Aging remains one of the most enigmatic biological processes, intricately tied to the accumulation of cellular damage and decline in tissue function. A key cellular phenomenon that has garnered intense scientific scrutiny in recent years is cellular senescence—a state of permanent cell cycle arrest coupled with profound alterations in cellular function. Senescent cells, while initially protective by preventing the proliferation of damaged cells, paradoxically contribute to tissue dysfunction when they accumulate. A groundbreaking review published by Majewska and Krizhanovsky in Nature Aging now sheds light on the crucial role the immune system plays in identifying and clearing these senescent cells, thereby maintaining tissue homeostasis and delaying the onset of age-associated pathologies.

At the core of this review is the concept that senescent cells, despite being growth-arrested, are immunogenic entities. These cells secrete a complex array of signaling molecules collectively termed the senescence-associated secretory phenotype (SASP), which modulates the local microenvironment and recruits immune cells. In youthful tissues, the SASP effectively serves as a distress signal, prompting various arms of the immune system—including natural killer (NK) cells, macrophages, neutrophils, dendritic cells, T lymphocytes, and B cells—to target and eliminate senescent cells. This process of immunosurveillance is fundamental for tissue repair and regeneration, preventing the detrimental buildup of senescent populations.

However, this surveillance mechanism deteriorates with age. The immune system’s efficiency wanes, resulting in an increased burden of senescent cells within aged tissues. This accumulation is implicated not only in normal aging but also in the pathogenesis of diverse age-related diseases such as cancer, fibrosis, and chronic inflammatory conditions. Majewska and Krizhanovsky meticulously dissect the cellular and molecular underpinnings of how immunosenescence— the aging of the immune system—undermines the clearance of senescent cells, creating a vicious cycle that exacerbates tissue dysfunction and reduces organismal healthspan.

.adsslot_sQ0gU8ebNc{width:728px !important;height:90px !important;}
@media(max-width:1199px){ .adsslot_sQ0gU8ebNc{width:468px !important;height:60px !important;}
}
@media(max-width:767px){ .adsslot_sQ0gU8ebNc{width:320px !important;height:50px !important;}
}

ADVERTISEMENT

Natural killer cells emerge as frontline effectors in the elimination of senescent cells. These innate immune cells possess cytotoxic capabilities and can distinguish senescent cells through altered expression of ligands for NK cell receptors. The review highlights how senescent cells modulate the expression of stress-induced ligands, which makes them susceptible to NK cell-mediated apoptosis. Yet, with aging, both the cytolytic activity and the recruitment of NK cells to senescent cell niches diminish, facilitating senescent cell persistence.

Similarly, macrophages, well-known for their versatility and plasticity, are pivotal in engulfing and digesting senescent cells. Their role encompasses both clearance and modulation of inflammation. The review underscores how senescent cells influence macrophage polarization states through the SASP, often skewing them towards pro-inflammatory phenotypes that paradoxically can intensify tissue damage. Changes in macrophage functionality and impaired phagocytic capacity during aging further compromise the immune system’s ability to resolve senescent cell accumulation effectively.

Neutrophils and dendritic cells also assume critical roles within the senescence immunosurveillance network. Neutrophils contribute not only through their conventional roles in pathogen defense but also via the release of neutrophil extracellular traps (NETs) that may entrap senescent cells and aid in their clearance. Dendritic cells, key antigen-presenting cells, bridge innate and adaptive immunity by priming T cells against senescence-related antigens. This immunological crosstalk is essential for mounting a robust adaptive immune response capable of targeting senescent cells.

The adaptive arm of immunity, comprising T and B cells, is intricately involved in senescent cell surveillance as well. Cytotoxic CD8+ T cells recognize and lyse senescent cells presenting altered antigenic profiles, while CD4+ helper T cells orchestrate immune responses by modulating cytokine environments and enhancing cytotoxic functions. B cells contribute by producing antibodies that might opsonize senescent cells, facilitating their elimination. Yet, aging disrupts the repertoire diversity and effector functions of these lymphocytes, rendering immunosurveillance inefficient.

