Senescence, NK cells, and cancer: navigating the crossroads of aging and disease

The World Health Organization (WHO) estimates that by 2050, over 2 billion people will be aged 60 or older (1). However, while overall age increases, the number of years in good health remains constant, suggesting that the extended years are often accompanied by illness. As shown in Figure 1, aging is associated with cellular senescence, age-related various diseases, genetic mutations, and increased cancer incidence, whereas physical fitness progressively declines. Research indicates that the incidence of chronic diseases such as heart disease, diabetes, neurodegeneration, and cancer increases steeply with older age (2). With this increased prevalence of age-related disease comes associated healthcare costs. For instance, the economic burden of dementia is projected to rise from $263 billion in 2019 to $1.6 trillion by 2050 (3). Similarly, the cancer-attributable costs in the United States are projected to increase from $183 billion in 2015 to $246 billion by 2030 (4). These trends highlight an urgent need for effective healthcare strategies to address the challenges posed by an aging population as part of this demographic shift.

According to the ‘Geroscience Hypothesis’, targeting fundamental aging mechanisms at the molecular and cellular level, rather than treating age-related diseases one by one, could better expand lifespan and reduce the risk of chronic disease (5). These fundamental aging mechanisms, known as the hallmarks of aging, have been well established and include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, dysregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, progenitor cell exhaustion, and altered intercellular communication (6). Since these fundamental aging mechanisms are interconnected, the Unitary Theory of Fundamental Aging Processes suggests that interventions targeting any fundamental mechanism might positively influence others (5). For example, addressing cellular senescence could reduce inflammation, improve mitochondrial function, restore proteostasis, and reduce various signs of aging and disease. Given these insights, it’s clear that understanding the interactions between these mechanisms is crucial for developing effective therapeutic interventions.

The relationship between senescence, natural killer (NK) cells, and cancer constitutes a pivotal axis in oncology and gerontology, presenting both challenges and opportunities for therapeutic intervention (7). Cellular senescence, a state of stable cell cycle arrest, emerges as a double-edged sword in cancer biology, acting as a barrier against tumorigenesis in young organisms while potentially promoting tumor growth and metastasis in the aging population through the senescence-associated secretory phenotype (SASP) (8, 9). Further, NK cells, which are critical components of the innate immune system, play a significant role in the surveillance and elimination of malignant and senescent cells, slowing down the progression of cancer and the accumulation of senescent cells that contribute to aging (10). However, the efficacy/integrity of NK cell function diminishes with age, a process known as immunosenescence, which reduces the organism’s ability to fight infections, eliminate senescent cells, and suppress tumor formation. This decline is further complicated by the presence of persistent senescent NK cells, which may contribute to the aged immune phenotype and exacerbate age-related diseases, including cancer (11). Accordingly, preserving the function of NK cells during aging is essential for promoting healthy aging and longevity. Additionally, NK cell-based therapies, particularly adoptive NK cell therapy, demonstrate promise not only in treating cancer and viral infections but also in rejuvenating the aging immune system, eliminating senescent cells (SNCs), and alleviating the effects of SASPs, thereby mitigating the effects of aging and disease progression (12, 13).

This review is structured into four sections: I. Exploring the intricate relationship between aging, senescence, and cancer. II. The impact of senescence on the immune system. III. Highlighting the critical role of NK cells in the removal of senescent cells. IV. An overview of innovative therapeutic strategies, with a particular focus on the potential of adoptive NK cell therapy as an effective solution to age-related issues.

Cellular senescence is a state of stable cell cycle arrest in which cells are resistant to apoptosis and remain metabolically active. Initially discovered in the 1960s by Leonard Hayflick, this cell state has emerged as a pivotal mechanism in aging and cancer (14). Hayflick originally identified senescence in the context of replicative lifespan limits due to telomere shortening. However, it has since been understood to encompass a response to various forms of cellular stress, including genomic damage, oxidative stress, and oncogenic signaling (8, 15). Therefore, this process plays a crucial role as a potent tumor suppressor and is intricately linked to age-related pathologies, playing roles in wound healing and development. The following sections explore the diverse roles of triggers of cellular senescence, markers of cellular senescence, senescence related signaling pathways, and SASP, along with their implications for aging and cancer.

