What Is Cellular Senescence?
The Role of Senescent Cells in Aging
Current Research and Theories
Therapeutic Strategies
Challenges and Controversies
Future Outlook
Aging is a complex biological process characterized by the progressive decline of physiological integrity, leading to impaired function and increased vulnerability to disease. It is the strongest risk factor for numerous chronic conditions, including neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease.
Among the various cellular and molecular changes associated with aging, cellular senescence (a state of permanent cell cycle arrest triggered by damage or stress) has emerged as a key player.
Senescent cells secrete pro-inflammatory and tissue-degrading factors, collectively known as the senescence-associated secretory phenotype (SASP), which can impair neighboring cell function and tissue homeostasis.
While cellular senescence plays an essential role in processes like wound healing and development, its chronic accumulation contributes to age-related dysfunction.
This duality raises a compelling question at the heart of aging research: Is cellular senescence merely one feature of aging, or is it the primary driver of age-related decline and disease? Addressing this question could redefine strategies for promoting healthy aging.1
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What Is Cellular Senescence?
Cellular senescence is a stress response in which cells permanently stop dividing to prevent the spread of damage. It acts as a protective mechanism, halting the proliferation of cells that have undergone deoxyribonucleic acid (DNA) damage, telomere shortening, oxidative stress, or oncogene activation.
The key feature of senescence is irreversible growth arrest, enforced by two critical tumor suppressor pathways: the Cyclin-dependent kinase inhibitor 2A / Retinoblastoma protein (p16INK4a/Rb) pathway and the Tumor protein p53 / Cyclin-dependent kinase inhibitor 1A (p53/p21CIP1) pathway. These systems block the cell cycle, ensuring damaged cells do not divide.2
Beyond growth arrest, senescent cells undergo profound changes: they remodel chromatin, reprogram metabolism, and increase autophagy. They also release a range of inflammatory molecules called the SASP, which can signal the immune system to remove them but may also harm surrounding tissues.2
Senescence is beneficial in development, wound healing, and tumor suppression. However, over time, senescent cells accumulate and are not efficiently cleared, contributing to aging and age-related diseases by promoting chronic low-grade inflammation.
Excitingly, research shows that removing senescent cells genetically or pharmacologically can extend lifespan and reduce age-related decline, highlighting the dual role of senescence in both protecting and impairing tissue health.1,2
Overview of Cell Senescence
The Role of Senescent Cells in Aging
Senescent cells are cells that have permanently stopped dividing, usually in response to stressors such as persistent DNA damage. This process, known as cellular senescence, serves as a defense mechanism against cancer. However, as senescent cells accumulate with age, they begin to negatively impact tissues through the SASP- a pro-inflammatory secretion profile.3
SASP includes a mix of cytokines, chemokines, growth factors, and proteases. While it plays beneficial roles in acute tissue repair, immune surveillance, and developmental processes, its chronic activation leads to tissue dysfunction, low-grade inflammation, and age-related diseases. SASP factors can reinforce senescence in the same cell (autocrine effect) or spread it to nearby cells (paracrine senescence), altering the tissue microenvironment.3
A key internal trigger for SASP is the cyclic GMP-AMP synthase–stimulator of interferon genes (cGAS–STING) pathway, which is activated by abnormal cytoplasmic DNA fragments.
These fragments often result from reduced activity of DNA-degrading enzymes like DNase2 and Three Prime Repair Exonuclease 1 (TREX1) in senescent cells, leading to type I interferon signaling and inflammation.3
External triggers such as deoxycholic acid (DCA) and lipoteichoic acid (LTA)- byproducts of gut microbiota- can also induce SASP in cells like hepatic stellate cells, promoting liver cancer. Controlling SASP, including through senolysis (selective elimination of senescent cells), may offer therapeutic strategies for aging and age-associated disorders.3
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Current Research and Theories
Cellular senescence and SASP are now understood as a key driver of aging and numerous age-related diseases. While senescence initially protects against cancer by halting the proliferation of damaged cells, its chronic accumulation leads to tissue dysfunction and persistent inflammation.2
In cardiovascular tissues, senescent endothelial cells and vascular smooth muscle cells contribute to atherosclerosis by increasing inflammation and impairing vascular integrity. Animal studies reveal that these senescent cells accumulate in atherosclerotic plaques.
Pharmacological clearance using senolytic agents like dasatinib and quercetin, or navitoclax, enhances plaque stability, improves cardiac function after myocardial infarction (heart attack), and reduces tissue damage following ischemia-reperfusion injury.2,4
In osteoarthritis, senescent chondrocytes secrete inflammatory cytokines such as interleukin-1 beta (IL-1β) and tissue-degrading enzymes like matrix metalloproteinases.
These exacerbate cartilage deterioration. Preclinical studies show that eliminating senescent cells from joint tissue improves mobility and reduces joint inflammation.2,4
Senescence acts as a double-edged sword in cancer. Although it prevents tumor formation through growth arrest, the SASP can promote tumor progression by modifying the tissue environment and enabling immune evasion. Cytokines like IL-6 and IL-8 released by senescent cells facilitate tumorigenesis.2,4
Senescence also impairs stem cell regeneration, promotes metabolic disorders, and triggers chronic low-grade inflammation- termed "inflammaging."
