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Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles of SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allowed for inducible SnC elimination (senolysis) in a cell-specific manner and compared the effects of local versus systemic senolysis during aging using bone as a prototype tissue. Specific removal of Sn osteocytes prevented age-related bone loss at the spine, but not the femur, by improving bone formation without affecting osteoclasts or marrow adipocytes. By contrast, systemic senolysis prevented bone loss at the spine and femur and not only improved bone formation, but also reduced osteoclast and marrow adipocyte numbers. Transplantation of SnCs into the peritoneal cavity of young mice caused bone loss and also induced senescence in distant host osteocytes. Collectively, our findings provide proof-of-concept evidence that local senolysis has health benefits in the context of aging, but, importantly, that local senolysis only partially replicates the benefits of systemic senolysis. Furthermore, we establish that SnCs, through their senescence-associated secretory phenotype (SASP), lead to senescence in distant cells. Therefore, our study indicates that optimizing senolytic drugs may require systemic instead of local SnC targeting to extend healthy aging.

Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of p21+ cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, p21+ neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while p21+ OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was p21+ and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells were key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings established contextual roles of p21+ versus p16+ senescent/senescent-like cells that may be leveraged for therapeutic opportunities.

There is an increasing need for biomarkers of senescent cell burden to facilitate the selection of participants for clinical trials. p16Ink4a is encoded by the CDKN2A locus, which produces five variant transcripts in humans, two of which encode homologous p16 proteins: p16Inka4a, encoded by p16_variant 1, and p16ɣ, encoded by p16_variant 5. While distinct quantitative polymerase chain reaction primers can be designed for p16_variant 5, primers for p16_variant 1 also measure p16_variant 5 (p16_variant 1 + 5). In a recent clinical trial evaluating the effects of the senolytic combination, dasatinib + quercetin (D + Q), on bone metabolism in postmenopausal women, we found that women in the highest tertile for T‐cell expression of p16_variant 5 had the most robust skeletal responses to D + Q. Importantly, the assessment of p16_variant 5 was more predictive of these responses than p16_variant 1 + 5. Here, we demonstrate that in vitro, p16_variant 1 + 5 increased rapidly (Week 1) following the induction of DNA damage, whereas p16_variant 5 increased later (Week 4), suggesting that p16_variant 5 becomes detectable only when the abundance of senescent cells reaches some threshold. Further analysis identified a SASP panel in plasma that performed as well in identifying postmenopausal women with a positive skeletal response to D + Q. Collectively, our findings provide further support for the T‐cell p16_variant 5 assay as a biomarker for selecting participants in clinical trials of senolytic interventions. In addition, our data indicate that correlated plasma SASP markers could be used in lieu of the more technically challenging T‐cell p16 assay. Trial Registration: ClinicalTrials.gov identifier: NCT04313634. Assessment of T‐cell p16_variant 5 expression may be useful for selecting participants in clinical trials of senolytics. We further characterize p16_variant 5 expression in the context of senescence and demonstrate that correlated plasma senescence‐associated secretory phenotype factors could be used in lieu of the technically challenging T‐cell p16_variant 5 assay.

Purpose of Review Beyond aging, senescent cells accumulate during multiple pathological conditions, including chemotherapy, radiation, glucocorticoids, obesity, and diabetes, even earlier in life. Therefore, cellular senescence represents a unifying pathogenic mechanism driving skeletal and metabolic disorders. However, whether senescent bone marrow adipocytes (BMAds) are causal in mediating skeletal dysfunction has only recently been evaluated. Recent Findings Despite evidence of BMAd senescence following glucocorticoid therapy, additional evidence for BMAd senescence in other conditions has thus far been limited. Because the study of BMAds presents unique challenges making these cells difficult to isolate and image, here we review issues and approaches to overcome such challenges, and present advancements in isolation and histological techniques that may help with the future study of senescent BMAds. Summary Further insights into the roles of BMAd senescence in the pathogenesis of skeletal dysfunction may have important basic science and clinical implications for human physiology and disease.

Cellular senescence is a heterogeneous phenotype characterized primarily in mesenchymal cells, but the extent to which immune cells differ in their senescence phenotype, or \"senotype,\" is unclear. Here, we applied single-cell approaches alongside both global and cell-specific genetic senolytic mouse models to evaluate the senotype of immune cells in the bone marrow of aging mice. We found that myeloid-lineage cells exhibited the highest expression of p16 and senescence-associated secretory phenotype markers among all immune cell types. In contrast with clearance of p16+ senescent mesenchymal cells, targeted clearance of p16+ myeloid cells in aged mice had only minor effects on age-related bone loss in male mice, with no effects in females. In more detailed analyses, p16+ myeloid cells were only acutely cleared, being repopulated back to basal levels within a short time. This led to a lack of long-lasting reduction in senescent cell burden, unlike when targeting bone mesenchymal cells. In vitro, myeloid-lineage cells differed markedly from mesenchymal cells in the development of a senescent phenotype. Collectively, our findings indicate that aged bone marrow myeloid cells do not achieve the fully developed senescent phenotype originally described in mesenchymal cells, justifying further characterization of senotypes of immune cells across tissues.

