Orr, Miranda E.

Abstract The National Institute on Aging-funded Geroscience Education and Training Network held the “Building an Interdisciplinary Workforce in Geroscience: Aligning Perspectives and Educational Goals” preconference workshop at the 2023 Gerontological Society of America’s Annual Meeting. Parties involved in geroscience education and interested stakeholders addressed the development of didactic educational materials, training, and career development opportunities to equip learners with the skills to meet the demands of the emerging field of geroscience, from research to clinic and industry. Recent successes were presented, existing opportunities, gaps, and challenges identified and discussed, and solutions and future directions described.

Abstract The aging process is universal, and it is characterized by a progressive deterioration and decrease in physiological function leading to decline on the organismal level. Nevertheless, a number of genetic and nongenetic interventions have been described, which successfully extend healthspan and lifespan in different species. Furthermore, a number of clinical trials have been evaluating the feasibility of different interventions to promote human health. The goal of the annual Biological Sciences Section of the Gerontological Society of America meeting was to share current knowledge of different topics in aging research and provide a vision of the future of aging research. The meeting gathered international experts in diverse areas of aging research including basic biology, demography, and clinical and translational studies. Specific topics included metabolism, inflammaging, epigenetic clocks, frailty, senescence, neuroscience, stem cells, reproductive aging, inter-organelle crosstalk, comparative transcriptomics of longevity, circadian clock, metabolomics, and biodemography.

Abstract Senescent cell accumulation contributes to the progression of age-related disorders including Alzheimer’s disease (AD). Clinical trials evaluating senolytics, drugs that clear senescent cells, are underway, but lack standardized outcome measures. Our team recently published data from the first open-label trial to evaluate senolytics (dasatinib plus quercetin) in AD. After 12-weeks of intermittent treatment, we reported brain exposure to dasatinib, favorable safety and tolerability, and modest post-treatment changes in cerebrospinal fluid (CSF) inflammatory and AD biomarkers using commercially available assays. Herein, we present more comprehensive exploratory analyses of senolytic associated changes in AD relevant proteins, metabolites, lipids, and transcripts measured across blood, CSF, and urine. These analyses included mass spectrometry for precise quantification of amyloid beta (Aß) and tau in CSF; immunoassays to assess senescence associated secretory factors in plasma, CSF, and urine; mass spectrometry analysis of urinary metabolites and lipids in blood and CSF; and transcriptomic analyses relevant to chronic stress measured in peripheral blood cells. Levels of Aß and tau species remained stable. Targeted cytokine and chemokine analyses revealed treatment-associated increases in inflammatory plasma fractalkine and MMP-7 and CSF IL-6. Urinary metabolites remained unchanged. Modest treatment-associated lipid profile changes suggestive of decreased inflammation were observed both peripherally and centrally. Blood transcriptomic analysis indicated downregulation of inflammatory genes including FOS, FOSB, IL1β, IL8, JUN, JUNB, PTGS2. These data provide a foundation for developing standardized outcome measures across senolytic studies and indicate distinct biofluid-specific signatures that will require validation in future studies. ClinicalTrials.gov: NCT04063124.

Abstract Cellular senescence has been identified as a pathological mechanism linked to tau and amyloid beta (Aβ) accumulation in mouse models of Alzheimer's disease (AD). Clearance of senescent cells using the senolytic compounds dasatinib (D) and quercetin (Q) reduced neuropathological burden and improved clinically relevant outcomes in the mice. Herein, we conducted a vanguard open-label clinical trial of senolytic therapy for AD with the primary aim of evaluating central nervous system (CNS) penetrance, as well as exploratory data collection relevant to safety, feasibility, and efficacy. Participants with early-stage symptomatic AD were enrolled in an open-label, 12-week pilot study of intermittent orally-delivered D+Q. CNS penetrance was assessed by evaluating drug levels in cerebrospinal fluid (CSF) using high performance liquid chromatography with tandem mass spectrometry. Safety was continuously monitored with adverse event reporting, vitals, and laboratory work. Cognition, neuroimaging, and plasma and CSF biomarkers were assessed at baseline and post-treatment. Five participants (mean age: 76±5 years; 40% female) completed the trial. The treatment increased D and Q levels in the blood of all participants ranging from 12.7 to 73.5 ng/ml for D and 3.29-26.30 ng/ml for Q. D levels were detected in the CSF of four participants ranging from 0.281 to 0.536 ng/ml (t(4)=3.123, p=0.035); Q was not detected. Treatment was well-tolerated with no early discontinuation and six mild to moderate adverse events occurring across the study. Cognitive and neuroimaging endpoints did not significantly differ from baseline to post-treatment. CNS levels of IL-6 and GFAP increased from baseline to post-treatment (t(4)=3.913, p=008 and t(4)=3.354, p=0.028, respectively) concomitant with decreased levels of several cytokines and chemokines associated with senescence, and a trend toward higher levels of Aβ42 (t(4)=-2.338, p=0.079). Collectively the data indicate the CNS penetrance of D and provide preliminary support for the safety, tolerability, and feasibility of the intervention and suggest that astrocytes and Aβ may be particularly responsive to the treatment. While early results are promising, fully powered, placebo-controlled studies are needed to evaluate the potential of AD modification with the novel approach of targeting cellular senescence.

AbstractBackgroundSenescent cells accumulate with advanced age and contribute to dysfunction and disability. We recently discovered that tau protein accumulation induces cellular senescence in Alzheimer’s disease and other tauopathies, a group of brain diseases characterized by the deposition of tau protein (Musi et al., 2018). Treating mice with senolytics, drugs that specifically target senescent cells for their removal, reduced pathology and improved brain structure and function in tauopathy mice. Our initial study focused on dasatinib plus quercetin (D+Q). We now report results from directly comparing D+Q to fisetin (FIS) to determine differences in efficacy, toxicity, and sex and genotype as we work to translate this therapy to clinical studies.MethodFourteen‐month old male and female wild type (WT) and tau transgenic (rTg4510) mice were treated intermittently (3 days on, 11 days off, for 6 cycles) with D+Q, FIS, or vehicle by oral gavage. Physical and behavioral outcomes were measured before and after treatment.ResultBoth senolytic therapies significantly enhanced female rTg4510 mouse performance in the y‐maze (increased preference for novel arm (p = 0.00093 and p = 0.0015, D+Q and FIS, respectively); no treatment changes were noted in WT females or male mice. Pre‐ and post‐treatment comparisons of body weight revealed that D+Q uniquely increased body weight in female mice (WT: p=0.0005 and t: p = 0.024). Similarly, body length was increased by D+Q in WT (p= 0.0012) and rTg4510 (p= 0.0457) females, and WT males (p= 0.0481). Physical performance measures included run speed whereby D+Q increased WT female (p= 0.0002) and male (p=0.0267) velocity. FIS only affected WT males (p= 0.0022) but not females; and rTg4510 male (p=0.0015) but not female mice. Additional genotype, sex and treatment specific effects were observed in measures of frailty, grip strength, stride length, and nerve conduction. Our on‐going analyses of brain volumetry changes (MRI), axon integrity, transcriptomics, tau pathology, and inflammatory changes among the groups will provide mechanistic insights responsible for these behavioral phenotypes.ConclusionOur study suggests that tailoring senolytic therapies to specific individuals based on sex and disease state may provide the most benefit as we translate this promising therapy to clinical use.