Immunosenescence refers to the gradual deterioration of the immune system associated with aging, leading to increased vulnerability to infections, diminished response to vaccination, and a higher risk of developing cancer (139). This process affects both the innate and adaptive components of the immune system, resulting in a compromised ability to respond to pathogens and to internal threats such as tumorigenesis. The significance of immuno-senescence extends beyond individual health, impacting public health policy and healthcare strategies for the aging population.

NK cells, essential players in innate immunity, offer the first line of defense against a wide range of pathogens and play a critical role in the detection and elimination of cancerous cells (199, 200). Unlike adaptive immune cells, NK cells do not require prior sensitization to recognize and attack their targets. This immediate response is mediated through a sophisticated network of activating and inhibitory receptors, which enables NK cells to differentiate between infected or malignant cells and healthy cells (10).

NK cells originate from hematopoietic stem cells in the bone marrow and undergo a series of differentiation and maturation stages guided by a complex interplay of cytokines and transcription factors (201). They are not a homogeneous population but consist of various subsets distinguished by their surface receptor expression, functional capabilities, and tissue localization. The classification of these subsets and their distinct roles in immune responses, from cytokine production to direct cytotoxicity, are discussed (202). A delicate balance between signals governed the ability of NK cells to identify and kill target cells from activating and inhibitory receptors. Upon activation, NK cells employ several mechanisms to kill target cells, including releasing cytotoxic granules containing perforin and granzymes and engaging death receptor pathways (203).

Chemokines CCL2 and CXCL8 serve as chemotactic signals that guide NK cells to senescent cells. CCL2 is known to bind to its receptor CCR2 on NK cells, facilitating their migration toward high CCL2 concentrations typically found in the senescent cell milieu (204). Similarly, CXCL8 interacts with CXCR1 and CXCR2 receptors on NK cells, further directing their migration to the sites of senescence (205). The orchestrated action of these chemokines ensures that NK cells are efficiently recruited to areas where their surveillance and cytotoxic functions are required. In addition to chemokines, NK cell migration is influenced by tissue-homing receptors, which are regulated by environmental signals and enable NK cells to reach specific tissues where senescent cells accumulate. The expression of selectins, integrins, and other adhesion molecules on NK cells facilitates their trafficking and extravasation into tissues undergoing senescence or inflammation (206). For instance, the interaction between the integrin LFA-1 on NK cells and its ligand ICAM-1, which can be upregulated on senescent cells or within the senescent tissue microenvironment, is crucial for NK cell tissue infiltration (207). Finally, SASP not only serves to attract NK cells but also modulates their effector functions. Recent studies suggest that specific SASP components can enhance the cytotoxic activity of NK cells. For example, IL-15 is a potent stimulator of NK cell proliferation, survival, and activation (208). This suggests that the SASP can prime NK cells for enhanced recognition and elimination of senescent cells, in addition to recruiting them to sites of senescence.

