Senescent cells accumulate with age in tissues throughout the body. Senescent cells are created throughout life, largely because somatic cells reach the Hayflick limit on replication, but also as a result of various stresses. In youth, newly created senescent cells are cleared rapidly by the immune system. In later life, that capability declines, and senescent cells begin to linger as a result. While senescent cells never make up more than a tiny fraction of all cells in a tissue, they energetically produce inflammatory signaling, in what is known as the senescence-associated secretory phenotype (SASP). It is this signaling that causes harm when sustained over time, disruptive to cell and tissue function, and a contributing cause of age-related conditions.
There are a few different approaches to the problem of senescent cells. Firstly one can try to selectively destroy senescent cells via the use of senolytic therapies. This is the most well developed and most easily implemented approach, and has the largest set of animal and human data to suggest that it will be beneficial. In mice, certainly, it produces by far the largest and most rapid reversal of specific age-related conditions so far observed. The second approach is to prevent cells from becoming senescent, and thus allow the immune system to catch up and reduce the burden of lingering senescent cells. Therapies that upregulate autophagy, such as mTOR inhibitors, are the best example of this strategy.
The third approach is to interfere in the ability of senescent cells to generate the SASP. This is likely the most challenging of the options on the table, as it requires a much greater understanding than presently exists of the regulation of the SASP and its most important component molecules. Further, what is known of the SASP suggests that both it and its regulation are very complex. Any one protein or protein interaction target is unlikely to address more than a modest fraction of the overall problem. It seems doubtful that SASP modulation could be more effective than clearance of senescent cells, which obviously reduces the SASP quite readily, to the degree to which it reduces the burden of senescence.
Modulation of the SASP has gained attention as a therapeutic strategy for combating age-related diseases, tissue degeneration, and cancer progression. While preclinical studies show promise, clinical translation remains limited due to the heterogeneous and context-specific nature of SASP, as well as its complex crosstalk with immune pathways. Addressing these challenges requires integrated efforts in molecular biology, pharmacology, and computational sciences to develop targeted, tissue-specific therapies.
The SASP is not a uniform signature but varies depending on cell type, senescence trigger, tissue environment, and duration. While core components like IL-6, IL-8, and CXCL1 are commonly expressed, others such as extracellular vesicle-derived microRNAs and long non-coding RNAs show high tissue specificity. This molecular diversity complicates biomarker discovery and universal therapy design. Advances in single-cell RNA sequencing and spatial transcriptomics have enhanced our understanding of SASP heterogeneity, although technical limitations persist. Machine learning tools capable of integrating multi-omic datasets may help create personalized approaches for SASP modulation.
Therapeutically, SASP displays both beneficial and detrimental roles depending on context. Acute SASP promotes regeneration, wound healing, and embryonic development, but chronic SASP contributes to inflammaging, fibrosis, and cancer. For instance, senescent fibroblasts secrete pro-angiogenic factors, aiding repair while also facilitating tumor growth and immune evasion in epithelial tissues. Mitochondrial dysfunction, particularly via the cGAS-STING pathway, may drive chronic SASP and associated inflammation, yet targeting mitochondria raises concerns over the long-term effects on metabolic integrity.
The immune system is both influenced by and responsive to the SASP. Early SASP supports immune recruitment through cytokines like IL-6 and CXCL2, promoting senescent cell clearance. However, a persistent SASP can drive immune exhaustion and chronic inflammation, suppressing anti-tumor responses through elevated levels of IL-6 and TGF-β. Immunotherapies such as PD-1/PD-L1 inhibitors offer partial success but require a deeper understanding of SASP-immune dynamics to improve consistency and efficacy.
Translating preclinical findings into clinical applications presents further obstacles. Murine models often fail to replicate human senescence biology due to species-specific differences in SASP and immune responses. Emerging platforms such as humanized organoid systems and grafts of patient-derived aged tissues offer better fidelity but are hampered by inconsistent induction methods and limited standardization. Collaborative research frameworks and harmonized protocols will be essential for achieving reproducible clinical outcomes.
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