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Decoding Cellular Senescence: From Molecular Mechanisms to Cutting-Edge Intervention Strategies

05 November 2025

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Introduction

Cellular senescence is a multifaceted state of stable growth arrest triggered by diverse intracellular and extracellular stressors, representing a systemic homeostatic response that coordinates the clearance of damaged cells and tissue regeneration. Cellular senescence can be classified into two principal types: replicative senescence and stress-induced premature senescence [1].

Figure 1. Cellular senescence description.

Decoding Cellular Senescence: Unveiling the SASP Mechanism

· Replicative senescence: occurs primarily due to telomere shortening and diminished telomerase activity, ultimately culminating in the Hayflick limit. · Stress-induced premature senescence: is independent of chronological aging and is triggered by various pathological factors, including DNA damage, oxidative stress, and oncogenic activation.

I. Cellular Senescence Phenotypes and Biomarkers

Cellular senescence does not constitute a conventional phase of the cell cycle; rather, it represents a permanent "exit" or "arrested" state from the cell cycle.

A normal, proliferative cell (such as a skin cell or intestinal epithelial cell) undergoes a cyclical process termed the "cell cycle," which includes:

1. Interphase (G1, S, G2 phases): The cell grows, replicates its DNA, and prepares for division.
2. Mitotic phase (M phase): The cell divides into two daughter cells.

This cycle repeats continuously, ensuring tissue growth and renewal.

Cellular senescence is an irreversible, stable state of growth arrest. When a cell receives specific stress or damage signals, it permanently exits the cell cycle and ceases division, yet does not undergo immediate apoptosis.

Senescence Phenotypes [2]

Table 1. Senescence phenotypes. [2]

Common Senescence Biomarkers Include:

· β-galactosidase (SA-β-gal)
· DNA damage markers (e.g., γ-H2AX)
· SABG, p16, and p21

Figure 2. Phenotypes and biomarkers of cellular senescence. [2]

DNA damage during cellular senescence leads to increased phosphorylation of γH2AX. Senescence-associated heterochromatin foci (SAHF) accumulate, while Lamin B1 is downregulated in senescent cell nuclei. Senescent cells exhibit increased lysosomal content (SA-β-gal), endoplasmic reticulum stress, and mitochondrial dysfunction. Additionally, cellular senescence is accompanied by aberrations in lipid metabolism, glutaminolysis, and NAD+ metabolism [2].

II. Mechanistic Analysis

Hallmarks of Senescence

The mechanistic understanding of senescence begins with the systematic characterization of "hallmarks of senescence." These hallmarks have undergone multiple rounds of validation; a 2025 article published in Cell updated the framework to include 14 hallmarks, incorporating two critical new dimensions: "extracellular matrix (ECM) alterations" and "psychosocial isolation." These hallmarks are not independent pathways but rather systemically interconnected [3].

The 14 Hallmarks of Senescence:

1. Genomic instability—DNA damage from internal and external factors, coupled with declining repair capacity, leads to mutation accumulation.
2. Telomere attrition—The protective caps at chromosome ends shorten with each division; excessive shortening triggers cellular senescence or death.
3. Epigenetic alterations—Dysregulation of gene "switches" leads to aberrant cellular function.
4. Loss of proteostasis—Accumulation of misfolded proteins disrupts cellular function.
5. Disabled autophagy—The cellular "waste disposal" mechanism weakens, leading to accumulation of damaged organelles.
6. Deregulated nutrient sensing—Cellular nutrient perception becomes disordered, resulting in metabolic imbalance.
7. Mitochondrial dysfunction—The cellular "powerhouse" declines in function, reducing energy supply and releasing excessive free radicals.
8. Cellular senescence—Senescent cells release inflammatory factors that "poison" surrounding cells.
9. Stem cell exhaustion—Stem cell numbers decrease and function declines, impairing tissue repair.
10. Altered intercellular communication—Abnormal cellular signaling reduces tissue coordination capacity.
11. Chronic inflammation—Aging-associated persistent low-grade inflammation damages tissues.
12. Dysbiosis—Disruption of micro-ecological balance in skin and other tissues.
13. Extracellular matrix alterations (newly added)—Changes in matrix composition and structure affect cellular function and tissue homeostasis.
14. Psychosocial isolation (newly added)—Social relationships and psychological isolation accelerate aging through mind-body interactions.

Figure 3. The 14 hallmarks of senescence. [3]

The Mechanisms of SASP

A critical component of senescence is the senescence-associated secretory phenotype (SASP), which comprises numerous pro-inflammatory cytokines, chemokines, growth factors, and proteases. SASP serves as a crucial mediator of cellular communication between senescent cells and their microenvironment, inducing senescence in neighboring cells through paracrine mechanisms.

SASP Production

SASP production primarily involves activation of the DNA damage response (DDR) pathway, which triggers p53 and p16 signaling cascades [4,5].

DDR activation leads to upregulation of p53 expression, which in turn promotes p21 production. p21 inhibits the interaction between CDK2 and cyclin E, blocking cell cycle transition from G1 to S phase. Simultaneously, p16 inhibits CDK4/6 and cyclin D activity, preventing Rb phosphorylation and maintaining it in an active hypophosphorylated state, thereby continuously inactivating E2F transcription factors. This results in cell cycle arrest and ultimately promotes SASP secretion [6].

Concurrently, mitochondrial dysfunction and endoplasmic reticulum stress in senescent cells are recognized as important drivers of SASP secretion. These insults play crucial roles in promoting reactive oxygen species (ROS) production, activating inflammatory responses, and maintaining SASP secretion [7].

SASP production is also closely associated with various senescence-inducing factors. These factors primarily include replicative senescence (RS, triggered by telomere shortening and replicative stress), therapy-induced senescence (chemotherapy, radiotherapy, and immunotherapy), and oncogene-induced senescence (gene mutation and overexpression).

