Reducing pathogenic senescent CD8 T cells

The following papers suggest that removal/reduction of pathological,senescent, memory, CD8 T cells may have beneficial effects in preventing or treating early Alzheimer’s disease.

There are several emerging methods—some in clinical or preclinical stages—to reduce the amount of senescent CD8+ T cells in humans, but no universally proven, widely adopted regimen yet exists. The main approaches under investigation include senolytic drugs, cytokine therapies, metabolic and epigenetic modulators, and targeted immunotherapies.

Senolytic Drugs and Immunotherapies

Senolytics, such as BCL-2 inhibitors (e.g., Navitoclax/ABT263), have demonstrated the ability to selectively induce apoptosis in senescent immune cells including CD8+ T cells, both in animal models and preliminary human studies. These agents may help remove senescent cells prior to or in concert with other therapies, showing promise for immunosenescence reversal and potentially for age-related disease management.^[19]^[20]
Engineered CAR-T cells against uPAR (senescence marker) or vaccines targeting CD153-expressing senescent T cells have shown efficacy in mouse models for reducing senescent CD8+ T cells, but clinical translation is still underway.^[19]
Antibody -Drug Conjugates
Activated NK infusions

Cytokine Modulation

Gamma chain cytokines, especially IL-7, are known to promote the survival and expansion of non-senescent T cells and can partially rejuvenate immune responses. IL-7 treatment in animal models and select clinical trials increases naive and memory T cell expansion and may decrease the proportion of senescent T cells, although specificity to CD8+ T cells varies.^[21]^[22]^[23]

Metabolic and Epigenetic Modulation

Pharmacologic agents targeting transcription factors and epigenetic regulators (KLF5, AP1/c-JUN, RUNX2) can modulate senescence gene expression profiles in CD8+ T cells. Recent studies show that inhibiting these nodes in vitro reduces senescence-associated gene signatures in CD8+ T cells, with potential for translational application.^[24]^[25]
Nicotinamide mononucleotide supplementation ameliorated interferon-induced CD8+ T cell senescence and restored function in preclinical cancer models, suggesting some metabolic interventions could reduce or reverse senescence pathways.^[26]

Other Approaches

Physical exercise and caloric restriction have been associated with reduced accumulation of senescent T cells, attributed to increased blood oxygenation and improved immune surveillance.^[22]
Activation of TLR8 signaling in regulatory T cells and tumor environments can suppress or reverse the induction of senescence in responder CD8+ T cells.^[27]^[28]
Targeted Leukaphreresis/Apheresis – Senescent Memory CD8 T cell affinity column
Anti Senescent Exosomes with miRNA, circular RNA, and proapoptotic proteins.
Mitochondrial Metabolite induced apoptosis

Current Status and Limitations

While these methods show promise, most lack robust, long-term data demonstrating selective and sustained reduction of senescent CD8+ T cells in humans. The field is rapidly advancing, and new strategies may soon be refined for clinical use.^[29]^[30]^[31]

In summary, several experimental and early clinical approaches, such as senolytics, cytokine modulation, metabolic therapies, and engineered immunotherapies, can reduce senescent CD8+ T cells in humans, but large-scale, proven interventions are still being validated.^[25]^[21]^[19]

Reducing pathogenic senescent CD8 T cells

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