This paper presents the beam dynamics systematic corrections and their uncertainties for the Run-1 dataset of the Fermilab Muong−2Experiment. Two corrections to the measured muon precession frequencyωamare associated with well-known effects owing to the use of electrostatic quadrupole (ESQ) vertical focusing in the storage ring. An average vertically oriented motional magnetic field is felt by relativistic muons passing transversely through the radial electric field components created by the ESQ system. The correction depends on the stored momentum distribution and the tunes of the ring, which has relatively weak vertical focusing. Vertical betatron motions imply that the muons do not orbit the ring in a plane exactly orthogonal to the vertical magnetic field direction. A correction is necessary to account for an average pitch angle associated with their trajectories. A third small correction is necessary, because muons that escape the ring during the storage time are slightly biased in initial spin phase compared to the parent distribution. Finally, because two high-voltage resistors in the ESQ network had longer than designedRCtime constants, the vertical and horizontal centroids and envelopes of the stored muon beam drifted slightly, but coherently, during each storage ring fill. This led to the discovery of an important phase-acceptance relationship that requires a correction. The sum of the corrections toωamis0.50±0.09ppm; the uncertainty is small compared to the 0.43 ppm statistical precision ofωam.

In the following years the Fermilab Muon Campus will deliver highly polarized muon beams to the storage ring of the Muon g-2 Experiment. The Muon Campus contains a target section wherein secondaries are produced, the Delivery Ring which separates the muons from the rest of the beam and a straight section that transports them to the storage ring. Here, we report the first experimental results and experience gained from commissioning the Muon Campus, including the interaction of the proton beam with the target, the transport of secondary beam over long sections, the monitoring of muons from the available diagnostics and the development of techniques for measuring the beam optics. We present detailed comparisons between experimental data and simulation and discuss the similarities and differences observed.

Cells expressing features of senescence, including upregulation of p21 and p16, appear transiently following tissue injury, yet the properties of these cells or how they contrast with age-induced senescent cells remains unclear. Here, we used skeletal injury as a model and identified the rapid appearance following fracture of p21+ cells expressing senescence markers, mainly as osteochondroprogenitors (OCHs) and neutrophils. Targeted genetic clearance of p21+ cells suppressed senescence-associated signatures within the fracture callus and accelerated fracture healing. By contrast, p21+ cell clearance did not alter bone loss due to aging; conversely, p16+ cell clearance, known to alleviate skeletal aging, did not affect fracture healing. Following fracture, p21+ neutrophils were enriched in signaling pathways known to induce paracrine stromal senescence, while p21+ OCHs were highly enriched in senescence-associated secretory phenotype factors known to impair bone formation. Further analysis revealed an injury-specific stem cell-like OCH subset that was p21+ and highly inflammatory, with a similar inflammatory mesenchymal population (fibro-adipogenic progenitors) evident following muscle injury. Thus, intercommunicating senescent-like neutrophils and mesenchymal progenitor cells are key regulators of tissue repair in bone and potentially across tissues. Moreover, our findings establish contextual roles of p21+ p16+ senescent/senescent-like cells that may be leveraged for therapeutic opportunities.

We present a new measurement of the positive muon magnetic anomaly, \\(a_\\mu \\equiv (g_\\mu - 2)/2\\), from the Fermilab Muon \\(g\\!-\\!2\\) Experiment using data collected in 2019 and 2020. We have analyzed more than 4 times the number of positrons from muon decay than in our previous result from 2018 data. The systematic error is reduced by more than a factor of 2 due to better running conditions, a more stable beam, and improved knowledge of the magnetic field weighted by the muon distribution, \\(\\tilde{\\omega}'^{}_p\\), and of the anomalous precession frequency corrected for beam dynamics effects, \\(\\omega_a\\). From the ratio \\(\\omega_a / \\tilde{\\omega}'^{}_p\\), together with precisely determined external parameters, we determine \\(a_\\mu = 116\\,592\\,057(25) \\times 10^{-11}\\) (0.21 ppm). Combining this result with our previous result from the 2018 data, we obtain \\(a_\\mu\\text{(FNAL)} = 116\\,592\\,055(24) \\times 10^{-11}\\) (0.20 ppm). The new experimental world average is \\(a_\\mu (\\text{Exp}) = 116\\,592\\,059(22)\\times 10^{-11}\\) (0.19 ppm), which represents a factor of 2 improvement in precision.