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Although lifespan extension remains the gold standard for assessing interventions proposed to impact the biology of aging, there are important limitations to this approach. Our reanalysis of lifespan studies from multiple sources suggests that short lifespans in the control group exaggerate the relative efficacy of putative longevity interventions. Results may be exaggerated due to statistical effects (e.g. regression to the mean) or other factors. Moreover, due to the high cost and long...

Inbreeding depression has been documented in various fitness traits in a wide range of species and taxa, however, the mutational basis is not yet well understood. We investigate how putatively deleterious variation influences fitness and is shaped by individual ancestry by re-sequencing complete genomes of 37 individuals in a natural arctic fox (Vulpes lagopus) population subjected to both inbreeding depression and genetic rescue. We find that individuals with high proportion of homozygous loss...

Living longer and healthier boosts individual and family welfare. As part of the World Bank's Healthy Longevity Initiative, we quantified the economic value of achieving the highest possible life span. We estimated the economic value of reducing avoidable mortality, defined as the difference between observed (or projected) mortality and lowest achieved (or projected) mortality, by world regions, sex, and age, between 2000 and 2021, with projection to 2050. In 2019, 69% of mortality, or 40...

With population aging, national health systems face difficult trade-offs in allocating resources. The World Bank launched the Healthy Longevity Initiative to generate evidence for investing in policies that can improve healthy longevity and human capital. As part of this initiative, we quantified the economic value of reducing avoidable mortality from major noncommunicable diseases and injuries. We estimated avoidable mortality-the difference between lowest-achieved mortality frontiers and...

A decline in mitochondrial function is a hallmark of aging and neurodegenerative diseases. It has been proposed that changes in mitochondrial morphology, including fragmentation of the tubular mitochondrial network, can lead to mitochondrial dysfunction, yet the mechanism of this loss of function is unclear. Most proteins contained within mitochondria are nuclear-encoded and must be properly targeted to the mitochondria. Here, we report that sustained mRNA localization and co-translational...

In this high-throughput proteomic study of autosomal dominant Alzheimer's disease (ADAD), we sought to identify early biomarkers in cerebrospinal fluid (CSF) for disease monitoring and treatment strategies. We examined CSF proteins in 286 mutation carriers (MCs) and 177 non-carriers (NCs). The developed multi-layer regression model distinguished proteins with different pseudo-trajectories between these groups. We validated our findings with independent ADAD as well as sporadic AD datasets and...

Synaptic dysfunction is recognized as an early step in the pathophysiology of parkinsonism. Several genetic mutations affecting the integrity of synaptic proteins cause or increase the risk of developing disease. We have identified a candidate causative mutation in synaptic "SH3GL2 Interacting Protein 1" (SGIP1), linked to early-onset parkinsonism in a consanguineous Arab family. Additionally, affected siblings display intellectual, cognitive, and behavioral dysfunction. Metabolic network...

Accurate predictive models of future disease onset are crucial for effective preventive healthcare, yet longitudinal data sets linking early risk factors to subsequent health outcomes are limited. To overcome this challenge, we introduce a novel framework, Predictive Risk modeling using Mendelian Randomization (PRiMeR), which utilizes genetic effects as supervisory signals to learn disease risk predictors without relying on longitudinal data. To do so, PRiMeR leverages risk factors and genetic...

Despite recent advances, severe acute pancreatitis (SAP) remains a lethal inflammation with limited treatment options. Here, we provide compelling evidence of GV-971 (sodium oligomannate), an anti-Alzheimer's medication, as being a protective agent in various male mouse SAP models. Microbiome sequencing, along with intestinal microbiota transplantation and mass cytometry technology, unveil that GV-971 reshapes the gut microbiota, increasing Faecalibacterium populations and modulating both...

Brain-wide profiling of diverse biological components is fundamental for understanding complex brain pathology. Despite the availability in whole-brain imaging, it is still challenging to conduct multiplexed, brain-wide analysis with current tissue clearing techniques. Here, we propose SOLID, a hydrophobic tissue clearing method that can minimize tissue distortion while offering impressive clearing performance. SOLID achieves high-quality imaging of multi-color labeled mouse brain, and the...

The recent, controversial approval of antibody-based treatments for Alzheimer's disease (AD) is fueling a heated debate on the molecular determinants of this condition. The discussion should also incorporate a critical revision of the limitations of preclinical mouse models in advancing our understanding of AD. We critically discuss the limitations of animal models, stressing the need for careful consideration of how experiments are designed and results interpreted. We identify the shortcomings...

Huntington disease (HD) is a genetic neurodegenerative disease caused by cytosine, adenine, guanine (CAG) expansion in the Huntingtin (HTT) gene, translating to an expanded polyglutamine tract in the HTT protein. Age at disease onset correlates to CAG repeat length but varies by decades between individuals with identical repeat lengths. Genome-wide association studies link HD modification to DNA repair and mitochondrial health pathways. Clinical studies show elevated DNA damage in HD, even at...

Science, Volume 385, Issue 6716, September 2024.