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Drug-Based Lifespan Extension in Mice Strongly Affects Lipids Across Six Organs
Tuesday, March 25, 2025

Caloric restriction is associated with slow aging in model organisms. Additionally, some drugs have also been shown to slow aging in rodents. To better understand metabolic mechanisms that are involved in increased lifespan, we analyzed metabolomic differences in six organs of 12-month-old mice using five interventions leading to extended longevity, specifically caloric restriction, 17-α estradiol, and caloric restriction mimetics rapamycin, canagliflozin, and acarbose. These interventions...


Heterogeneity analysis provides evidence for a genetically homogeneous subtype of bipolar-disorder
Wednesday, January 29, 2025

CONCLUSIONS: Our methodology has successfully identified a replicable homogeneous genetic subgroup of bipolar disorder. This subgroup may represent a collection of correlated genetic risk-factors for BDI. By investigating the subgroup's bicluster-informed polygenic-risk-scoring (PRS), we find that the disease-specific pattern highlighted by the bicluster can be leveraged to eliminate noise from our GWAS analyses and improve risk prediction. This improvement is particularly notable when using...


Causal mediation analysis of the neuroprotection of APOE2 through lipid pathways
Monday, January 13, 2025

CONCLUSIONS: We found that the combined indirect effect through all lipids could mediate 10%-27% of the total direct effect of APOE2 on CDT times. We identified both protective and deleterious lipids, providing insights for new therapeutics targeting those lipids to modulate the protective effects of APOE2 on cognition.


Candida albicans: a comprehensive view of the proteome
Tuesday, January 07, 2025

We describe a new release of the Candida albicans PeptideAtlas proteomics spectral resource (build 2024-03), providing a sequence coverage of 79.5% at the canonical protein level, matched mass spectrometry spectra, and experimental evidence identifying 3382 and 536 phosphorylated serine and threonine sites with false localization rates of 1% and 5.3%, respectively. We provide a tutorial on how to use the PeptideAtlas and associated tools to access this information. The C. albicans PeptideAtlas...


SNP rs6543176 is associated with extreme human longevity but increased risk for cancer
Friday, January 03, 2025

Using whole-genome sequencing (WGS) might offer insights into rare genetic variants associated with healthy aging and extreme longevity (EL), potentially pointing to useful therapeutic targets. In this study, we conducted a genome-wide association study using WGS data from the Long Life Family Study and identified a novel longevity-associated variant rs6543176 in the SLC9A2 gene. This SNP also showed a significant association with reduced hypertension risk and an increased, though not...


Downregulation of the NF-κB protein p65 is a shared phenotype among most anti-aging interventions
Thursday, December 12, 2024

Many aspects of inflammation increase with aging in mice and humans. Transcriptomic analysis revealed that many murine anti-aging interventions produce lower levels of pro-inflammatory proteins. Here, we explore the hypothesis that different longevity interventions diminish NF-κB levels, potentially mediating some of the anti-inflammatory benefits of lifespan-extending interventions. We found that the NF-κB protein p65 is significantly downregulated in the liver of several kinds of slow-aging...


The Proteomics Standards Initiative Standardized Formats for Spectral Libraries and Fragment Ion Peak Annotations: mzSpecLib and mzPAF
Friday, November 08, 2024

Mass spectral libraries are collections of reference spectra, usually associated with specific analytes from which the spectra were generated, that are used for further downstream analysis of new spectra. There are many different formats used for encoding spectral libraries, but none have undergone a standardization process to ensure broad applicability to many applications. As part of the Human Proteome Organization Proteomics Standards Initiative (PSI), we have developed a standardized format...


Metabolite signatures of chronological age, aging, survival, and longevity
Wednesday, November 06, 2024

Metabolites that mark aging are not fully known. We analyze 408 plasma metabolites in Long Life Family Study participants to characterize markers of age, aging, extreme longevity, and mortality. We identify 308 metabolites associated with age, 258 metabolites that change over time, 230 metabolites associated with extreme longevity, and 152 metabolites associated with mortality risk. We replicate many associations in independent studies. By summarizing the results into 19 signatures, we...


The Circulating Proteome─Technological Developments, Current Challenges, and Future Trends
Thursday, October 31, 2024

Recent improvements in proteomics technologies have fundamentally altered our capacities to characterize human biology. There is an ever-growing interest in using these novel methods for studying the circulating proteome, as blood offers an accessible window into human health. However, every methodological innovation and analytical progress calls for reassessing our existing approaches and routines to ensure that the new data will add value to the greater biomedical research community and avoid...


Detecting Boolean Asymmetric Relationships with a Loop Counting Technique and its Implications for Analyzing Heterogeneity within Gene Expression Datasets
Tuesday, October 29, 2024

Many traditional methods for analyzing gene-gene relationships focus on positive and negative correlations, both of which are a kind of 'symmetric' relationship. Biclustering is one such technique that typically searches for subsets of genes exhibiting correlated expression among a subset of samples. However, genes can also exhibit 'asymmetric' relationships, such as 'if-then' relationships used in boolean circuits. In this paper we develop a very general method that can be used to detect...