The NKG2D is an activating receptor of NK cells that recognizes a variety of ligands, including MHC class I chain-related proteins A and B (MICA and MICB) and the UL16-binding proteins (ULBPs). These ligands are typically upregulated on cells undergoing stress or transformation, such as senescent cells, making them targets for NK cell-mediated cytotoxicity (209, 210). Upon ligand recognition and activation, NK cells mainly use two mechanisms to eliminate senescence cells (SNCs): direct and indirect killing (Figure 2). In direct killing, NK cells activating receptor NKG2D can recognize stress ligands like MICA, MICB, and ULBPs known to upregulate in senescent cells, activating NK cells. The activated NK cells release cytolytic granules and cytokines. Released cytolytic granules like perforin and granzyme lyse the SNCs, and cytokines like IFN-Y activate dendritic cells and macrophages (Figure 2). The activated macrophages kill the senescence cells, and activated dendritic cells present epitopes to activate T cells, eliminating the senescence cells. Studies have further elucidated the mechanisms underlying the upregulation of these stress ligands in response to cellular stress and damage, highlighting the role of DDR pathways and oncogenic signaling in promoting their expression on the cell surface (211, 212). The balance between activating and inhibitory signals is critical for NK cell response. MHC class I molecules generally provide inhibitory signals to NK cells through their interaction with killer-cell immunoglobulin-like receptors (KIRs), preventing the destruction of healthy cells. This delicate balance, which is a testament to the immune system’s complexity, is crucial for the effective function of NK cells. However, senescent cells often exhibit altered expression of MHC class I molecules, reducing the inhibitory signals and making them more susceptible to NK cell recognition and elimination (213). This alteration in MHC class I expression is a key factor in the “missing-self” hypothesis, which suggests that cells lacking sufficient MHC class I molecules become targets for NK cell-mediated lysis (214). Further, components of the SASP can directly or indirectly influence NK cell response, either by upregulating ligands for activating receptors such as MICA and MICB on target cells, enhancing NK cell activity and proliferation by IL-15, or by modulating the expression of MHC class I molecules and other “self” markers (215, 216).

The interaction between Fas ligand (FasL) on NK cells and the Fas receptor on senescent cells is another pathway leading to apoptosis (217). Furthermore, cytokines produced by NK cells, such as IFN-γ, play a crucial role in inhibiting proliferation and inducing apoptosis in target cells (218). This comprehensive approach of NK cells in eliminating senescent cells reassures us about the effectiveness of the immune system. Despite these mechanisms, some senescent cells can evade NK cell-mediated clearance through various strategies, including the downregulation of activating ligands or the secretion of immunosuppressive components of the SASP (219).

Like cancer cells, senescent cells can alter the expression of surface ligands necessary for NK cell recognition. They can decrease the expression of NKG2D ligands through various mechanisms, thereby reducing their visibility to NK cells. This evasion strategy involves transcriptional downregulation of ligand genes and the shedding of ligands from the cell surface. The latter process is mediated by metalloproteinases, which cleave membrane-bound ligands, releasing them in a soluble form that can bind to NKG2D receptors decoy, leading to receptor downmodulation (220). Additionally, senescent cells express decoy receptors that bind to and sequester activating ligands, preventing engagement with NK cell receptors. This not only prevents the ligands from engaging with their cognate-activating receptors on NK cells but may also lead to the depletion of these ligands in the microenvironment (211). Soluble NKG2D ligands, such as MICA and MICB, are cleaved from the cell surface and bind to NKG2D, leading to receptor downmodulation and impaired NK cell function (221). Furthermore, senescent cells can upregulate the expression of specific “self” molecules, like HLA-E, which bind to the inhibitory receptor NKG2A on NK cells, providing inhibitory signals that counteract activating signals and protect senescent cells from NK cell-mediated killing (222).

