News in brief
Authors: Jack Williamson
Journal: The Lancet Healthy Longevity (2021)

Being older than 65 years is one of the primary risk factors for osteoporosis; a multifactorial disorder characterised by low bone density, enhanced skeletal fragility, and the accumulation of bone-marrow adipose tissue. Although substantial progress has been made in our understanding of the transcription factors that mediate the differentiation of mesenchymal stem cells (MSCs) into either osteoblasts or adipocytes, the epigenetic factors that underpin these processes are still poorly understood. Having previously shown that the epigenetic factor histone lysine demethylase 4B (KDM4B) has an important role in the osteogenic differentiation of MSCs, Peng Deng (University of California, Los Angeles, CA, USA) and colleagues used a combination of genetic, epigenetic, and pharmacological approaches in KDM4B knockout mice to explore the role of KDM4B in skeletal ageing. Their study showed that loss of KDM4B in MSCs accelerates skeletal ageing and osteoporosis by reducing bone formation and increasing marrow adiposity (by increasing the heterochromatin mark H3K9me3), providing early evidence that targeting epigenetic factors such as KDM4B could represent a new avenue for combating skeletal ageing. Age-related loss of arterial elasticity is associated with an increased risk of cardiovascular disease and all-cause mortality. Similarly, advancing age is also associated with loss of muscle mass, strength, and function. Although evidence from several studies indicates that there is a bidirectional relationship between arterial stiffness and skeletal muscle health, evidence on this relationship is still inconclusive. Using handgrip strength as a surrogate measure of overall muscle strength, Maximilian König (Charité–Universitätsmedizin Berlin, Berlin, Germany) and colleagues compared handgrip strength and arterial function (measured using pulse wave velocity) between individuals who were at high risk of cardiovascular events (n=598) and healthy individuals (n=913), with a median age of 68·5 years for both groups. Overall, the results of their cross-sectional analysis showed that low handgrip strength was associated with increased arterial stiffness, irrespective of age, sex, and cardiovascular comorbidity. While the causality of this inverse association is still unknown, this study provides early evidence for handgrip strength as an easily accessible, cost-effective, and simple candidate biomarker for cardiovascular disease. Frequently thought of in connection to its mutation or inactivation in many cancers, cellular tumour antigen p53 has been shown to be overexpressed in a range of neurodegenerative conditions, such as Alzheimer's disease, Parkinson's disease, and Huntington's disease. Seeking to better understand the role of p53 in amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), both devastating neurodegenerative disorders linked by mutations in the C9orf72 gene, Maya Maor-Nof (Stanford University School of Medicine, Stanford, CA, USA) and colleagues showed that C9orf72 mutations associated with ALS and FTD activate a specific transcriptional programme that converges on p53 to drive neurodegeneration in mouse, fly, and human stem cell-based C9orf72 models. Their study provides evidence that, first, p53 is robustly stabilised and activates a transcriptional programme in response to C9orf72 poly(PR) and, second, p53 is required for neurodegeneration in vitro and in vivo. These new insights into the detrimental role of p53 in neurodegeneration could be important not only for future research on ALS and FTD but also for a wide range of other neurodegenerative conditions. Above the body mass index (BMI) range of 22·5–25·0 kg/m2, each additional 5 kg/m2 is associated with around 30% higher all-cause mortality. Moreover, although the mean worldwide BMI has been increasing since 1975, interventions to address obesity have been associated with low effectiveness or long-term weight regain. In the Semaglutide Treatment Effect in People with Obesity (STEP) 1 double-blind randomised controlled trial, led by John P H Wilding (University of Liverpool, Liverpool, UK) and colleagues, participants with a BMI of ≥30 kg/m2 (or ≥27 kg/m2 with at least one coexisting condition) were randomly assigned to receive once-weekly subcutaneous injection of the glucagon-like peptide-1 analogue semaglutide alongside lifestyle intervention methods (n=1306) or placebo alongside lifestyle intervention methods (n=655). After 68 weeks, the co-primary endpoints were both superior in the semaglutide group compared with placebo: percentage change in bodyweight from baseline to week 68 (–14·9% for the semaglutide group vs –2·4% for the placebo group) and reduction in bodyweight of ≥5% from baseline to week 68 (86·4% vs 31·5%). Although these clinically meaningful results are encouraging, the higher frequency of adverse events (eg, cholelithiasis, nausea, and diarrhoea) in the semaglutide group compared with placebo, as well as the low diversity of participants enrolled in the trial, are reasons for future studies exploring semaglutide for weight loss to progress with caution.