXA; a broad-spectrum senolytic effect has been demonstrated both in vitro and in vivo | Potential cardiac toxicity | [184] |
Fisetin | PI3K/Akt and mTOR pathway inhibition | MRL/lpr mice with lupus nephritis (in vivo) | No clinical trials | I | Reduced senescent tubular epithelial cells, inhibited fibroblast proliferation, reduced fibrosis, and improved kidney function | No significant adverse effects reported | [185] |
Postmenopausal women, survivors of stage I–III breast cancer after chemotherapy (in vivo) | Yes, Phase II NCT05595499 | I | Study ongoing; results not yet available | Study ongoing; adverse effects not yet reported | [186] | ||
mGL392 (micelle-encapsulated GL392) | Selective delivery to senescent cells via lipofuscin-binding domain dasatinib-induced apoptosis | Senescent IMR-90 human fibroblasts (in vitro) | No clinical trials | II | Effectively eliminates senescent cells, demonstrated improved tissue function and reduced SASP in animal models. | No significant adverse effects reported | [187] |
uPAR-targeting CAR T cells | uPAR-targeted recognition and elimination of senescent cells (CAR T cells) | Senescent IMR-90 (in vitro) mouse models of liver fibrosis (in vivo) mouse models of lung adenocarcinoma (in vivo) | No clinical trials | II | Selectively eliminate senescent cells, restore tissue homeostasis, reduce fibrosis, and improve physical function in vivo | CRS, transient weight loss, hypothermia, increased serum cytokines at high doses; mild, transient macrophage infiltration in lungs; no significant toxicity at therapeutic doses | [170] |
GPNMB-targeted senolytic vaccine | Induction of immune responses against GPNMB-expressing senescent cells | Senescent mouse fibroblasts (in vitro) aged mouse models (in vivo) | No clinical trials | II | Selectively eliminates senescent cells, improves physical function, delays age-related pathologies, and extends lifespan in mice | No significant adverse effects reported | [36] |
Compound/Class | Mechanism of Action | Cell Type/Model | Clinical Status | Main Findings/Conclusions | Adverse Effects/Risks (Reported) | Ref. |
---|---|---|---|---|---|---|
Rapamycin (Sirolimus) | mTOR inhibition suppression of SASP factors | Genetically heterogeneous mice (in vivo) | Approved for other indications (immunosuppression), not approved for anti-aging | Feeding rapamycin late in life (600 days of age) significantly extended median and maximal lifespan in both male and female mice. Effect observed despite late intervention. | No significant adverse effects reported | [190] |
Older adults with periodontal disease | Yes, Phase II—RAPID | Results pending | No significant adverse effects reported | [191] | ||
Women aged 35–45 (in vivo) | Yes, Phase I NCT05836025 | Ovarian aging deceleration (~20%) potential menopause delay (~5 years) Improvement of memory, energy, skin, hair | No significant adverse effects reported | [192] | ||
Metformin | Upregulation of endoplasmic reticulum (GPX7), reduction of cellular oxidative stress | IMR-90 human lung fibroblasts (in vitro) | Approved for other indications (type 2 diabetes), not approved for anti-aging | Alleviation of cellular aging, reduction of senescence-associated markers, improvement of redox homeostasis | Not applicable | [193] |
AMPK activation, improved insulin sensitivity, possible reduction of neuroinflammation | Older adults with amnestic Mild Cognitive Impairment (in vivo) | Yes, Phase II NCT00620191 | Improvement in memory and cognitive function in metformin group versus placebo | No significant adverse effects reported | [194] | |
Simvastatin | Induction of endothelial nitric oxide synthase (eNOS) via Akt pathway, inhibition of endothelial senescence | HUVEC—human endothelial cells (in vitro) Mice (in vivo) | Approved for hypercholesterolemia, no clinical trials for anti-aging in this model | Suppression of endothelial cell senescence, improved endothelial function, reduction of senescence markers both in vitro and in vivo | No significant adverse effects reported | [195] |
Reduction of cholesterol levels, potential modulation of neuroinflammation | Older adults with mild to moderate Alzheimer’s disease (in vivo) | Yes, Phase III NCT00053599 | No slowing of cognitive decline or disease progression despite significant lipid lowering | No significant difference in serious adverse effects compared to placebo | [196] | |
Resveratrol | Inhibits TLR4 oligomerization and pro-inflammatory signaling (NF-κB, STAT1/3, Akt), suppresses cytokine (IL-6, TNF-α, IL-1β) production; inhibits Aβ-induced microglial/macrophage activation | Murine microglial and macrophage cell line (in vitro) | No clinical trials | Significantly decreased cytokine production and inflammatory signaling in LPS- and Aβ-stimulated cells. | Not applicable | [197] |
Reduces number of activated microglia around amyloid plaques in the brain (partly independent of amyloid burden) | APP/PS1 transgenic mice (in vivo) | No clinical trials | Reduces activation of microglia surrounding amyloid plaques in the cortex | No significant adverse effects reported | ||
Reduction of neuroinflammation (↓ MMP9 in CSF), induction of adaptive immunity (↑ IL-4, MDC, FGF-2 in CSF | Patients with mild to moderate Alzheimer’s disease (in vivo) | Yes, Phase II NCT01504854 | 52 weeks of treatment significantly reduced MMP9 in CSF, increased anti-inflammatory and neuroprotective cytokines (IL-4, MDC, FGF-2) in CSF, attenuated the decline in cognitive (MMSE) and functional (ADCS-ADL) scores compared to placebo | Well-tolerated overall; most common: nausea, diarrhea, weight loss | [198] |
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Klepacki, H.; Kowalczuk, K.; Łepkowska, N.; Hermanowicz, J.M. Molecular Regulation of SASP in Cellular Senescence: Therapeutic Implications and Translational Challenges. Cells 2025, 14, 942. https://doi.org/10.3390/cells14130942
Klepacki H, Kowalczuk K, Łepkowska N, Hermanowicz JM. Molecular Regulation of SASP in Cellular Senescence: Therapeutic Implications and Translational Challenges. Cells. 2025; 14(13):942. https://doi.org/10.3390/cells14130942
Chicago/Turabian StyleKlepacki, Hubert, Krystyna Kowalczuk, Natalia Łepkowska, and Justyna Magdalena Hermanowicz. 2025. "Molecular Regulation of SASP in Cellular Senescence: Therapeutic Implications and Translational Challenges" Cells 14, no. 13: 942. https://doi.org/10.3390/cells14130942
APA StyleKlepacki, H., Kowalczuk, K., Łepkowska, N., & Hermanowicz, J. M. (2025). Molecular Regulation of SASP in Cellular Senescence: Therapeutic Implications and Translational Challenges. Cells, 14(13), 942. https://doi.org/10.3390/cells14130942