The SASP of senescent cells includes a variety of cytokines, chemokines, and growth factors, some of which can have immunosuppressive effects. For example, senescent cells can produce factors like TGF-β and interleukin-10 (IL-10), suppressing NK cell activity and reducing their cytotoxic response towards senescent cells. TGF-β can inhibit NK cell activity by downregulating the expression of NK cell activating receptors, such as NKG2D, and impairing the production of key cytokines like IFN-γ (223). This results in diminished NK cell-mediated cytotoxicity against target cells, including senescent cells. Additionally, TGF-β has been shown to promote the conversion of effector T cells into regulatory T cells (Tregs), further suppressing immune responses (224). IL-10 is well recognized for its ability to inhibit the function of immune cells, including NK cells. It can suppress the cytotoxic activity of NK cells by downregulating the expression of activating receptors and inhibiting the secretion of pro-inflammatory cytokines such as IFN-γ (225, 226). The presence of IL-10 in the tissue microenvironment can thus create an immunosuppressive milieu that protects senescent cells from NK cell-mediated clearance. SASP factors can also recruit and activate immune regulatory cells, such as Tregs and myeloid-derived suppressor cells (MDSCs), which further create an immunosuppressive microenvironment. This can inhibit the activity of NK cells and other effector immune cells, aiding in the evasion of immune surveillance (227). MDSCs are a heterogeneous population of cells that arise from myeloid progenitors and have potent immunosuppressive activities. They can suppress the activities of NK cells and cytotoxic T lymphocytes (CTLs) by producing arginase, nitric oxide, ROS, and cytokines like IL-10 and TGF-β. SASP factors, such as IL-6, IL-1β, and VEGF, have been implicated in the recruitment and activation of MDSCs within the tumor microenvironment or sites of tissue senescence, further contributing to immune evasion (228, 229).

Senescent cells contribute to the remodeling of the ECM by secreting various MMPs, fibronectin, and collagen, which can lead to increased tissue stiffness and the development of fibrotic lesions (230). This fibrotic tissue can act as a physical barrier, impeding the infiltration and mobility of immune cells within the tissue. For instance, increased collagen deposition has been shown to limit T cell penetration into tumor microenvironments, a phenomenon that is likely applicable to areas with high concentrations of senescent cells (231). The secretion of ECM components by senescent cells also leads to alterations in the biochemical properties of the tissue microenvironment. These changes can affect the expression of adhesion molecules and chemokines, further modulating the recruitment and retention of immune cells. For example, the altered ECM can influence the gradients of chemokines required for the guided migration of immune cells, such as NK and T cells, thereby affecting their ability to locate and eliminate senescent cells (232).

These mechanisms contribute to the ability of senescent cells to evade clearance by NK cells, allowing their accumulation in tissues, which is associated with chronic inflammation, tissue dysfunction, and various age-related pathologies. Understanding the interactions between senescent cells and the immune system, particularly NK cells, is crucial for developing therapies aimed at targeting senescent cells to improve age-related diseases and promote healthy aging.

The preventive approach to aging involves understanding the biological mechanisms of aging and intervening early to slow down or reverse these processes. By treating aging as a “treatable” condition, the aim is to extend the healthspan, the period of life spent in good health and free from chronic diseases, rather than just prolonging life without quality.

Senolytic drugs work in senescent cells by selectively inducing apoptosis. These drugs target specific pathways like the BCL-2 family, p53, and the PI3K/AKT pathway, crucial for the survival of senescent cells (233). The elimination of these cells has shown potential in reducing the burden of age-related diseases, including Alzheimer’s disease, cardiovascular diseases, and cancers, thereby significantly improving the quality of life for older adults (234).

One of the first senolytic combinations discovered, Dasatinib (a tyrosine kinase inhibitor) and Quercetin (a flavonoid with anti-inflammatory properties), have shown promising results in preclinical models. A landmark study reported the effectiveness of Dasatinib plus Quercetin in decreasing senescent cell abundance in humans, specifically in a clinical trial involving individuals with diabetic kidney disease. This open-label Phase 1 pilot study demonstrated the potential of senolytic drugs to decrease senescent cell abundance, marking a significant step forward in senolytic therapy research (235). Targeting the inflammatory milieu through the administration of anti-inflammatory drugs, such as metformin or rapamycin, has also shown promise in reducing the deleterious effects of senescent cells on tissue homeostasis and function (236, 237). Clinical trials investigating SASP inhibitors, like the IL-1β inhibitor canakinumab, have shown reduced incidence of lung cancer, highlighting the potential of this approach (238). These strategies, aiming to either suppress the SASP or enhance the immune system’s capacity to eliminate senescent cells, offer a two-pronged approach to combating the negative consequences of cellular senescence.

