A pilot study of senolytics to improve cognition and mobility in older adults at risk for Alzheimer's disease

Abstract

Background: This single-arm study evaluates the feasibility, safety, and preliminary effects of two senolytic agents, Dasatinib and Quercetin (DQ), in older adults at risk of Alzheimer's disease.

Methods: Participants took 100 mg of Dasatinib and 1250 mg of Quercetin for two days every two weeks over 12 weeks. Recruitment rate, adverse events, absolute changes in functional outcomes, and percent changes in biomarkers were calculated. Spearman correlations between functional and biomarker outcomes were performed.

Findings: Approximately 10% of telephone-screened individuals completed the intervention (n = 12). There were no serious adverse events related to the intervention. Mean Montreal Cognitive Assessment (MoCA) scores non-significantly increased following DQ by 1.0 point (95% CI: -0.7, 2.7), but increased significantly by 2.0 points (95% CI: 0.1, 4.0) in those with lowest baseline MoCA scores. Mean percent change in tumour necrosis factor-alpha (TNF-α), a key product of the senescence-associated secretory phenotype (SASP), non-significantly decreased following DQ by -3.0% (95% CI: -13.0, 7.1). Changes in TNF-α were significantly and inversely correlated with changes in MoCA scores (r = -0.65, p = 0.02), such that reductions in TNF- α were correlated with increases in MoCA scores.

Interpretation: This study suggests that intermittent DQ treatment is feasible and safe; data hint at potential functional benefits in older adults at risk of Alzheimer's disease. The observed reduction in TNF-α and its correlation with increases in MoCA scores suggests that DQ may improve cognition by modulating the SASP. However, there was not an appropriate control group. Data are preliminary and must be interpreted cautiously.

Funding: National Institute on Ageing grants R21AG073886 and R33AG061456 funded this research.

Keywords: Ageing; Cognitive impairment; Flavonoids; Gait; Geroscience; Senolytics.

Fig. 1

Flow chart of recruitment for the STAMINA Study. MCI, mild cognitive impairment.

Fig. 2

The frequency of clinical safety adverse events in the STAMINA study. Clinical blood safety measures were evaluated prior to each administration of the 2-day dose of Dasatinib and Quercetin. If the Laboratory results deviated from a pre-determined safety range (described in full elsewhere³³) by more than 20% and/or newly appeared, they were considered adverse events. Each colour represents a different participant (n = 12). AE, adverse events; ALT, alanine-aminotransferase; GFR, glomerular filtration rate.

Fig. 3

The frequency of self-reported symptoms adverse events in the STAMINA study. Self-reported symptoms were evaluated once before and two times after each 2-day drug treatment of Dasatinib and Quercetin. If the symptom newly appeared or was reported to be more severe than usual, then it was considered an adverse event. Each colour represents a different participant (n = 12). AE, adverse events.

Fig. 4

Percent change of select senescence biomarkers. The percent change between screening and final follow-up values (∼14 weeks) was calculated for each biomarker in STAMINA (n = 12, blue circle) and Biomarker Control (n = 10, red square) participants. All data points are displayed on the figure with the mean expressed as the larger shape and 80% confidence intervals expressed as the solid line. IL, interleukin; MMP, matrix metalloproteinase; p16^INK4a, a genetic marker of senescent cells; PDL-2, programmed cell death-ligand 2; TNF-α, tumour necrosis factor alpha.

Fig. 5

(a and b) Spearman correlations between change in cognitive scores and biomarkers. The absolute change of MoCA scores after treatment was correlated with percent change of TNF-α (a) and PDL-2 (b) in 12 participants. MoCA, Montreal Cognitive Assessment; PDL-2, programmed cell death-ligand 2; TNF-α, tumour necrosis factor alpha.