Functional Features of Senescent Cells and Implications for Therapy
Abstract
1. Introduction
2. Markers of Senescent Cells Dysfunction
2.1. Cell Cycle Arrest
2.2. Lysosome Dysfunction
2.3. Mitochondria Dysfunction
2.4. Senescence-Associated Secretory Phenotype
3. Implications for Anti-Aging Therapy
3.1. Senolytic Therapy
3.2. Senomorphic Therapy
3.3. Clinical Trials of Anti-Aging Agents
4. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
References
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Organs and Tissues | SASP Factors | Other Senescent Markers |
---|---|---|
Adipose tissue | IL-6, TNF-α, IL-1β, IL-1α, MCP-1, IL-8, MMP 3, 12 | p16, p21, p53, γH2AX, SA-β-gal, LMNB1 |
Skin | IL-6, TNF-α, IL-1β, IL-1α, TGF-β, MCP-1, IL-8, MMP 1, 3, 9 | p16, p21, γH2AX, SA-β-gal, lipofuscin, LMNB1, telomere length |
Cardiovascular system | IL-6, TNF-α, IL-1β, IL-1α, TGF-β, MCP-1, MMP 3, 9, 12 | p16, p21, p53, γH2AX, SA-β-gal, telomere length |
Bone marrow | IL-6, TNF-α, IL-1β, IL-1α, TGF-β, MCP-1, MMP 9, 12, ICAM-1, IL-17a, IFN-γ, VEGF | p16, p21, p53, SA-β-gal |
Central nervous system | IL-6, TNF-α, IL-1β, IL-1α, TGF-β, MCP-1, IL-8, MMP 3, 12, TIMP | p16, p21, p53, γH2AX, SA-β-gal, LMNB1, BCL-2 |
Kidneys | IL-6, TNF-α, IL-1β, TGF-β, MCP-1, MMP 1, 12 | p16, p21, γH2AX, SA-β-gal, telomere length |
Liver | IL-6, TNF-α, IL-1α, TGF-β, MCP-1, MMP 1, 3 | p16, p21, p53, γH2AX, SA-β-gal |
Lungs | IL-6, TNF-α, IL-1β, IL-1α, IL-8, TGF-β, MMP 12, VEGF | p16, p21, p53, γH2AX, SA-β-gal |
Pancreas | IL-6, TNF-α, IL-1β, IL-1α, TGF-β, ICAM-1 | p16, p21, p53, γH2AX, SA-β-gal |
Ovary | IL-6, IL-1β, IL-1α, TGF-β, MCP-1, IL-8, TIMP | p16, p21, γH2AX, SA-β-gal, lipofuscin, BCL-2 |
Bone tissue | IL-6, TNF-α, IL-1β, IL-1α, TGF-β, MCP-1, IL-8, MMP 1, 3, 9, 12, ICAM-1, IL-17a, IFN-γ, VEGF, TIMP | p16, p21, p53, LMNB1, BCL-2 |
Senolytic Molecule | Molecular Targets | Effects |
---|---|---|
Dasatinib | Primary target: SCAP inhibition (tyrosine kinases, ephrin receptors) [65,86] | ↓ SA-β-gal+ cells in models of induced senescence of BM-MSC, adipocyte progenitors, human endothelial cells, human gingival keratinocytes, in skeletal myocytes of old C57BL/6 mice, and in ovarian cells of doxorubicin-treated C57BL/6 mice [67,68,69,70]. ↓ expression of cell cycle inhibitors p16 and p21 in jejunum epithelial cell of old C57BL/6 mice and in ovarian cells of doxorubicin-treated C57BL/6 mice [70,71]. |
Quercetin | SCAP inhibition (PI3K/AKT, BCL-2/BCL-xL, MDM2, TP53/P21) [66,86] MAPK pathway inhibition [87] Cyclooxygenase inhibition [87] Nrf2/HO1 activation [88] SIRT1 activation [89] | |
Fisetin | NF-κB and PTEN-PKCδ-NOX1 pathway downregulation [79] Nrf2 pathways activation [90] MAPK pathway inhibition [91] PI3K/AKT pathway activation [91] BCL-2 protein family inhibition [92] SIRT1 activation [89] | ↓ expression of cell cycle inhibitors p16 and p21 in ovarian cells of doxorubicin-treated C57BL/6 mice [70]. ↓ SA-β-gal+ cells in murine and human fibroblasts, astrocytes, microglial cells in old sheep [76,77,78]. |
Navitoclax | BCL-2 protein family inhibition [81] | ↓ number of senescent bone marrow hematopoietic stem cells and myoblasts in mice; in HUVECs, IMR-90 and MEF cell lines; in UV-irradiated senescent melanocytes; in brain endothelial cells in a model of accelerated aging in mice [81,82,83,84]. |
Senomorphic Molecule | Molecular Targets | Effects |
---|---|---|
Rapamycin | Primary target: mTOR pathway [103] | ↑ lifespan in mice; ↓ cataract development, ↓ age-related muscle loss, ↑ periodontal bone regeneration [103,104,105]. |
Quercetin | NF-κB, JNK, ERK, JAK-STAT, mTOR pathway downregulation [111] | ↓ SASP and SA-β-gal activity [67]. |