While senolytic drugs offer a novel approach to treating age-related diseases, they also present challenges, particularly regarding their long-term effects and potential off-target impacts. Most senolytic drugs were initially developed for other purposes and repurposed for targeting senescence, necessitating thorough evaluations to ensure their safety and efficacy for long-term use (239). Additionally, ongoing clinical trials aim to assess the effects of senolytic drugs on various age-related conditions, offering hope and a path toward clinical translation (240).

Combining senolytic drugs with strategies to enhance NK cell function, including allogeneic NK cell therapy, may provide a synergistic approach to more effectively clear senescent cells, potentially leading to more profound rejuvenation and longevity effects (241).

By targeting metabolic pathways influenced by mTORC1, researchers have identified opportunities to augment NK cell-mediated tumor control, presenting new therapeutic avenues for treating age-related diseases and cancer. One study reveals that IL-10 significantly elevates IFN-γ production in expanded NK cells by approximately 18-fold, highlighting the critical role of mTORC1 in NK cell activation and suggesting that modulating metabolic pathways could improve NK cell responses in therapeutic settings (242). Wang et al., demonstrated that cytokine stimulation activates NK cells through metabolic reprogramming, increasing both glycolysis and mitochondrial oxidative phosphorylation (243). Poznanski et al., discussed the metabolic regulation of NK cell effector functions, identifying mTORC1 as a critical regulator of NK cell metabolic reprogramming. The study suggests that targeting mTORC1-dependent pathways could enhance NK cell effector function, offering potential therapeutic targets for immune interventions (244). The regulatory role of mTORC1 in NK cell metabolic reprogramming provides a valuable target for enhancing NK cell-mediated tumor control and immune responses. Research exploring the KLRG1-AMPK pathway provides insights into its role in NK cell function, particularly in the context of aging and cancer. The accumulation of KLRG1 bright NK cells, which are more prevalent in older individuals, is associated with the activation of AMPK. This association indicates a potential mechanism through which aging may impact NK cell activity and points to the KLRG1-AMPK pathway as a target for rejuvenating NK cell in aged populations.

Most cancers are known to impair the functionality of NK cells, which reduces the effectiveness of cell-based therapies for solid tumors. The mechanisms by which cancers diminish NK cell response are not fully understood, making it a key objective of immunotherapy to overcome this resistance. In a recent report, Portale et al. identified autophagy as a crucial regulator of NK cell anti-tumor activity. Using preclinical models of prostate cancer (PCa), they demonstrated that autophagy is essential for the tumor-killing capabilities of NK cells (245). Their findings suggest that cancer cells suppress the autophagic response by activating the CXCR4-C/EBPβ pathway in tumor-infiltrating NK cells, thereby undermining their ability to combat tumors. Furthermore, the study indicates that reactivating the autophagic pathway through pharmacological treatments or genetic modifications can restore the functional deficits of NK cells within tumors, enhancing their effectiveness in killing cancer cells in laboratory settings. This research highlights autophagy as an important intracellular checkpoint for NK cells and suggests that regulating autophagy could be a promising strategy to improve NK cell-based immunotherapies (245).

The enhancement of NK cell function through cytokine activation is a promising strategy for clearing pre-malignant senescent cells. Activation of NK cells with IL-2 has been shown to increase their ability to lyse tumor cells by enhancing perforin binding to the target cell membrane. IL-2 is pivotal for the proliferation, survival, and activation of NK cells, and it has been utilized in clinical settings to augment NK cell responses against tumor cells (246). IL-12, a pro-inflammatory cytokine, plays a critical role in the activation of NK cells, inducing the production of IFN-γ, which further stimulates the cytotoxic activity of NK cells against tumor cells (247). IL-15 has emerged as a potent stimulator, promoting their proliferation and sustained activation of NK cells without inducing the activation-induced cell death commonly seen with prolonged IL-2 exposure (248). IL-15’s role in supporting the development and function of memory-like NK cells, which exhibit enhanced responsiveness upon re-stimulation, represents a significant advancement in NK cell-based therapies (249). Moreover, the combination of IL-18 with IL-12 or IL-15 has been reported to synergistically enhance NK cell activation and improve their anti-tumor activity. IL-18 contributes to NK cell activation by upregulating the expression of perforin and granzymes, and when used in conjunction with IL-12 or IL-15, it can significantly boost NK cell-mediated cytotoxicity against various cancer cell lines (250). Among these cytokines, IL-15, an essential cytokine for NK cell proliferation and activation, is being tested in clinical trials to enhance NK cell responses in older adults and cancer patients (251).

