News in Brief
Authors: Charlotte Leigh
Journal: The Lancet Healthy Longevity (2021)

Over time, senescent cells accumulate in the body and are responsible for the development of age-related dysfunction and disease. The current model for cellular senescence proposes that senescence is caused by the erosion of telomeres (caps at the ends of chromosomes that prevent degradation). Telomeres shorten slightly each time a cell divides and, at a certain point, shortened telomeres can no longer sit in a protective loop shape and the subsequent DNA damage response (DDR) leads to senescence. However, this thinking relies on a single dysfunctional telomere event being sufficient to trigger senescence, which does not appear to be the case. To investigate this, Sabrina Ghadaouia (Université de Montréal, Montreal, QC, Canada) and colleagues from the team of Francis Rodier triggered cellular ageing and telomere erosion in normal human cells, and used advanced imaging equipment to see in real time what was happening inside these cells. They observed that, instead of telomere erosion being enough to trigger senescence, it was telomeric dysfunction plus irreversible non-telomeric DNA breaks (confirmed via telomeric fluorescence in situ hybridisation) and genomic instability (defined as micronuclei, mitotic catastrophes, or chromosome bridges) that led to senescence. Notably, it seems that cells can still try to divide with dysfunctional telomeres, and it is this improper proliferation that can cause sister chromatid fusions and a stronger DDR that leads to genomic instability. This new multistep model for telomere-initiated senescence opens up new research opportunities. Interventions that target the pre-senescent state to repair telomeres could prevent senescence and genome instability, and the cellular dysfunction associated with ageing. In late-stage Parkinson's disease, the drug levodopa becomes less effective at treating symptoms because of the loss of dopamine-releasing neurons. In a new mouse model of Parkinson's disease, Patricia González-Rodríguez (Northwestern University, Chicago, IL, USA) and colleagues prompted progressive parkinsonism and loss of dopamine release, via intersectional genomics, by deleting the gene encoding an essential subunit of the mitochondrial complex I (MCI) catalytic core, Ndufs2, in dopaminergic neurons. This is the first animal model to faithfully replicate the progressive neuronal pathology underlying motor symptoms in Parkinson's disease. Although loss of MCI is a hallmark of Parkinson's disease, it was previously unclear whether this dysfunction was a side-effect or a cause of the disease pathology. Owing to the human-like staging of neuropathology in this model, it was possible to relate regional loss of dopamine release to behaviour. Contrary to long-held theory, dopamine depletion in the striatum was not sufficient to produce parkinsonism. Rather, dopamine depletion throughout the basal ganglia was necessary. Then, the authors delivered a virus containing the genetic instructions for making AADC (a protein that converts levodopa to dopamine) directly to the substantia nigra of the mice. This targeted gene therapy boosted the ability of levodopa to restore movement in parkinsonian mice (tested via open-field ambulation), suggesting that an AADC gene therapy targeting the small, output nucleus of the basal ganglia might be an effective treatment for mid to late-stage Parkinson's disease. Whilst these studies are preclinical, they could help to develop therapies to slow disease progression and treat late-stage disease. Surgery is the most common treatment for hip fracture. Observational studies have suggested that spinal anaesthesia might be a safer option than general anaesthesia, but evidence from randomised trials is scarce and conflicting. In their randomised, superiority trial across 46 hospitals in the USA and Canada, Mark D Neuman (University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA) and his team compared spinal anaesthesia with general anaesthesia during surgery for hip fracture in individuals aged 50 years and over who could walk independently before the fracture. The primary outcome was a composite of death and an inability to walk about 3 m independently (or with a walker or cane) at 60 days after randomisation, with death within 60 days, delirium, hospital stay, and ambulation at 60 days as secondary outcomes. 1600 patients (median age 78 years, 33% male, 89% White, 8% Black) were randomly assigned (1:1) to receive either spinal anaesthesia (n=795) or general anaesthesia (n=805). Spinal anaesthesia was not superior to general anaesthesia for the primary outcome (18·5% vs 18·0%, respectively; relative risk 1·03, 95% CI 0·83–1·28). Incidence of mortality (about 4%), new-onset delirium (about 20%), inability to walk without assistance (about 15%), and duration of hospital stay (Canada: 6 days, USA: 3 days) were also similar between the two types of anaesthesia. Given that complications at 60 days were similar, regardless of anaesthesia strategy, perioperative decisions about spinal versus general anaesthesia for hip surgery can be guided by patient and clinical preference.