Low-energy differential target multiplexed SCS derivative reduces pain and improves quality of life through 12 months in patients with chronic back and/or leg pain.

INTRODUCTION: Energy-reducing spinal cord stimulation (SCS) approaches have the potential to impact patient experience with rechargeable and non-rechargeable SCS devices through reducing device recharge time or enhancing device longevity. This prospective, multi-center study evaluated the safety, effectiveness, and actual energy usage of differential target multiplexed (DTM) endurance therapy, a reduced energy DTM SCS derivative. METHODS: Subjects who reported an overall pain visual analog score (VAS) of ≥6/10 cm and an Oswestry Disability Index score of 21-80 out of 100 at baseline with moderate to severe chronic, intractable back and/or leg pain were eligible. Evaluation visits occurred at 1, 3, 6, and 12 months post-device activation. The primary objective was to characterize change in overall pain intensity, as measured by VAS, from baseline to 3-month visit. RESULTS: Fifty-seven subjects enrolled at 12 US sites from November 2020 through June 2021, 35 were implanted with a rechargeable SCS device, and 27 completed the 12-month visit. Subjects experienced a 50.4% mean reduction in overall pain from baseline at the 3-month follow-up that was sustained through 12 months. Additional outcomes including changes in overall, back, and leg pain intensity, quality of life, disability, therapy satisfaction, safety, and current battery usage are shown through 12-month follow-up. CONCLUSION: The use of DTM endurance SCS therapy in this study resulted in reductions in pain relief through 12 months, demonstrating that energy-reducing stimulation patterns can provide clinical benefit. Clinically effective, reduced energy SCS derivatives have the potential to impact patient experience through either reduced recharge requirements or increased device longevity.

Colour polymorphism is prevalent on islands but shows no association with range size in web-building spiders.

One of the most evident sources of phenotypic diversity within a population is colouration, as exemplified by colour polymorphism. This is relevant to a greater extent in animals with visually-biased sensory systems. There is substantial evidence suggesting that different colour morphs can access a broader range of habitats or niches, leading to larger geographic range sizes. However, this hypothesis has been tested in few lineages, comprising species where colour is likely to be involved in sexual selection. Furthermore, some available evidence considers geographical variation as polymorphism, thus limiting our comprehension of how sympatric colour polymorphism can influence a species' geographic range. Through an extensive systematic literature review and a comparative analysis, we examined the relationship between colour polymorphism and range size or niche breadth in web-building spiders. We identified 140 colour polymorphic spider species, belonging mainly to the families Araneidae and Theridiidae. We found no evidence that colour polymorphic species differ significantly from non-polymorphic species in terms of range size and niche breadth, after accounting for phylogenetic relationships and other covariates. However, we did observe that colour polymorphic species were more likely to be found on islands compared to non-polymorphic species. Overall, our results indicate that the association between colour polymorphism and geographic range size may not exist among web-building spiders, or be as pronounced as in other lineages. This suggests that the strength of the association between colour polymorphism and ecological success might depend on the ecological role that colouration plays in each clade.

Twelve-month results from a randomized controlled trial comparing differential target multiplexed spinal cord stimulation and conventional spinal cord stimulation in subjects with chronic refractory axial low back pain not eligible for spine surgery.