Besides the enhancement of endogenous NK cells, allogeneic NK cell therapy for senescence has recently drawn more and more attention. Allogeneic NK cells from different sources: peripheral blood NK cells from young, healthy donors (252), CB NK cells (253), NK92 cell line (254), CB CD34+ derived NK cells (255), placenta-derived NK cells (256), and iPSC derived NK cells (257) could address the immune aging of endogenous NK cells. Recently, Celularity reported in-vitro data demonstrating placental hematopoietic stem cells (CD34+) derived unmodified NK cells (CYNK-001) can preferentially eliminate chemotherapy drugs induced senescent non-small cell lung carcinoma tumor cell line A549 cells compared to non-treated A549 cells (258). In the same study, the authors improved the persistence and efficacy of CYNK-001 cells by ectopically expressing soluble IL-15 and a high IgG binding affinity and protease cleavage-resistant CD16 variant (CYNK-201). The genetically modified CYNK-201 also showed higher killing of drugs-induced senescent A549 than non-treated A549, suggesting the potential of allogeneic NK cell therapy to remove senescent cells. These innovative approaches demonstrated the potential of allogeneic NK cell therapy, not only in removing senescent cell accumulation but also in rejuvenating the aging immune system.

Furthermore, methods already successfully utilized in cancer treatment, such as chimeric antigen receptor (CAR) and monoclonal antibodies, can also be applied to the NK cell platform. Compared to the autologous CAR-T cells approach, allogeneic CAR-NK cells might be a valuable tool for senescence immune surveillance with off-the-shelf, no GvHD, better safety profile clinically, and cost-effectiveness. The safety and efficacy of CAR-NK have been demonstrated using CB-derived NK cells expressing anti-CD19 chimeric antigen receptor and interleukin-15 (CAR19/IL-15) in 37 patients with CD19⁺ B cell malignancies (259). Figure 3 illustrates how genetically engineered allogeneic CAR-NK cells can specifically eliminate senescent cells but not healthy cells. Multiple CAR targets have been evaluated under preclinical autologous CAR-T cell space, which could be applied in the allogenic CAR-NK cell field. Following the identification of NKG2D ligands upregulation in senescent cells, Yang et al., have shown that NKG2D-CAR T cells can eliminate senescent cells in aged mice and nonhuman primates (260). It was reported that high expression of fibroblast activation protein (FAP) in active cardiac fibroblasts drives abundant cardiac fibrosis and consequent myocardial disease. Adoptive transfer of FAP CAR-CD8⁺ T cells results in a significant reduction in cardiac fibrosis and restoration of function after injury in mice (261). The expression of Urokinase-type plasminogen activator receptor (uPAR), a cell-surface protein, is highly upregulated during senescence (262). uPAR-specific CAR T cells can safely eliminate senescent cells in young and aging mice. Treatment with anti-uPAR CAR-T cells improves exercise capacity in physiological aging. It ameliorates metabolic dysfunction (for example, improving glucose tolerance) in aged mice and mice on a high-fat diet (262, 263). While CAR-NK cells have not yet been tested for the removal of senescent cells, the CAR technology used to create CAR-T cells can also be utilized for CAR-NK cells. Furthermore, there should be a sustained effort to identify new antigens to develop more effective CAR-NK cells specifically designed for targeting and clearing senescent cells. One of the new targets could be DPP4-CAR NK cells. DPP4 (dipeptidyl peptidase 4) protein is selectively expressed on the surface of senescent, but not proliferating, human diploid fibroblasts (264). Higher DPP4 expression was found in peripheral blood samples from older subjects (78–88 years of age) compared to younger subjects (27–36 years of age), and this expression was more associated with monocytes and lymphocytes. Silencing the gene encoding DPP4 in these cells reduced the senescent phenotype, with decreased expressions of p21, p53, and p16 and increased expression of sirtuin1 (264). DPP4 is related to the cell surface expression of caveolin 1, which activates NF-κB and produces SASPs. Thus, DPP4-CAR NK cells could be a new therapeutic for senolysis.

