Can removing cells that have permanently stopped dividing help fight infection?

Since the previous research note · Earlier expectation not tested

Track continuity

Since the previous research note: Could removing senescent cells help an aging immune system?

Previous expectation: Removing harmful senescent-cell activity before vaccination might improve protection in older adults if benefit and safety were demonstrated.

What this study adds: The October 2023 review connects direct drug effects and an aged-mouse influenza example to a specific concern about memory formation and later immune recall. It does not establish whether pre-vaccination treatment improves protection in older adults.

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What changed in this study

The immune system has to solve two problems at different times. It must respond effectively to an infection happening now, then preserve enough information to respond faster when the same threat appears again. Treatments designed to remove senescent cells could influence both stages, but possibly in different ways.

An October 10, 2023 review, Impact of senolytic treatment on immunity, aging, and disease, brings together cell-culture experiments, studies of isolated human immune cells, animal models, human observations from other treatment settings, and clinical-trial designs. It describes reasons to think that reducing senescent-cell activity might ease harmful inflammation, while raising a specific unresolved concern: a treatment that changes the first response could also affect the formation of lasting immune memory.

A cell can stop dividing and still change its neighborhood

Cellular senescence is a state in which a cell permanently stops dividing after stress, damage, or reaching its replicative limit. That arrest can protect the body by preventing damaged cells from continuing to multiply. Senescence also contributes to fetal development, tissue repair, wound healing, and tumor suppression.

Senescent cells are not inactive, however. They remain metabolically active and can release a mixture of inflammatory cytokines, chemokines, proteases, growth factors, and matrix-related proteins known as the senescence-associated secretory phenotype, or SASP. These signals influence nearby cells and can reinforce senescence in the surrounding tissue. The exact mixture varies with the cell type, the trigger, and the species involved.

Immune cells are part of the body’s normal response to this burden. Natural killer cells, T cells, and macrophages can help identify and clear senescent cells after signals from damaged tissue recruit them. With aging and disease, surveillance and clearance can become less effective. Senescent cells may also evade detection by changing surface signals or increasing molecules that inhibit immune-cell activation. The result can be an accumulation of cells whose secretions contribute to an inflammatory tissue environment.

Senolytics are drugs intended to exploit survival pathways that senescent cells rely on, pushing them toward programmed cell death while leaving quiescent and actively dividing cells relatively less affected. Fisetin and the combination of dasatinib plus quercetin, often abbreviated D + Q, are among the candidates discussed in the review. Their effects are not limited to senescent cells, though. The same pathways used by immune cells to activate, migrate, communicate, or survive can also be affected by these drugs.

A drug can alter immune signaling without killing the cell

Dasatinib illustrates why the phrase “senolytic treatment” does not automatically describe every biological effect of the treatment. Dasatinib acts on several signaling proteins, including Src-family tyrosine kinases involved in T-cell development, signaling, and activation.

In experiments using T cells from healthy human donors, the review reports that low concentrations of dasatinib interfered with T-cell receptor signaling. Activated T cells showed reduced downstream signaling, and the activation marker CD69 was completely inhibited under the tested conditions. Proliferation was also reduced. Yet the cells did not simply disappear: after 20 hours of exposure, they remained in culture rather than undergoing widespread cell death. Some activity returned when the cells received a different activating stimulus, and adding interleukin-2 restored proliferation in the reported experiments.

This is a different result from selectively eliminating a senescent cell. It shows that a drug can leave an immune cell alive while temporarily changing how it receives or processes an activation signal. The effect also depends on dose, timing, cell type, and the signals present around the cell.

Neutrophils provide another reason not to describe immune function as moving in one direction. In an ex vivo study discussed by the review, dasatinib altered several neutrophil functions in a dose-dependent way. It impaired integrin-related signaling, migration, granule exocytosis, adherence, and some forms of activation linked to immune-complex or microbial-ligand recognition. At the same time, the reported experiments found that tumor-necrosis-factor signaling, phagocytosis, and bacterial killing were not impaired under the tested conditions.

The practical meaning is not that senolytics are simply immunosuppressive or immune-enhancing. A drug may reduce one inflammatory activity while preserving another, and the balance may differ between T cells, neutrophils, natural killer cells, and other immune populations. Effects seen in studies that were not designed specifically to eliminate senescent cells therefore matter when assessing what these treatments could do in the body.

An influenza experiment separated treatment from infection

The review describes an aged-mouse influenza experiment that helps separate drug exposure from the later immune response. Older mice received D + Q over a treatment period, followed by a five-day resting interval intended to allow the drugs to clear before influenza infection. The timing was important because it reduced the chance that the measured response simply reflected dasatinib or quercetin still acting directly during the infection.