Background: Successful treatments for intractable chronic low back pain (CLBP) in patients who are not eligible for surgical interventions are scarce. The superior efficacy of differential target multiplexed spinal cord stimulation (DTM SCS) to conventional SCS (Conv-SCS) on the treatment of CLBP in patients with persistent spinal pain syndrome (PSPS) who have failed surgical interventions (PSPS-T2) motivated the evaluation of DTM SCS versus Conv-SCS on PSPS patients who are non-surgical candidates (PSPS-T1). Methods: This is a prospective, open label, crossover, post-market randomized controlled trial in 20 centers across the United States. Eligible patients were randomized to either DTM SCS or Conv-SCS in a 1:1 ratio. Primary endpoint was CLBP responder rate (percentage of subjects with ≥50% CLBP relief) at 3-month in randomized subjects who completed trialing (modified intention-to-treat population). Patients were followed up to 12 months. Secondary endpoints included change of CLBP and leg pain, responder rates, changes in disability, quality of life, patient satisfaction and global impression of change, and safety profile. An optional crossover was available at 6-month to all patients. Results: About 121 PSPS-T1 subjects with CLBP and leg pain mostly associated with degenerative disc disease and radiculopathy and who were not eligible for spine surgery were randomized. CLBP responder rate with DTM SCS (93.5%) was superior to Conv-SCS (36.4%) at the primary endpoint. Superior CLBP responder rates (88.1%-90.5%) were obtained with DTM SCS at all other timepoints. Mean CLBP reduction with DTM SCS (6.52 cm) was superior to that with Conv-SCS (3.01 cm) at the primary endpoint. Similar CLBP reductions (6.23-6.43 cm) were obtained with DTM SCS at other timepoints. DTM SCS provided significantly better leg pain reduction and responder rate, improvement of disability and quality of life, and better patient satisfaction and global impression of change. 90.9% of Conv-SCS subjects who crossed over were CLBP responders at completion of the study. Similar safety profiles were observed between the two groups. Conclusion: DTM SCS for chronic CLBP in nonsurgical candidates is superior to Conv-SCS. Improvements were sustained and provided significant benefits on the management of these patients.

Five lessons for avoiding failure when scaling in conservation.

Many attempts to scale conservation actions have failed to deliver their intended benefits, caused unintended harm or later been abandoned, hampering efforts to bend the curve on biodiversity loss. Here we encourage those calling for scaling to pause and reflect on past scaling efforts, which offer valuable lessons: the total impact of an action depends on both its effectiveness and scalability; effectiveness can change depending on scale for multiple reasons; feedback processes can change socio-ecological conditions influencing future adoption; and the drive to scale can incentivize bad practices that undermine long-term outcomes. Cutting across these themes is the recognition that monitoring scaling can enhance evidence-informed adaptive management, reporting and research. We draw on evidence and concepts from disparate fields, explore new linkages between often isolated concepts and suggest strategies for practitioners, policymakers and researchers. Reflecting on these five lessons may help in the scaling of effective conservation actions in responsible ways to meet the triple goals of reversing biodiversity loss, combating climate change and supporting human wellbeing.

Connexin Hemichannel Inhibition and Human Genodermatoses.

Pathogenic variants in genes encoding connexins that cause skin diseases, such as keratitis-ichthyosis-deafness (KID) syndrome and hidrotic ectodermal dysplasia (HED) or Clouston syndrome, display increased hemichannel activity. Mechanistic insights derived from biophysical studies of the variant connexins support the hypothesis that inhibition of the acquired hemichannel activity could alleviate epidermal pathology. Use of pharmacological blockers and engineered mAbs in mouse models of HED and KID confirm that hemichannel inhibition is a promising target for new therapeutic approaches to KID and HED. Insights from this work could apply to other connexin-based genetic skin diseases in which hemichannel activity is elevated.

Loss of HD-PTP function results in lipodystrophy, defective cellular signaling, and altered lipid homeostasis.

His Domain Protein Tyrosine Phosphatase (HD-PTP) facilitates function of the endosomal sorting complexes required for transport (ESCRTs) during multivesicular body (MVB) formation. To uncover its role in physiological homeostasis, embryonic lethality caused by a complete lack of HD-PTP was bypassed through generation of hypomorphic mice expressing reduced protein, resulting in animals that are viable into adulthood. These mice exhibited marked lipodystrophy and decreased receptor-mediated signaling within white adipose tissue (WAT), involving multiple prominent pathways including RAS/MAPK, PI3K/AKT and RTKs such as EGFR. EGFR signaling was dissected in vitro to assess the nature of defective signaling, revealing decreased trans-autophosphorylation and downstream effector activation, despite normal EGF binding. This corresponds to decreased plasma membrane cholesterol and increased lysosomal cholesterol, likely resulting from defective endosomal maturation necessary for cholesterol trafficking and homeostasis. ESCRT components Vps4 and HRS have previously been implicated in cholesterol homeostasis, thus these findings expand knowledge on which ESCRT subunits are involved in cholesterol homeostasis and highlight a non-canonical role for HD-PTP in signal regulation and adipose tissue homeostasis.

