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Calorie restriction (CR) with adequate nutrient intake is a potential geroprotective intervention. To advance this concept in humans, we tested the hypothesis that moderate CR in healthy young-to-middle-aged individuals would reduce circulating biomarkers of cellular senescence, a fundamental mechanism of aging and aging-related conditions. Using plasma specimens from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) phase 2 study, we found that CR significantly reduced the concentrations of several senescence biomarkers at 12 and 24 months compared to an ad libitum diet. Using machine learning, changes in biomarker concentrations emerged as important predictors of the change in HOMA-IR and insulin sensitivity index at 12 and 24 months, and the change in resting metabolic rate residual at 12 months. Finally, using adipose tissue RNA-sequencing data from a subset of participants, we observed a significant reduction in a senescence-focused gene set in response to CR at both 12 and 24 months compared to baseline. Our results advance the understanding of the effects of CR in humans and further support a link between cellular senescence and metabolic health.

Studies in mice and cross-sectional studies in humans support the premise that cellular senescence is a contributing mechanism to age-associated deficits in physical function. We tested the hypotheses that circulating proteins secreted by senescent cells are (i) associated with the incidence of major mobility disability (MMD), the development of persistent mobility disability (PMMD), and decrements in physical functioning in older adults, and (ii) influenced by physical activity (PA). Using samples and data obtained longitudinally from the Lifestyle Interventions in Elders Study clinical trial, we measured a panel of 27 proteins secreted by senescent cells. Among 1 377 women and men randomized to either a structured PA intervention or a healthy aging (HA) intervention, we observed significant associations between several senescence biomarkers, most distinctly vascular endothelial growth factor A (VEGFA), tumor necrosis factor receptor 1 (TNFR1), and matrix metallopeptidase 7 (MMP7), and the onset of both MMD and PMMD. Moreover, VEGFA, GDF15, osteopontin, and other senescence biomarkers were associated with reductions in short physical performance battery scores. The change in senescence biomarkers did not differ between PA and HA participants. In the whole cohort, higher levels of PA were associated with significantly greater reductions in 10 senescence-related proteins at 12 and/or 24 months. These data reinforce cellular senescence as a contributing mechanism of age-associated functional decline and the potential for PA to attenuate this hallmark of aging. Clinical Trials Registration Number: NCT01072500 [ABSTRACT FROM AUTHOR]

Senescent cells compromise tissue structure and function in older organisms. We recently identified senescent fibroadipogenic progenitors (FAPs) with activated chemokine signaling pathways in the skeletal muscle of old mice, and hypothesized these cells may contribute to the age‐associated accumulation of immune cells in skeletal muscle. In this study, through cell–cell communication analysis of skeletal muscle single‐cell RNA‐sequencing data, we identified unique interactions between senescent FAPs and macrophages, including those mediated by Ccl2 and Spp1. Using mouse primary FAPs in vitro, we verified increased expression of Ccl2 and Spp1 and secretion of their respective proteins in the context of both irradiation‐ and etoposide‐induced senescence. Compared to non‐senescent FAPs, the medium of senescent FAPs markedly increased the recruitment of macrophages in an in vitro migration assay, an effect that was mitigated by preincubation with antibodies to either CCL2 or osteopontin (encoded by Spp1). Further studies demonstrated that the secretome of senescent FAPs promotes polarization of macrophages toward an M2 subtype. These data suggest the unique secretome of senescent FAPs may compromise skeletal muscle homeostasis by recruiting and directing the behavior of macrophages. [ABSTRACT FROM AUTHOR]

Background: The Measurement Based Care in Mental Health Initiative launched by the Department of Veterans Affairs in 2016 is an example of an evidence-based practice that uses patient-reported outcome measures (PROMs) to improve patient outcomes. The acceptance of measurement-based care (MBC) among Veterans Affairs providers is relatively high. However, there are barriers to MBC for telehealth providers. Health information technologies might afford opportunities to address some of the barriers related to the uptake of MBC. Objective: This paper reports on an implementation effort to integrate MBC into mental health care telehealth practice using eHealth solutions. Methods: Qualitative data were generated from 22 semistructured interviews with psychiatrists (n=4), psychologists (n=3), social workers (n=3), nurses (n=6), a pharmacist (n=1), and administrative staff (n=5) who provide telemental health care through a community-based outpatient clinic in the rural Midwestern United States. The interviews were conducted during the pilot phase of an implementation initiative to increase the adoption of MBC by revising clinic workflows to integrate the use of eHealth technologies. Data were analyzed using thematic analysis. Results: Time burden and workflow issues were the most common barrier to provider adoption of MBC; sharing and reviewing pencil-and-paper measures and results in the same room was no longer possible in novel telehealth workflows necessitated by the COVID-19 pandemic. Providers voiced concerns about how long it would take to collect, adequately score, interpret, share, and document the PROMs during the telehealth visit. Concerns about time might also correspond to a gap in providers' familiarity with these assessments, greater comfort in assessing symptoms through clinical interviews, and being accustomed to using the assessments as screening tools more so than longitudinal outcome measures. Capacities associated with eHealth technologies may address workflow concerns and promote providers' understanding and use of the measures as tracking tools. Conclusions: The need to use limited appointment time well was a top priority for telemental health providers. eHealth technologies provided operative supports that protect time in appointments by shifting when and how PROMs are collected. Bolstering providers' familiarity with how to use PROMs in the course of treatment may impact providers' buy-in by encouraging them to reconsider how sharing and acting on PROMs could be time well spent. [ABSTRACT FROM AUTHOR]