Allogeneic NK cell therapy offers several advantages, including the potential for off-the-shelf safety, cost effectiveness, and the use of NK cells from young, healthy donors with optimal functional capacity. However, several challenges must be addressed to realize the full potential of NK cell therapy. First, the major barrier to NK cell therapy is the lack of persistence in vivo in the absence of cytokine support. While the short-term persistence in patients is desirable for safety, it is a limiting factor for efficacy. NK cell engineering strategies incorporate genes to ectopically express cytokines such as IL-15 to improve persistence (265). Another challenge is graft rejection by the host’s immune system. To protect allogeneic NK cells from being rejected, scientists are using stealth techniques, including knocking down MHC Class I and Class II molecules and overexpressing HLA-E/CD47 (266). Additionally, NK cells are vulnerable to damage during the freeze-thaw process. NK cells are susceptible to the freeze-thaw process. Thawing procedures significantly reduce the survival rate and cytotoxic capabilities of NK cells, but functional activity may be restored by incubation with interleukin-2 (IL-2) (267). Therefore, developing an optimal cryopreservation and recovery protocol is essential for NK cell therapy to become a viable “off-the-shelf” treatment. Senolytic drugs represent a crucial component of the therapeutic arsenal against cellular senescence, offering a direct means to reduce the senescent cell burden. The combination of senolytic drugs and adoptive NK cell therapy could provide a comprehensive approach to combat the deleterious effects of aging and improve overall healthspan.

Aging is a universal process associated with an increased risk of various diseases, including Alzheimer’s, cardiovascular diseases, and cancers. Preventing aging at its source offers the prospect of extending healthy, productive years, significantly enhancing individuals’ quality of life. By reducing the prevalence of age-related diseases, individuals can maintain independence and physical and cognitive function well into later life, benefiting society by preserving knowledge and experience. The intricate relationship between NK cell senescence and cancer highlights the dual roles of cellular senescence in tumor suppression and promotion, particularly within the aging immune system. Immunosenescence leads to a decline in NK cell function, contributing to increased vulnerability to infections and malignancies in older adults. Understanding the mechanisms that drive NK cell senescence and their impact on cancer progression is crucial for developing effective therapeutic strategies. Adoptive NK cell therapy emerges as a promising approach, potentially rejuvenating the immune surveillance system by targeting both malignant and senescent cells. Recent advances in biotechnology and medicine have offered the possibility of preventing or significantly delaying the aging process rather than merely treating its associated diseases. Further research into senolytic drugs and the enhancement of NK cell function could provide synergistic effects, enhancing the clearance of senescent cells and improving outcomes for age-related diseases. Addressing these challenges through innovative therapeutic strategies holds the promise of extending healthspan and improving the quality of life for the aging population.

We thank Adrian Kilcoyne for conceptualization and reviewing the manuscript.

The author(s) declare that financial support was received for the research and/or publication of this article. This work was supported by Celularity Inc.

MG: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. RB: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing – original draft, Writing – review & editing. SK: Conceptualization, Writing – review & editing, Data curation. AG: Writing – review & editing, Writing – original draft. LK: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Supervision, Writing – original draft, Writing – review & editing. RH: Conceptualization, Writing – review & editing.

All authors were employed by Celularity Inc.

The author(s) declare that no Generative AI was used in the creation of this manuscript.

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