Cellular senescence is a hallmark of aging, with senescent cells exhibiting a range of dysfunctions, including metabolic reprogramming, DNA damage, oxidative stress, and secretion of the senescence-associated secretory phenotype (SASP). Although senescence accrues with age, it can occur at any point during the life cycle and contributes to chronic disease risk. Immunosenescence is particularly deleterious, with a dysregulated immune response lying at the core of many age-related pathologies and disease conditions.
The hallmarks of senescence are broadly categorized into cell damage and functional decline, epigenetic alterations, and immunosenescence. DNA damage and associated genomic instability, loss of telomere integrity, and mitochondrial impairment combine to induce progressive cellular injury and functional decline, while an imbalance in DNA methylation patterns, chromatin remodeling, and abnormal histone modifications disrupt epigenetic control mechanisms of gene expression. Finally, maladaptive immune system changes and correlated inflammaging predispose immunosenescence.
The immune system is one of the organ systems most severely impacted by aging. Both innate and adaptive immune branches are equally affected, conferring diminished resilience to infections, response to vaccines, tumor surveillance, and inflammation resolution. Responsible for establishing long-term memory to invading pathogens, T cells and B cells of the adaptive immune system exhibit numerous alterations over the lifespan. Ordinarily, effector or memory T cells are charged with immune response, and regulatory T cells (Tregs) suppress immune overreactivity and assist in immune resolution.
While the total quantity of T cells does not substantially attenuate with age, several subpopulations are vulnerable to maladaptive changes. Age-associated thymus atrophy results in lower T cell generation and T cell receptor diversity, causing a depression of naive T cell populations and a concomitant rise in both Treg cells and certain memory and effector T cells. The two latter populations compete for nutrient resources, inciting a faltering of DNA repair processes and subsequent DNA damage and genomic instability. This stimulates extracellular regulated protein kinases 1/2 (ERK1/2) and p38 pathways, followed by signal transducer and activator of transcription 1/3 (STAT1/3) activation and downstream increases in p21-p16-p53, leading to functional decline and senescence.
Moreover, differentiated T cells enter a senescent stage with age, displaying the three corresponding hallmarks of immunosenescence. Aged, senescent T cells are inflammatory in nature and exhibit weakened antigen detection, mistakenly attacking surrounding healthy tissue. Additionally, senescent T cells interact with other immune cell populations to reprogram the immune microenvironment and cultivate immunosuppression.
B cells are the second cell type involved in the adaptive immune response, participating in antibody synthesis and antigen presentation, as well as cytokine release. B cells are equally affected by the aging process, largely decreasing with advancing age due to a decline in new cell production and lower B cell receptor diversity, similar to that experienced by T cells. The ability to generate high-affinity protective antibodies is subsequently impaired in the elderly. Aging also exacerbates B cell clonal expansion, and elicits a shift from naive immunoglobulin to memory immunoglobulin.
Natural killer cells, neutrophils, and macrophages, along with several other immune cell types, coordinate the innate immune response. Natural killer cells engage in both cotytoxic and immunomodulatory behaviors, and tend to increase in number with age. However, their cytotoxic and proliferative potential become compromised, contributing to weakened potency. Neutrophils take part in phagocytosis, antimicrobial secretion, and formation of extracellular traps. Aging causes diminished efficiency of neutrophils, resulting in impaired migration and invasion, cytokine synthesis, and phagocytotic clearance.
Macrophages are also known for their phagocytic activity, well equipped to engulf and digest pathogens and other debris that maintains tissue homeostasis. Macrophage senescence potentiates a dwindling of phagocytic capabilities and a shift in cytokine release. Collectively, such alterations in innate defense enfeeble immune response and promote immunosuppression. Meanwhile, inadequate clearance provokes persistent inflammatory activity.
Immune cell dysfunction combined with immunosenescence potentiates a state of low-grade, chronic inflammation characteristic of aging. Secretion of the SASP by senescent cells perpetuates this process and coaxes neighboring cells into a senescent state. Immune decline accelerates as a consequence, augmenting susceptibility to autoimmune disease, infection, and cancer. Elimination of senescent cells is thus becoming a strongly researched topic, with immunotherapy gaining considerable traction as a novel therapeutic strategy.
Immunotherapy exploits the body’s own immune system to reprogram and rejuvenate immune cell function, thereby restoring the ability to detect and eliminate abnormal or damaged cells. Several immunotherapeutic approaches have been explored with varrying success, such as chimeric antigen receptor (CAR) immunocytotherapy, senolytic vaccines, immune checkpoint blockade (ICB), and antibody-drug conjugates (ADCs).
In CAR-T cell therapy, active T cells are isolated, reconstructed, and expanded, conferring the capacity to recognize specific antigens on target cells, including markers of senescence. However, the existing limitations of these re-engineered T cells prevents their widespread implementation. Current markers of senescence are not absolutely specific, opening up the door to improper cell clearance and tissue injury. Secondly, CAR-T cell therapy relies upon the quality and function of a patient’s own T cells, and is thus less effective in the elderly population where it is needed most.
Allogeneic CAR-NK cells have also been investigated as an alternative to autologous CAR-T cells owing to their better safety profile, cost-effectiveness, off-the-shelf, and no graft-versus-host disease qualities. They have yet to be studied in the context of senescent cell clearance, although there is a theoretical basis for supplementing functional NK cells or improving their targeting potential via CAR technology.
Senolytic vaccination is being developed with the objective of enhancing biosynthesis of antibodies or T cells trained to recognize and clear senescent cells. Nevertheless, the challenges to overcome include selection of more specific antigens to attenuate risk of autoimmunity and navigating poor vaccine response in the elderly. Additionally, it will be critical to design vaccines capable of eliciting long-term and stable immune memory absent of immune over-activation and chronic inflammation.
ICB therapy, on the other hand, attempts to disable senescent cell exploitation of immune checkpoint molecules. Programmed death-ligand 1 (PD-L1), a key immune checkpoint molecule, can bind to PD-1 on immune cells to preclude their activation, proliferation, and cytotoxicity. Senescent cells hijack such machinery, expressing PD-L1 on their surface to elude immunosurveillance and elimination. However, inhibition of immune checkpoints is a dangerous proposition with a potential consequence of autoimmune reactions.
Immunotherapy is an exciting field of study with considerable and broad application potential. The technology is still in its early stages with many challenges to overcome. Future research will be critical to guide the maturation of immunotherapy as a viabile treatment for immunosenescence.
Zhang W, Chen S, Zhuang X. Immunotherapy for senescent cell clearance: Hallmarks, strategies and translational challenges. Ageing Res Rev. 2026;119:103174. doi:10.1016/j.arr.2026.103174