A striking insight from the review is the observation that immune cells themselves are subject to senescence, further compounding the decline in immune function known as immunosenescence. Senescent immune cells display altered cytokine secretion, reduced proliferative ability, and impaired responsiveness, thus failing to adequately replenish and sustain the anti-senescent cell immune repertoire. This self-amplifying dysfunction impairs the immune system’s capacity to manage not only senescent cells but also emerging cancerous clones, linking senescence immunosurveillance directly to oncological outcomes.

Understanding why senescent cells evade immune elimination is a frontier of intense research. The review elaborates on various escape mechanisms employed by senescent cells, including downregulation of immune recognition markers and secretion of immunosuppressive factors that actively inhibit or confuse immune effectors. This immune evasion resembles tumor immune escape strategies, highlighting a convergence of cellular pathways between aging and cancer biology.

Therapeutic strategies to enhance the immunosurveillance of senescent cells are poised to revolutionize the treatment of age-associated diseases. Majewska and Krizhanovsky discuss the promise of senolytics—agents that selectively induce death in senescent cells—and immunomodulatory approaches designed to rejuvenate immune compartments or boost specific immune cell populations. Such interventions could restore effective clearance, reduce inflammation, and promote tissue regeneration, with far-reaching implications for healthspan extension.

Another exciting avenue is the manipulation of the SASP itself. By modulating this secretory profile, it may be possible to alter the immune milieu favorably, enhancing immune recognition while minimizing the chronic inflammatory state that accelerates aging and disease progression. The authors postulate that combining SASP modulators with immune-enhancing therapies could synergistically potentiate senescent cell clearance.

Fundamental to these translational advances is an improved molecular understanding of senescence immunosurveillance pathways. The review integrates recent discoveries on cell surface molecules, receptor-ligand interactions, intracellular signaling cascades, and epigenetic modifications that define how immune cells recognize and respond to senescent cells. Deciphering these details paves the way for precise biomedical interventions.

In clinical contexts, the accumulation of senescent cells is correlated with functional decline of multiple organs, including the cardiovascular system, kidneys, and skeletal muscles. The immune system’s faltering ability to purge these deleterious cells contributes mechanistically to conditions such as atherosclerosis, renal fibrosis, sarcopenia, and neurodegeneration. The reviewed literature connects these pathological states to immunosenescence-mediated senescent cell persistence, underscoring a fundamental axis in aging biology.

Moreover, the interplay between senescence and cancer immunity is intricate. While senescence acts as a barrier to tumor progression, failure to clear senescent cells can create an immunosuppressive tumor microenvironment, fostering malignant transformation. Immunosurveillance mechanisms that target senescent pre-malignant cells are therefore essential cancer protective measures that decline with age.

Majewska and Krizhanovsky’s comprehensive review serves as a compelling call to action for researchers and clinicians alike. It consolidates the paradigm that aging and age-related diseases are not simply the result of cellular wear but are critically influenced by the immune system’s capacity to detect and remove dysfunctional senescent cells. As the global population ages, harnessing and restoring this immunosurveillance axis offers perhaps the most promising strategy to mitigate senescence-driven morbidity and mortality.

In summary, the dynamic interplay between senescent cells and the immune system defines the boundary between healthy aging and disease. The progressive decline in immune surveillance capacity during aging underscores a pivotal vulnerability that governs tissue homeostasis, regenerative potential, and cancer susceptibility. Therapeutic innovation targeting this nexus may ultimately unlock transformative possibilities for extending human healthspan and effectively treating a wide spectrum of age-associated pathologies.

Subject of Research: Immune surveillance of senescent cells and its role in aging and age-related diseases.

Article Title: Immune surveillance of senescent cells in aging and disease.

Article References:
Majewska, J., Krizhanovsky, V. Immune surveillance of senescent cells in aging and disease. Nat Aging 5, 1415–1424 (2025). https://doi.org/10.1038/s43587-025-00910-5

Image Credits: AI Generated

DOI: https://doi.org/10.1038/s43587-025-00910-5

Tags: aging and immune responseB cells in tissue repaircellular senescence and tissue dysfunctionimmune clearance of senescent cellsimmune surveillance mechanisms in agingimmune system and agingimmunogenic properties of senescent cellsimplications of cellular senescence on healthmacrophages and tissue homeostasisrole of natural killer cells in agingsenescence-associated secretory phenotypeT lymphocytes and senescent cell elimination