Metformin | AMPK-dependent pathways, NF-κB, JAK-STAT, mTOR pathway downregulation [107] | ↑ lifespan of C. elegans and mice [108]; restoration of tissue metabolism and improvement of clinical parameters in patients with age-associated disorders including diabetes mellitus, cardiovascular diseases, neurodegenerative diseases, degenerative musculoskeletal diseases, obesity [108]; ↓ senescence biomarkers in monkeys, neuroprotective effect, tendency to rejuvenation of multidimensional aging clock [109]. |
Resveratrol | SIRT1 activation [110] NF-κB pathway inhibition [110] | ↓ SASP and ROS production [110]. |
Simvastatin | HMG-CoA reductase inhibition [30] | ↓ SASP and ROS production, ↑ mitochondrial respiration in aging cells [30]. |
Geroprotective Agents | Clinical Trial | Age-Associated Conditions | Study Results |
---|---|---|---|
Rapamycin | NCT03103893 | Dermal thickness and senescence | Clinical improvement in skin appearance, improvement in histological appearance of skin tissue, histological markers of aging, increase in collagen VII [114] (phase II) |
NCT05414292 | Muscle mass during physical training in healthy individuals aged 50–90 years | N/A (recruiting healthy male volunteers) | |
NCT04200911 | Cognitive functions in early Alzheimer’s disease | N/A (early phase I) | |
Dasatinib + Quercetin | NCT02848131 | Chronic kidney disease | Reduction in SASP, p16, and p21 expression in patients with diabetic kidney disease in combination with Dasatanib [72] (phase II) |
Dasatinib + Quercetin + Fisetin | NCT04313634 | Bone resorption/bone formation markers in elderly women | Reduction in bone resorption in postmenopausal women in combination with Quercetin and Fisetin [75,115] (phase II) |
Fisetin | NCT04210986 | Osteoarthritis-related articular cartilage degeneration | N/A (phase II) |
NCT03325322 | Chronic kidney disease | N/A (phase I) | |
Navitoclax | NCT02079740 | Advanced or metastatic solid tumors | MAPK pathway inhibition, reductions in KRAS/NRAS mutation levels [116] (phase II) |
NCT03181126 | Relapsed/refractory acute lymphoblastic leukemia or relapsed/refractory lymphoblastic lymphoma | Complete remission (60% patients) [117] | |
NCT06156774 | Sarcopenia and simplified geriatric assessment in lymphoma patients | N/A (observational study) | |
CAR-T cell therapy | NCT04300998 | Older patients with hematologic malignancies | N/A (observational study) |
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Kirichenko, T.V.; Markina, Y.V.; Markin, A.M.; Vasilyev, V.S.; Hua, H.; Li, D.; Woo, A.Y.-H.; Deev, R.V.; Eremin, I.I.; Kotenko, K.V. Functional Features of Senescent Cells and Implications for Therapy. Int. J. Mol. Sci. 2025, 26, 5390. https://doi.org/10.3390/ijms26115390
Kirichenko TV, Markina YV, Markin AM, Vasilyev VS, Hua H, Li D, Woo AY-H, Deev RV, Eremin II, Kotenko KV. Functional Features of Senescent Cells and Implications for Therapy. International Journal of Molecular Sciences. 2025; 26(11):5390. https://doi.org/10.3390/ijms26115390
Chicago/Turabian StyleKirichenko, Tatiana V., Yuliya V. Markina, Alexander M. Markin, Vyacheslav S. Vasilyev, Huiming Hua, Dahong Li, Anthony Yiu-Ho Woo, Roman V. Deev, Ilya I. Eremin, and Konstantin V. Kotenko. 2025. "Functional Features of Senescent Cells and Implications for Therapy" International Journal of Molecular Sciences 26, no. 11: 5390. https://doi.org/10.3390/ijms26115390
APA StyleKirichenko, T. V., Markina, Y. V., Markin, A. M., Vasilyev, V. S., Hua, H., Li, D., Woo, A. Y.-H., Deev, R. V., Eremin, I. I., & Kotenko, K. V. (2025). Functional Features of Senescent Cells and Implications for Therapy. International Journal of Molecular Sciences, 26(11), 5390. https://doi.org/10.3390/ijms26115390