A toolbox for the longitudinal assessment of healthspan in ageing mice

The number of people aged over 65 is expected to double in the next 30 years. For many, living longer will mean spending more years with the burdens of chronic diseases such as Alzheimer’s, cardiovascular disease, and diabetes. Although researchers have made rapid progress in developing geroprotective interventions that target mechanisms of ageing and delay or prevent the onset of multiple concurrent age-related diseases, a lack of standardized techniques to assess healthspan in preclinical murine studies has resulted in reduced reproducibility and slowed progress. To overcome this, major centres in Europe and the USA skilled in healthspan analysis came together to agree upon a toolbox of techniques which can be used to consistently assess the healthspan of mice. Here, we describe the agreed toolbox which contains protocols for echocardiography, novel object recognition, grip strength, rotarod, glucose and insulin tolerance tests, body composition, and energy expenditure. They can be performed longitudinally in the same mouse over a period of 4-6 weeks to test how candidate geroprotectors affect cardiac, cognitive, neuromuscular and metabolic health

Circadian glucocorticoid oscillations preserve a population of adult hippocampal neural stem cells in the aging brain.

A decrease in adult hippocampal neurogenesis has been linked to age-related cognitive impairment. However, the mechanisms involved in this age-related reduction remain elusive. Glucocorticoid hormones (GC) are important regulators of neural stem/precursor cells (NSPC) proliferation. GC are released from the adrenal glands in ultradian secretory pulses that generate characteristic circadian oscillations. Here, we investigated the hypothesis that GC oscillations prevent NSPC activation and preserve a quiescent NSPC pool in the aging hippocampus. We found that hippocampal NSPC populations lacking expression of the glucocorticoid receptor (GR) decayed exponentially with age, while GR-positive populations decayed linearly and predominated in the hippocampus from middle age onwards. Importantly, GC oscillations controlled NSPC activation and GR knockdown reactivated NSPC proliferation in aged mice. When modeled in primary hippocampal NSPC cultures, GC oscillations control cell cycle progression and induce specific genome-wide DNA methylation profiles. GC oscillations induced lasting changes in the methylation state of a group of gene promoters associated with cell cycle regulation and the canonical Wnt signaling pathway. Finally, in a mouse model of accelerated aging, we show that disruption of GC oscillations induces lasting changes in dendritic complexity, spine numbers and morphology of newborn granule neurons. Together, these results indicate that GC oscillations preserve a population of GR-expressing NSPC during aging, preventing their activation possibly by epigenetic programming through methylation of specific gene promoters. Our observations suggest a novel mechanism mediated by GC that controls NSPC proliferation and preserves a dormant NSPC pool, possibly contributing to a neuroplasticity reserve in the aging brain

Search for heavy resonances decaying to a top quark and a bottom quark in the lepton+jets final state in proton–proton collisions at 13 TeV

A search is presented for narrow heavy resonances decaying to a top quark and a bottom quark using data collected by the CMS experiment at √s = 13TeV in 2016. The data set analyzed corresponds to an integrated luminosity of 35.9 fb−1. Final states that include a single lepton (e, μ), multiple jets, and missing transverse momentum are analyzed. No evidence is found for the production of a W′ boson, and the production of right-handed W′ bosons is excluded at 95% confidence level for masses up to 3.6 TeV depending on the scenario considered. Exclusion limits for W′ bosons are also presented as a function of their coupling strength to left- and right-handed fermions. These limits on a W′ boson decaying via a top and a bottom quark are the most stringent published to date

Measurement of angular parameters from the decay B⁰ → K⁎0^{⁎0} μ⁺ μ⁻ in proton–proton collisions at √s 8 TeV

Angular distributions of the decay B⁰  → K$^{⁎0}$ μ⁺ μ⁻ are studied using a sample of proton–proton collisions at √s=8TeV collected with the CMS detector at the LHC, corresponding to an integrated luminosity of 20.5fb⁻¹ . An angular analysis is performed to determine the P₁ and P$^{\u27}$₅ parameters, where the P$^{\u27}$₅ parameter is of particular interest because of recent measurements that indicate a potential discrepancy with the standard model predictions. Based on a sample of 1397 signal events, the P₁ and P$^{\u27}$₅ parameters are determined as a function of the dimuon invariant mass squared. The measurements are in agreement with predictions based on the standard model