Characterization of Human Senescent Cell Biomarkers for Clinical Trials

Area of Science:

• Biomarkers
• Cellular Senescence
• Clinical Trials

Background:

• Senescent cell burden requires reliable biomarkers for clinical trial participant selection.
• The CDKN2A locus encodes multiple p16INK4a transcripts, including p16 variant 1 and p16 variant 5.
• Existing assays for p16INK4a variants have limitations in distinguishing specific transcript contributions.

Purpose of the Study:

• To evaluate the predictive value of p16INK4a variants as biomarkers for senescent cell burden.
• To assess the efficacy of T-cell p16 variant 5 expression in predicting response to senolytic treatment.
• To identify alternative biomarkers, such as plasma SASP panels, for senolytic intervention trials.

Main Methods:

• Analysis of T-cell p16INK4a variant expression (p16 variant 1+5 and p16 variant 5) in postmenopausal women undergoing senolytic therapy.
• In vitro experiments to track the temporal expression of p16INK4a variants following DNA damage induction.
• Identification and validation of plasma senescence-associated secretory phenotype (SASP) panels as potential biomarkers.

Main Results:

• Higher T-cell p16 variant 5 expression correlated with robust skeletal responses to dasatinib + quercetin.
• p16 variant 5 assessment was more predictive of skeletal response than the combined p16 variant 1+5 assay.
• p16 variant 5 expression increased later than p16 variant 1+5 after DNA damage, suggesting a threshold effect.
• A plasma SASP panel demonstrated comparable performance to the T-cell p16 assay in predicting treatment response.

Conclusions:

• T-cell p16 variant 5 serves as a valuable biomarker for selecting participants in senolytic clinical trials.
• Plasma SASP markers offer a promising alternative to T-cell based assays for predicting senolytic treatment outcomes.
• These findings advance the development of reliable biomarkers for targeting senescent cells in therapeutic interventions.