Detection and Quantification of Drug-Protein Adducts in Human Liver
Wednesday, October 23, 2024

Covalent protein adducts formed by drugs or their reactive metabolites are risk factors for adverse reactions, and inactivation of cytochrome P450 (CYP) enzymes. Characterization of drug-protein adducts is limited due to lack of methods identifying and quantifying covalent adducts in complex matrices. This study presents a workflow that combines data-dependent and data-independent acquisition (DDA and DIA) based liquid chromatography with tandem mass spectrometry (LC-MS/MS) to detect very low...


High-quality peptide evidence for annotating non-canonical open reading frames as human proteins
Tuesday, September 24, 2024

A major scientific drive is to characterize the protein-coding genome as it provides the primary basis for the study of human health. But the fundamental question remains: what has been missed in prior genomic analyses? Over the past decade, the translation of non-canonical open reading frames (ncORFs) has been observed across human cell types and disease states, with major implications for proteomics, genomics, and clinical science. However, the impact of ncORFs has been limited by the absence...


Comprehensive Overview of Bottom-Up Proteomics Using Mass Spectrometry
Wednesday, August 28, 2024

Proteomics is the large scale study of protein structure and function from biological systems through protein identification and quantification. "Shotgun proteomics" or "bottom-up proteomics" is the prevailing strategy, in which proteins are hydrolyzed into peptides that are analyzed by mass spectrometry. Proteomics studies can be applied to diverse studies ranging from simple protein identification to studies of proteoforms, protein-protein interactions, protein structural alterations, absolute...


Oxidative phosphorylation and fatty acid oxidation in slow-aging mice
Saturday, August 17, 2024

Oxidative metabolism declines with aging in humans leading to multiple metabolic ailments and subsequent inflammation. In mice, there is evidence of age-related suppression of fatty acid oxidation and oxidative phosphorylation in the liver, heart, and muscles. Many interventions that extend healthy lifespan of mice have been developed, including genetic, pharmacological, and dietary interventions. In this article, we review the literature on oxidative metabolism changes in response to those...


Complete sequencing of ape genomes
Monday, August 12, 2024

We present haplotype-resolved reference genomes and comparative analyses of six ape species, namely: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan, and siamang. We achieve chromosome-level contiguity with unparalleled sequence accuracy (<1 error in 500,000 base pairs), completely sequencing 215 gapless chromosomes telomere-to-telomere. We resolve challenging regions, such as the major histocompatibility complex and immunoglobulin loci, providing more in-depth evolutionary...


Denoising Search doubles the number of metabolite and exposome annotations in human plasma using an Orbitrap Astral mass spectrometer
Wednesday, August 07, 2024

Chemical exposures may impact human metabolism and contribute to the etiology of neurodegenerative disorders like Alzheimer's Disease (AD). Identifying these small metabolites involves matching experimental spectra to reference spectra in databases. However, environmental chemicals or physiologically active metabolites are usually present at low concentrations in human specimens. The presence of noise ions can significantly degrade spectral quality, leading to false negatives and reduced...


Blocking an inflammatory protein slows the pace of ageing
Monday, July 29, 2024

No abstract


Cross-platform proteomics signatures of extreme old age
Wednesday, July 24, 2024

In previous work, we used a SomaLogic platform targeting approximately 5000 proteins to generate a serum protein signature of centenarians that we validated in independent studies that used the same technology. We set here to validate and possibly expand the results by profiling the serum proteome of a subset of individuals included in the original study using liquid chromatography tandem mass spectrometry (LC-MS/MS). Following pre-processing, the LC-MS/MS data provided quantification of 398...


Exploring the Genetic Heterogeneity of Alzheimer's Disease: Evidence for Genetic Subtypes
Friday, July 12, 2024

CONCLUSIONS: This study unveils a hierarchical structure of AD genetic risk. Disease-relevant constellations may represent haplotype structure that does not increase risk directly but may alter the relative importance of other genetic risk factors. Biclusters may represent distinct AD genetic subtypes. This structure is replicable and relates to differential pathological accumulation and cognitive decline over time.


Discovery of genomic and transcriptomic pleiotropy between kidney function and soluble receptor for advanced glycation end products using correlated meta-analyses: The Long Life Family Study
Thursday, June 27, 2024

Patients with chronic kidney disease (CKD) have increased oxidative stress and chronic inflammation, which may escalate the production of advanced glycation end-products (AGEs). High soluble receptor for AGE (sRAGE) and low estimated glomerular filtration rate (eGFR) levels are associated with CKD and aging. We evaluated whether eGFR calculated from creatinine and cystatin C share pleiotropic genetic factors with sRAGE. We employed whole-genome sequencing and correlated meta-analyses on combined...