Differential Target Multiplexed Spinal Cord Stimulation for the Treatment of Chronic Intractable Upper Limb Pain: 12-Month Results From a Prospective, Multicenter Study.

OBJECTIVES: This prospective, open-label, single-arm, multicenter study evaluated the use of differential target multiplexed (DTM) spinal cord stimulation (SCS) therapy for chronic upper limb pain (ULP). MATERIALS AND METHODS: A total of 58 candidates for SCS who had chronic ULP were enrolled at 11 sites in the USA. The safety and effectiveness of DTM SCS for treating chronic intractable ULP were evaluated over 12 months. The primary end point was the percentage of responders (≥50% ULP relief versus baseline) to treatment at three months after device activation. This study also evaluated the extent of disability, patient satisfaction, and patient global impression of change with DTM SCS therapy. RESULTS: The mean baseline pain score (10-cm visual analog scale [VAS-10]) for ULP was 7.2 cm, with a mean age of 56 years and mean ULP duration of ten years; 47 subjects were assessed at the primary end point. The percentage of ULP responders was 92% at three months, which was consistent at six (91%) and 12 months (86%). Significant ULP relief (81% reduction in VAS-10) was observed at the primary end point and sustained throughout the study duration. Significant improvements in disability in addition to high levels (>95%) of satisfaction and feelings of improvement were reported. Frequency of study-related anticipated adverse events was in line with expectations of SCS therapy. CONCLUSION: In this patient population with difficult-to-treat conditions with limited clinical evidence of the effectiveness of SCS, subjects reported significant reduction in chronic ULP in response to treatment with DTM SCS.

Automated workflows using Quantitative Colour Pattern Analysis (QCPA): a guide to batch processing and downstream data analysis.

Animal and plant colouration presents a striking dimension of phenotypic variation, the study of which has driven general advances in ecology, evolution, and animal behaviour. Quantitative Colour Pattern Analysis (QCPA) is a dynamic framework for analysing colour patterns through the eyes of non-human observers. However, its extensive array of user-defined image processing and analysis tools means image analysis is often time-consuming. This hinders the full use of analytical power provided by QCPA and its application to large datasets. Here, we offer a robust and comprehensive batch script, allowing users to automate many QCPA workflows. We also provide a complimentary set of useful R scripts for downstream data extraction and analysis. The presented batch processing extension will empower users to further utilise the analytical power of QCPA and facilitate the development of customised semi-automated workflows. Such quantitatively scaled workflows are crucial for exploring colour pattern spaces and developing ever-richer frameworks for analysing organismal colouration accounting for visual perception in animals other than humans. These advances will, in turn, facilitate testing hypotheses on the function and evolution of vision and signals at quantitative and qualitative scales, which are otherwise computationally unfeasible. Supplementary Information: The online version contains supplementary material available at 10.1007/s10682-024-10291-7.

Connexin 50 Influences the Physiological Optics of the In Vivo Mouse Lens.

Purpose: The purpose of this study was to utilize multi-parametric magnetic resonance imaging (MRI) to investigate in vivo age-related changes in the physiology and optics of mouse lenses where Connexin 50 has been deleted (Cx50KO) or replaced by Connexin 46 (Cx50KI46). Methods: The lenses of transgenic Cx50KO and Cx50KI46 mice were imaged between 3 weeks and 6 months of age using a 7T MRI. Measurements of lens geometry, the T2 (water-bound protein ratios), the refractive index (n), and T1 (free water content) values were calculated by processing the acquired images. The lens power was calculated from an optical model that combined the geometry and the n. All transgenic mice were compared with control mice at the same age. Results: Cx50KO and Cx50KI46 mice developed smaller lenses compared with control mice. The lens thickness, volume, and surface radii of curvatures all increased with age but were limited to the size of the lenses. Cx50KO lenses exhibited higher lens power than Cx50KI46 lenses at all ages, and this was correlated with significantly lower water content in these lenses, which was probably modulated by the gap junction coupling. The refractive power tended to a steady state with age, similar to the control mice. Conclusions: The modification of Cx50 gap junctions significantly impacted lens growth and physiological optics as the mouse aged. The lenses showed delayed development growth, and altered optics governed by different lens physiology. This research provides new insights into how gap junctions regulate the development of the lens's physiological optics.