Figure 4. Inducers and relative pathways of cellular senescence. [8]

The Dual Immunoregulatory Role of SASP

SASP exerts anti-tumor effects in early stages by inducing cellular senescence, activating the immune system, and promoting tissue repair, serving as an intrinsic defense mechanism protecting cells from malignant transformation.

However, if senescent cells are not cleared, their persistent expression triggers chronic inflammation, alters cellular communication, and enables tumor cells to gradually adapt to immune pressure, thereby promoting tumor progression.

Conversely, sustained activation of inflammatory pathways such as NF-κB and cGAS-STING can maintain and enhance SASP expression, shifting the immune response from activation to suppression and increasing tumor microenvironment (TME) tolerance to immune attack.

The interplay between temporal dynamics and environmental changes drives the functional transition of SASP from "defense" to "offense," providing critical insights for the design of tumor immunotherapy strategies.

Figure 5. Mechanisms of cellular senescence and SASP. [8]

III. Therapeutic Strategies

Cellular senescence plays pivotal roles not only in embryonic development, tissue regeneration, and tumor suppression, but also in the pathogenesis of age-related degenerative diseases, malignancies, metabolic disorders, and renal diseases. Pharmacological interventions targeting cellular senescence are garnering increasing attention, with therapeutic breakthroughs focusing on three principal strategies:

1. "Clearance of Senescent Cells,"
2. "Inhibition of SASP," and
3. "Prevention of Senescence Induction."

The following represents an integrated approach based on recent advances [4,10]:

Figure 6. Anti-tumor immunotherapeutic agents targeting the senescence-associated secretory phenotype (SASP). [4]

A. Targeted Clearance of Senescent Cells (Senolytics)

· Principle: Selectively induce apoptosis in senescent cells while preserving healthy cells.
· Senolytics: Agents such as ABT-263 can selectively eliminate senescent cells and reverse the immunosuppressive microenvironment.

B. Neutralizing SASP Toxicity (Senomorphics)

· Principle: Block SASP signal release or inhibit downstream inflammatory cascades, suppressing detrimental cellular functions.
· Senomorphics: Rapamycin (an mTOR inhibitor) and Aspirin (an NF-κB inhibitor) can suppress SASP expression.

C. Prevention of Senescence Induction

· Principle: Enhance DNA damage repair capacity and antioxidant defenses to reduce damage-induced senescence.
· Strategies: Mitochondria-targeted antioxidants (e.g., MitoQ, Visomitin) inhibit ROS-induced senescence. Nrf2 activators (e.g., Sulforaphane, Oltipraz) enhance endogenous antioxidant enzyme expression.

AmBeed: Your Trusted Lab Partner

At AmBeed Life Science, we provide an extensive research portfolio for senescence and SASP studies:

1. Detection Reagents

· DPPH (A184173) – A stable free radical used for rapid assessment of antioxidant capacity.
· ABTS (A1369194) – Widely applied in HRP-based assays and ABTS radical scavenging activity evaluation.

2. Disease Modeling Agents

· D-Galactose (A665119) – A classic inducer of oxidative stress and aging models.
· DL-Homocysteine (A376004) – A neurotoxic metabolite for studying oxidative and metabolic dysfunctions.

3. Targeted Therapy Compounds

· Dasatinib (A355193) - a potent dual Abl/Src inhibitor with IC50 values of <1 nM and 0.8 nM, respectively. It also inhibits c-Kit (WT) and c-Kit (D816V) activity with IC50 values of 79 nM and 37 nM, respectively.
· ABT-263 (A204180) – BCL-2/BCL-xL inhibitor, a senolytic compound that promotes selective apoptosis of senescent cells.
· Rapamycin (A656002) – mTOR inhibitor suppressing SASP expression and extending cellular lifespan.
· Quercetin (A1453902) – Natural flavonoid with NF-κB inhibition and antioxidant activities.
· Sulforaphane (A1456978) – Nrf2 activator that enhances antioxidant defense and mitigates oxidative stress.
· SSK1 (A1555122) – β-galactosidase-activated prodrug selectively killing senescent cells via p38 MAPK pathway.
· MitoQ Mesylate (A723561) – Mitochondria-targeted antioxidant protecting against ROS-induced senescence.

4. Immunotherapy Tools

· Polzastobart (A2952543) – LILRB2/ILT4 antagonist reversing myeloid-cell-mediated immunosuppression.
· Bexmarilimab (A2952469) – STAB1 antibody reprograms macrophages from M2 to M1 phenotype.
· Cetuximab (A2952380) – EGFR monoclonal antibody widely used in cancer signaling research.
· Tildrakizumab (A2952222) – IL-23 inhibitor for studying immune-inflammatory disorders.

5. Molecular Screening Library

Anti-Aging Compound Library (A2872066) – Senescence（Aging）refers to the structural and functional degradation of organisms at the molecular, cell, tissue and organ levels over time. AmBeed anti-aging compound library contains 2300+ anti-aging compounds, which is an effective tool for anti-aging research, and can be used for Qualcomm and high content screening.

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References

[1]Nucleic Acids Res. 2022;50:10947–63.

[2]Cell Death Discov. 2024;10(1):62.

[3]Cell. 2025;188(8):2043-2062.

[4]Acta Pharm Sin B. 2025;15(9):4476-4496.

[5]Cell Biol. 2021;22:75–95.

[6]Nat Protoc. 2021;16(5):2471-2498.

[7]Redox Biol. 2024;78:103441.

[8]Nat Rev Nephrol. 2022;18(10):611-627.

[9]Nat Commun. 2025;16(1):1696.

[10]FEBS J. 2023;290(5):1362-1383.

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