The study focused on the composition of helper T cells in the lungs. Compared with younger infected mice, aged mice showed greater skewing toward regulatory T cells, or Tregs. In the setting discussed by the review, elevated Treg activity could restrain the adaptive response to influenza. D + Q treatment before infection was associated with fewer Tregs and a higher proportion of Th2 helper cells in the aged mice. The treated animals also had lower levels of TGF-beta in the lungs during infection.

TGF-beta is relevant because senescent cells can contribute to its production, and the review connects TGF-beta with the helper-T-cell changes seen in aged influenza infection. These findings offer a plausible route by which reducing the senescent environment might alter the early cellular response. They do not show that the mice gained lasting immunity, avoided reinfection, or survived influenza more successfully.

The interval addresses one confounding factor: direct drug effects during infection. It does not by itself establish that senescent-cell removal caused the helper-T-cell changes or identify which lasting effects of treatment mattered. These observations remain evidence from aged mice, not proof of clinical benefit in older adults.

The hard question arrives after the first response

An immune response is not finished when the immediate infection is controlled. Some activated T and B cells become memory cells. They persist in a different state and can respond more rapidly when the same pathogen is encountered again. This is one reason immune memory supports durable protection after infection or immunization.

The review’s concern is that the conditions helpful for an acute response may not be identical to the conditions required for memory formation. The aged-mouse influenza findings point to a change in T-cell composition and lower lung TGF-beta after D + Q treatment. Because TGF-beta is also involved in the development of CD4 and CD8 memory responses, reducing that signal could have consequences that appear only later.

That possibility is a hypothesis proposed by the review, not a demonstrated clinical loss of immune memory. The influenza findings presented here do not establish long-term recall protection or show that senolytic treatment weakens vaccination responses in older adults. It identifies a transition that future studies must measure directly: from the quality of the response during one infection to the ability to remember and control a later encounter.

The distinction matters for treatment timing. A short course given before an infection could change the tissue environment and immune-cell balance before the pathogen arrives. A treatment given during infection could also alter signaling in immune cells that are already responding. Either schedule might have different effects on recovery, tissue repair, and memory generation. The review does not establish a generally suitable human dose, schedule, or long-term safety profile for immune rejuvenation.

Human trials need more than a senescence marker

A reduction in a senescence-related marker is not the same as proof that a person resists infection better or retains stronger protection months or years later. The review emphasizes that many senolytic studies in older adults measure SASP, general inflammation, or markers on immune cells without testing the full function of the immune system.

The review lists SToMP-AD, an Alzheimer’s disease trial for adults aged 65 and older, with measurement of senescent CD3-positive T cells expressing p16 as an immune-cell endpoint. That endpoint could help show whether a population of senescence-marked T cells changes during treatment. It does not by itself reveal how well the person responds to influenza, produces antibodies, forms memory cells, or recovers from a later infection.

The review also lists an HIV study using dasatinib monotherapy with an age range of 18 to 65. Its immune-related measurements included senescence markers in peripheral blood lymphocytes. Because the upper age limit was 65 and the study’s endpoint focused on cellular markers, its design could not substitute for evidence about immune memory in substantially older adults.

This gap is especially important because immune cells work as a network. T cells, B cells, natural killer cells, macrophages, neutrophils, and antigen-presenting cells have different jobs, and an aggregate measurement of peripheral blood cells can hide changes in particular subgroups. Drug concentration and exposure time may also matter: the review describes studies using different doses, treatment windows, administration methods, and disease settings.

Clinical benefit would therefore require more than evidence that a treatment lowered inflammation or altered p16 expression. Researchers would need to connect senescent-cell removal with meaningful outcomes such as recovery from infection, preservation of tissue repair, effective immune-cell activation, and durable recall after a later exposure. The reviewed trials and preclinical studies had not yet supplied that complete chain.

What this could change

Senolytic treatment could eventually offer older adults a way to recover from infections with less inflammatory tissue injury while retaining protection against later encounters. That possibility depends on human evidence showing clinical benefit without disrupting immune memory, repair, or longer-term immune function.

A useful treatment would have to do more than remove a harmful cellular burden. It would need to improve the balance between immediate defense and the biological work that follows: clearing the infection, repairing tissue, and preserving cells capable of recognizing the threat again. The 2023 review makes that balance a central question for senolytic research. Until studies measure both timescales in people, an improved acute response remains a promising possibility rather than proof of durable immune protection.

Key Sources

• Primary source: Impact of senolytic treatment on immunity, aging, and disease.
  DOI or Journal Page · Review or Meta-Analysis · 2023-10-10