The flashy escape: support for dynamic flash coloration as anti-predator defence.

Dynamic flash coloration is a type of antipredator coloration where intermittently appearing colour patterns in moving animals misdirect predator attacks by obscuring the precise location and trajectory of the moving prey. Birds and butterflies with differing dorsoventral wing coloration or iridescent surface structures may potentially benefit from such effects. However, we lack an understanding of what makes for an effective dynamic flash colour design and how much it benefits the carrier. Here, we test the effect of colour flashing using small passerine birds preying upon colourful, moving, virtual 'prey' stimuli on a touchscreen. We show that at fast speeds, green-to-blue flashing colour patterns can reduce the likelihood of pecks hitting the target, induce greater error in targeting accuracy and increase the number of pecks at a stimulus relative to similarly coloured non-flashing targets. Our results support the idea that dynamic flash coloration can deflect predatory attacks at fast speeds, but the effect may be the opposite when moving slowly.

Virtual reality as an engaging and enjoyable method for delivering emergency clinical simulation training: a prospective, interventional study of medical undergraduates.

BACKGROUND: It is a requirement that medical students are educated in emergencies and feel well prepared for practice as a doctor, yet national surveys show that many students feel underprepared. Virtual reality (VR), combined with 360-degree filming, provides an immersive, realistic, and interactive simulation experience. Unlike conventional in-person simulation, it is scalable with reduced workforce demands. We sought to compare students' engagement and enjoyment of VR simulation to desktop computer-based simulation. METHODS: We conducted a prospective, interventional, evaluation study. The study was carried out on final year medical students undertaking their Pre-Foundation Assistantship (n = 116) at Imperial College School of Medicine (ICSM) in London. We compared objective engagement, subjective engagement, and subjective enjoyment of VR simulation to desktop computer-based simulation using cardiac arrest and life-threatening asthma scenarios. Engagement was measured objectively using students' physiological parameters, including heart rate and eye tracking, and facilitator observations using the validated 'Behavioural Engagement Related to Instruction' (BERI) protocol. Students' subjective engagement and enjoyment levels were measured using a post-session survey. RESULTS: Students' maximum heart rates were significantly higher during VR simulation with a mean difference of 4.2 beats per minute (3.2 to 5.2, p < 0.001), and eye tracking showed they spent a significantly greater mean percentage of time of 6.4% (5.1 to 7.7, p < 0.001) focusing on the scenarios in VR compared to standard desktop. Qualitative data showed students enjoyed and felt engaged with the sessions, which provided a safe space for learning. CONCLUSIONS: Our study shows that students found VR simulations enjoyable and were more engaged compared to standard desktop simulation. This suggests that 360-degree VR simulation experiences provide students with immersive, realistic training, which is scalable, giving them the unique opportunity to manage emergencies and work within emergency teams, which would not typically occur during traditional training.

Deceptive pollinator lures benefit from physical and perceptual proximity to flowers.

Predators often use deception to exploit sensory and cognitive biases in prey. In pollinating insects, these include preferences for conspicuous colours associated with flowers, which predators such as orb-web spiders display as prey lures. Theory predicts that deceptive signal efficacy should covary with both their perceptual similarity and physical proximity to the resources-here, flowers-whose cues they are imitating. Here I used the colour-polymorphic jewelled spider Gasteracantha fornicata to test this prediction. I first examined spiders' capture success in the field, and found their visual resemblance and physical proximity to flowers interacted to mediate capture rates, with colour-similarity becoming increasingly important as the distance between spiders and flowers decreased. I then replicated this interaction experimentally. Spiders adjacent to colour-matched flowers enjoyed heightened capture success relative to those with nearby but colour-mismatched flowers. While spiders with flowers placed at a distance (irrespective of colour) recorded the fewest captures. These results support 'neighbourhood' effects in aggressive deception as receivers' vulnerability to exploitation is mediated by the local signalling community. More generally, they emphasise the importance of the broader information landscape in the ecology of communication, and suggest misinformation is most effective when physically and perceptually proximate to the truth.

