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

Metabolic syndrome (MetS) is characterized by low-grade inflammation and insulin resistance, which increase the risk of heart disease. Eggs have numerous nutrients including choline, carotenoids, and fat-soluble vitamins that may protect against these conditions. Egg phosphatidylcholine (PC) is a major contributor of dietary choline in the American diet. However, uncertainty remains regarding eggs due to their high concentration of cholesterol. In this study, we evaluated the effect of two sources of choline, whole eggs (a source of PC) and a choline supplement (choline bitartrate, CB), on plasma lipids, glucose, insulin resistance, and inflammatory biomarkers. We recruited 23 subjects with MetS to participate in this randomized cross-over intervention. After a 2-week washout, with no choline intake, participants were randomly allocated to consume three eggs/day or CB (~400 mg choline/d for both) for 4 weeks. After a 3-week washout period, they were allocated to the alternate treatment. Dietary records indicated higher concentrations of vitamin E and selenium during the egg period (p < 0.01). Interestingly, there were no changes in plasma total, low density lipoprotein (LDL)- or high density lipoprotein (HDL)-cholesterol, triglycerides, or glucose, compared either to baseline or between treatments. In contrast, interleukin-6 was reduced, with both sources of choline compared to baseline, while eggs also had an effect on lowering C-reactive protein, insulin, and insulin resistance compared to baseline. This study demonstrates that in a MetS population, intake of three eggs per day does not increase plasma LDL cholesterol, and has additional benefits on biomarkers of disease compared to a choline supplement, possibly due to the presence of other antioxidants in eggs.

Frailty occurs in 10–15% of community-living older adults and inflammation is a key determinant of frailty. Though diet is a modulator of inflammation, there are few prospective studies elucidating the role of diet-associated inflammation on frailty onset. We sought to determine whether a proinflammatory diet was associated with increased odds of frailty in adults from the Framingham Heart Study (FHS). This study was nested in a prospective cohort that included individuals without frailty. Diet was assessed in 1998–2001 using a valid FFQ, and frailty was measured in 2011–2014. FFQ-derived energy-adjusted dietary inflammatory index (E-DII®) scores were computed, with higher E-DII scores indicating a more proinflammatory diet. Frailty was defined as fulfilling ≥3 of 5 Fried Phenotype criteria. Information on potential mediators, serum IL-6 and C-reactive protein was obtained in 1998–2001. Logistic regression estimated ORs and 95% CIs for E-DII (as continuous and in quartiles) and frailty onset adjusting for relevant confounders. Of 1701 individuals without frailty at baseline (mean ± SD age: 58 ± 8 y; range: 33–81 y; 55% female), 224 developed frailty (13% incidence) over ∼12 y. The mean ± SD E-DII score was −1.95 ± 2.20; range: −6.71 to +5.40. After adjusting for relevant confounders, a 1-unit higher E-DII score was associated with 16% increased odds of developing frailty (95% CI: 1.07, 1.25). In categorical analyses, participants in the highest (proinflammatory) compared with lowest quartile of E-DII had >2-fold increased odds of frailty (OR_{quartile4vs.1}: 2.22; 95% CI: 1.37, 3.60; P-trend < 0.01). IL-6 and C-reactive protein were not major contributors in the pathway. In this cohort of middle-aged and older adults, a proinflammatory diet was associated with increased odds of frailty over ∼12 y of follow-up. Trials designed to increase consumption of anti-inflammatory foods for frailty prevention are warranted.

The benefit of a Mediterranean-style diet in reducing frailty is not well established in older Americans. We sought to determine associations of a Mediterranean-style dietary pattern and related antioxidants with frailty onset and worsening of the Fried phenotype in adults. This prospective study included 2384 nonfrail adults from the Framingham Offspring Study with a Mediterranean-style dietary pattern score (MSDPS) and data on antioxidant intakes (vitamin C, E, and total carotenoids) estimated from an FFQ at the index examination (1998–2001) and 1 prior examination (if available), as well as a frailty assessment at the index examination and at least 1 follow-up. Frailty onset was defined as ≥3 of 5 Fried frailty phenotype criteria at follow-up and the worsening of the Fried frailty phenotype was defined as an increased number of frailty criteria over follow-up (yes or no). Logistic regression with generalized estimating equations estimated ORs and 95% CIs, adjusting for confounders. Analyses were stratified by age (<60 and ≥60 years) for significant interactions. The mean ± SD age was 60 ± 9 years (range, 33–86 years) and 55% were female. In adjusted models, a 1-unit higher MSDPS reduced the odds of frailty by 3% (OR, 0.97; 95% CI: 0.96–0.99). Each 10-mg higher total carotenoid and vitamin E intake reduced the odds of frailty by 16% (OR, 0.84; 95% CI: 0.73–0.98) and 1% (OR, 0.99; 95% CI: 0.98–1.00), respectively. No association with vitamin C (P = 0.36) was observed. The associations among participants aged <60 years of age were stronger for each 1-unit higher MSDPS (OR, 0.93; 95% CI: 0.89–0.96) and total carotenoid intake (OR, 0.59; 95% CI: 0.41–0.82) than those observed in older individuals [ORs, 0.98 (95% CI: 0.97–1.00) and 0.92 (95% CI: 0.79–1.08), respectively]. Our findings suggest that adherence to a Mediterranean-style diet and higher total carotenoid intake are associated with frailty prevention over time, particularly in adults <60 years.