This contributes to osteoporosis, type 2 diabetes, neurodegeneration, and other degenerative conditions. In vivo genetic mouse models, such as INK-linked Apoptosis Through Targeted Activation of Caspase (INK-ATTAC) and p16-driven Trimodality Reporter (p16-3MR), show that targeted removal of senescent cells delays age-related decline and extend health span.2,4
Together, these findings affirm that senescence is a central mechanism underlying age-related pathologies and a promising therapeutic target across multiple diseases.
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Therapeutic Strategies
Therapeutic strategies targeting cellular senescence are advancing, focusing on senolytic drugs and gene therapies. Senolytics are agents designed to selectively eliminate senescent cells, which accumulate with age and contribute to various chronic diseases.
Notable examples include dasatinib and quercetin; dasatinib is a tyrosine kinase inhibitor, while quercetin is a flavonoid, both shown to reduce senescent cell burden in preclinical studies.5
Gene therapies offer another avenue by introducing genetic material into cells to counteract aging processes. For example, BioViva has explored gene therapies to extend lifespan by targeting factors like telomerase and myostatin.6
Biotechnology firms are actively developing senolytic therapies. Unity Biotechnology focuses on creating treatments to clear senescent cells, particularly in age-related diseases such as diabetic macular edema.
Their investigational drug, foselutoclax (previously UBX1325), inhibits B-cell lymphoma-extra-large (Bcl-xL), a protein crucial for the survival of senescent cells in the retina, aiming to restore vision in diabetic macular edema patients.7
These advancements underscore the growing interest in targeting cellular senescence to promote healthier aging. These therapeutic strategies represent promising approaches to mitigate age-related diseases by addressing the underlying mechanisms of cellular senescence.
Challenges and Controversies
Cellular senescence plays a paradoxical role in health and disease. On one hand, it is essential for tissue remodeling, embryonic development, and wound healing.
Transient senescence, for instance, facilitates fibrosis resolution and immune clearance, offering protection against tumorigenesis. However, when senescent cells persist, they can contribute to chronic inflammation, tissue dysfunction, and aging-related pathologies.
This duality has fueled debate: should senescence be suppressed or supported? In the kidney, for example, senescence aids in recovery from acute injury but also accelerates chronic kidney disease progression.
The SASP further complicates this picture, as its cytokines can be either reparative or harmful depending on context. Moreover, the lack of highly specific biomarkers hampers accurate detection and targeted therapies.
While senolytic and senomorphic drugs show promise in animal models, translating these findings into safe and effective treatments for humans requires careful consideration of timing, dosage, and individual context.8
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Future Outlook
To validate causality and therapeutic viability of targeting cellular senescence, large-scale, placebo-controlled clinical trials are essential. These must assess senolytic and senomorphic interventions across diverse populations and disease contexts, with precise biomarkers to confirm senescent cell targeting.
Improved identification and classification of senescent cell subtypes using multi-omics and single-cell technologies will aid in understanding tissue-specific roles and intervention effects.
Investigating the senescent-like states of non-dividing cells, long-term safety of senotherapeutics, and their combination with disease-specific therapies will be crucial.
Further exploration of immune-based strategies and clarification of “beneficial” versus pathological senescence are also needed.9
References
- Gerdes, E. O. W., Zhu, Y., Weigand, B. M., Tripathi, U., Burns, T. C., Tchkonia, T., & Kirkland, J. L. (2020). Cellular senescence in aging and age-related diseases: Implications for neurodegenerative diseases. International review of neurobiology, 155, 203-234. https://doi.org/10.1016/bs.irn.2020.03.019
- McHugh, D., & Gil, J. (2018). Senescence and aging: Causes, consequences, and therapeutic avenues. Journal of Cell Biology, 217(1), 65-77. https://doi.org/10.1083/jcb.201708092
- Ohtani, N. (2022). The roles and mechanisms of senescence-associated secretory phenotype (SASP): can it be controlled by senolysis?. Inflammation and regeneration, 42(1), 11. https://doi.org/10.1186/s41232-022-00197-8
- Kumar, M., Yan, P., Kuchel, G. A., & Xu, M. (2024). Cellular senescence as a targetable risk factor for cardiovascular diseases: therapeutic implications: JACC family series. Basic to Translational Science, 9(4), 522-534. https://doi.org/10.1016/j.jacbts.2023.12.003
- Wang, X., Fukumoto, T., & Noma, K. I. (2024). Therapeutic strategies targeting cellular senescence for cancer and other diseases. The Journal of Biochemistry, 175(5), 525-537. https://doi.org/10.1093/jb/mvae015
- Parrish, E. BioViva’s CMV vector: a platform for better gene-therapy delivery. https://www.nature.com/articles/d43747-023-00117-w
- Hassan, J. W., & Bhatwadekar, A. D. (2022). Senolytics in the treatment of diabetic retinopathy. Frontiers in Pharmacology, 13, 896907. https://doi.org/10.3389/fphar.2022.896907
- Huang, W., Hickson, L. J., Eirin, A., Kirkland, J. L., & Lerman, L. O. (2022). Cellular senescence: the good, the bad and the unknown. Nature Reviews Nephrology, 18(10), 611-627. https://doi.org/10.1038/s41581-022-00601-z
- Zhu, Y., Anastasiadis, Z. P., Netto, J. M. E., Evans, T., Tchkonia, T., & Kirkland, J. L. (2024). Past and future directions for research on cellular senescence. Cold Spring Harbor Perspectives in Medicine, 14(2), a041205.
Further Reading