Evidence for phonon hardening in laser-excited gold using x-ray diffraction at a hard x-ray free electron laser.

Studies of laser-heated materials on femtosecond timescales have shown that the interatomic potential can be perturbed at sufficiently high laser intensities. For gold, it has been postulated to undergo a strong stiffening leading to an increase of the phonon energies, known as phonon hardening. Despite efforts to investigate this behavior, only measurements at low absorbed energy density have been performed, for which the interpretation of the experimental data remains ambiguous. By using in situ single-shot x-ray diffraction at a hard x-ray free-electron laser, the evolution of diffraction line intensities of laser-excited Au to a higher energy density provides evidence for phonon hardening.

Data reduction in protein serial crystallography.

Serial crystallography (SX) has become an established technique for protein structure determination, especially when dealing with small or radiation-sensitive crystals and investigating fast or irreversible protein dynamics. The advent of newly developed multi-megapixel X-ray area detectors, capable of capturing over 1000 images per second, has brought about substantial benefits. However, this advancement also entails a notable increase in the volume of collected data. Today, up to 2 PB of data per experiment could be easily obtained under efficient operating conditions. The combined costs associated with storing data from multiple experiments provide a compelling incentive to develop strategies that effectively reduce the amount of data stored on disk while maintaining the quality of scientific outcomes. Lossless data-compression methods are designed to preserve the information content of the data but often struggle to achieve a high compression ratio when applied to experimental data that contain noise. Conversely, lossy compression methods offer the potential to greatly reduce the data volume. Nonetheless, it is vital to thoroughly assess the impact of data quality and scientific outcomes when employing lossy compression, as it inherently involves discarding information. The evaluation of lossy compression effects on data requires proper data quality metrics. In our research, we assess various approaches for both lossless and lossy compression techniques applied to SX data, and equally importantly, we describe metrics suitable for evaluating SX data quality.

[Surgical reconstruction of chest wall instability : Indications, contraindications and timing of surgery]. / Operative Rekonstruktion der Thoraxwandinstabilität : Indikationen, Kontraindikationen und Operationszeitpunkt.

The impact of energy on the thorax can lead to serial rib fractures, sternal fractures, the combination of both and to injury of intrathoracic organs depending on the type, localization and intensity. Sometimes this results in chest wall instability with severe impairment of the respiratory mechanics. In the last decade the importance of surgical chest wall reconstruction in cases of chest wall instability has greatly increased. The evidence for a surgical approach has in the meantime been supported by prospective randomized multicenter studies, multiple retrospective data analyses and meta-analyses based on these studies, including a Cochrane review. The assessment of form and severity of the trauma and the degree of impairment of the respiratory mechanism are the basis for a structured decision on an extended conservative or surgical reconstructive strategy as well as the timing, type and extent of the operation. The morbidity (rate of pneumonia, duration of intensive care unit stay and mechanical ventilation) and fatality can be reduced by a timely surgery within 72 h after trauma. In this article the already established and evidence-based algorithms for surgical chest wall reconstruction are discussed in the context of the current evidence.

Physical Resilience as a Predictor of Lifespan and Late-Life Health in Genetically Heterogeneous Mice.