Background: The Trial of Nonpharmacologic Interventions in the Elderly (TONE) demonstrated the efficacy of weight loss and sodium reduction to reduce hypertension medication use in older adults. However, the longer-term effects of drug withdrawal (DW) on blood pressure (BP), adverse events, and orthostatic symptoms were not reported. Methods: TONE enrolled adults, ages 60–80 years, receiving treatment with a single antihypertensive and systolic BP (SBP)/diastolic BP <145/<85 mm Hg. Participants were randomized to weight loss, sodium reduction, both, or neither (usual care) and followed up to 36 months; ~3 months postrandomization, the antihypertensive was withdrawn and only restored if needed for uncontrolled hypertension. BP and orthostatic symptoms (lightheadedness, feeling faint, imbalance) were assessed at randomization and throughout the study. Two physicians independently adjudicated adverse events, masked to intervention, classifying symptomatic (lightheadedness, dizziness, vertigo), or clinical events (fall, fracture, syncope). Results: Among the 975 participants (mean age 66 years, 48% women, 24% black), mean (±SD) BP was 128 ± 9/71 ± 7 mm Hg. Independent of assignment, DW increased SBP by 4.59 mm Hg (95% confidence interval [CI]: 3.89, 5.28) compared with baseline. There were 113 adverse events (84 symptomatic, 29 clinical), primarily during DW. Compared with usual care, combined weight loss and sodium reduction mitigated the effects of DW on BP (β = −4.33 mm Hg; 95% CI: −6.48, −2.17) and reduced orthostatic symptoms long term (odds ratio = 0.62; 95% CI: 0.41, 0.92), without affecting adverse events (hazard ratio = 1.81; 95% CI: 0.90, 3.65). In contrast, sodium reduction alone increased risk of adverse events (hazard ratio = 1.75; 95% CI: 1.04, 2.95), mainly during DW. Conclusions: In older adults, antihypertensive DW may increase risk of symptomatic adverse events, highlighting the need for caution in withdrawing their antihypertensive medications. Clinical trials registration: Trial Number NCT00000535.

The process of cellular senescence is hypothesized to play a critical role in the development of age-related mobility and cognitive impairments, both of which precede the development of Alzheimer’s disease. Therefore, senolytic compounds that eliminate senescent cells represent an alternative strategy that may help improve mobility and cognition in older adults; however, clinical trials are lacking. The goal of this paper is to describe the rationale and study design of a 12-week single arm, open label, pre-post pilot study that administers intermittent doses of two senolytic compounds, Dasatinib and quercetin (DQ), in 12 older adults ≥ 65 years with slow gait speed (<1.0 m/sec) and mild cognitive impairment. Eligible participants are asked to take 1250 mg of and 100 mg of Dasatinib orally once a day for 2 days every 2 weeks, for 6 cycles over 12 consecutive weeks. Both physical and cognitive functional assessments are administered before treatment, as well as 6- and 12- weeks after treatment. Blood and urine samples are taken pre- and post-treatment to assess biomarkers of cellular senescence. The primary outcomes of this trial are feasibility and safety of the intervention, as well as preliminary efficacy on several clinical outcomes (e.g., cerebral blood flow velocity, gait speed, and biomarkers of cellular senescence). The study is approved by the Advarra IRB (#Pro00053594) and a Data Safety Monitoring Board. It is registered at Clinicaltrials.gov (Identifier:NCT05422885). The future results of this study may identify a novel approach for improving mobility and cognition in older adults, thereby preventing progression to Alzheimer’s disease.