Dynamic measures of resilience-the ability to resist and recover from a challenge-may be informative of the rate of aging before overt manifestations such as chronic disease, disability, and frailty. From this perspective mid-life resilience may predict longevity and late-life health. To test this hypothesis, we developed simple, reproducible, clinically relevant challenges, and outcome measures of physical resilience that revealed differences between and within age groups of genetically heterogeneous mice, and then examined associations between mid-life resilience and both lifespan and late-life measures of physiological function. We demonstrate that time to recovery from isoflurane anesthesia and weight change following a regimen of chemotherapy significantly differed among young, middle-aged, and older mice, and were more variable in older mice. Females that recovered faster than the median time from anesthesia (more resilient) at 12 months of age lived 8% longer than their counterparts, while more resilient males in mid-life exhibited better cardiac (fractional shortening and left ventricular volumes) and metabolic (glucose tolerance) function at 24 months of age. Moreover, female mice with less than the median weight loss at Day 3 of the cisplatin challenge lived 8% longer than those that lost more weight. In contrast, females who had more weight loss between Days 15 and 20 were relatively protected against early death. These data suggest that measures of physical resilience in mid-life may provide information about individual differences in aging, lifespan, and key parameters of late-life health.

An initiative to assess and improve the resources and patient care processes used among Chest Wall Injury Society collaborative centers study (CWIS-CC2).

BACKGROUND: Over the last two decades, the acute management of rib fractures has changed significantly. In 2021, the Chest Wall injury Society (CWIS) began recognizing centers that epitomize their mission as CWIS Collaborative Centers. The primary aim of this study was to determine the resources, surgical expertise, access to care, and institutional support that are present among centers. METHODS: A survey was performed including all CWIS Collaborative Centers evaluating the resources available at their hospital for the treatment of patients with chest wall injury. Data about each chest wall injury center care process, availability of resources, institutional support, research support, and educational offerings were recorded. RESULTS: Data were collected from 20 trauma centers resulting in an 80% response rate. These trauma centers were made up of 5 international and 15 US-based trauma centers. Eighty percent (16 of 20) have dedicated care team members for the evaluation and management of rib fractures. Twenty-five percent (5 of 20) have a dedicated rib fracture service with a separate call schedule. Staffing for chest wall injury clinics consists of a multidisciplinary team: with attending surgeons in all clinics, 80% (8 of 10) with advanced practice providers and 70% (7 of 10) with care coordinators. Forty percent (8 of 20) of centers have dedicated rib fracture research support, and 35% (7 of 20) have surgical stabilization of rib fracture (SSRF)-related grants. Forty percent (8 of 20) of centers have marketing support, and 30% (8 of 20) have a web page support to bring awareness to their center. At these trauma centers, a median of 4 (1-9) surgeons perform SSRFs. In the majority of trauma centers, the trauma surgeons perform SSRF. CONCLUSION: Considerable similarities and differences exist within these CWIS collaborative centers. These differences in resources are hypothesis generating in determining the optimal chest wall injury center. These findings may generate several patient care and team process questions to optimize patient care, patient experience, provider satisfaction, research productivity, education, and outreach. LEVEL OF EVIDENCE: Therapeutic/Care Management; Level V.

Calorie restriction reduces biomarkers of cellular senescence in humans.

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.

Senotherapeutic drug treatment ameliorates chemotherapy-induced cachexia.

Cachexia is a debilitating skeletal muscle wasting condition for which we currently lack effective treatments. In the context of cancer, certain chemotherapeutics cause DNA damage and cellular senescence. Senescent cells exhibit chronic activation of the transcription factor NF-κB, a known mediator of the proinflammatory senescence-associated secretory phenotype (SASP) and skeletal muscle atrophy. Thus, targeting NF-κB represents a logical therapeutic strategy to alleviate unintended consequences of genotoxic drugs. Herein, we show that treatment with the IKK/NF-κB inhibitor SR12343 during a course of chemotherapy reduces markers of cellular senescence and the SASP in liver, skeletal muscle, and circulation and, correspondingly, attenuates features of skeletal muscle pathology. Lastly, we demonstrate that SR12343 mitigates chemotherapy-induced reductions in body weight, lean mass, fat mass, and muscle strength. These findings support senescent cells as a promising druggable target to counteract the SASP and skeletal muscle wasting in the context of chemotherapy.

Biomarkers of Cellular Senescence Predict the Onset of Mobility Disability and Are Reduced by Physical Activity in Older Adults.

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.