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Diagnosing Alzheimer's disease (AD) in the early stage is challenging. Informative biomarkers can be of great value for population-based screening. Metabolomics studies have been used to find potential biomarkers, but commonly used tissue sources can be difficult to obtain. The objective of this study was to determine the potential utility of erythrocyte metabolite profiles in screening for AD. Unlike some commonly-used sources such as cerebrospinal fluid and brain tissue, erythrocytes are plentiful and easily accessed. Moreover, erythrocytes are metabolically active, a feature that distinguishes this sample source from other bodily fluids like plasma and urine. In this preliminary pilot study, the erythrocyte metabolomes of 10 histopathologically confirmed AD patients and 10 patients without AD (control (CTRL)) were compared. Whole blood was collected post-mortem and erythrocytes were analyzed using ultra-performance liquid chromatography tandem mass spectrometry. Over 750 metabolites were identified in AD and CTRL erythrocytes. Seven were increased in AD while 24 were decreased (P<0.05). The majority of the metabolites increased in AD were associated with amino acid metabolism and all of the decreased metabolites were associated with lipid metabolism. Prominent among the potential biomarkers were 10 sphingolipid or sphingolipid-related species that were consistently decreased in AD patients. Sphingolipids have been previously implicated in AD and other neurological conditions. Furthermore, previous studies have shown that erythrocyte sphingolipid concentrations vary widely in normal, healthy adults. Together, these observations suggest that certain erythrocyte lipid phenotypes could be markers of risk for development of AD. [Display omitted] •Erythrocytes are metabolically active, and are a useful and accessible source of AD biomarkers.•750 metabolites were detected; 31 were significantly altered.•In AD, there is a consistent decrease in the relative concentrations of some sphingolipid and sphingolipid-related species.•A decrease in sphingolipid species in erythrocytes could suggest an overall systemic alteration.

Dietary protein is a critical regulator of metabolic health and aging. Low protein diets are associated with healthy aging in humans, and dietary protein restriction extends the lifespan and healthspan of mice. In this study, we examined the effect of protein restriction (PR) on metabolic health and the development and progression of Alzheimer’s disease (AD) in the 3xTg mouse model of AD. Here, we show that PR promotes leanness and glycemic control in 3xTg mice, specifically rescuing the glucose intolerance of 3xTg females. PR induces sex-specific alterations in circulating and brain metabolites, downregulating sphingolipid subclasses in 3xTg females. PR also reduces AD pathology and mTORC1 activity, increases autophagy, and improves the cognition of 3xTg mice. Finally, PR improves the survival of 3xTg mice. Our results suggest that PR or pharmaceutical interventions that mimic the effects of this diet may hold promise as a treatment for AD. There is growing need for ways to slow or prevent Alzheimer’s disease (AD). Here, the authors demonstrate that a low protein diet can protect against metabolic dysfunction, slow AD progression, and preserve cognitive function in a mouse model of AD.

Conservators’ decisions regarding the suitability of museum construction materials for use in proximity to artworks still rely heavily on accelerated corrosion tests like the Oddy test despite widespread criticisms. These issues include inconveniently long wait times, sensitivity to only those pollutants capable of tarnishing metals, a general sense of unreliability, exaggerated environmental conditions, and subjectivity in assessing the test’s results. Increasingly, alternative strategies that use instrumental approaches involving volatiles sampling coupled to gas chromatography with mass spectrometry (GC–MS) are being explored as faster, more comprehensive, potentially quantitative, and possible more ‘objective’ means of assessing the dangers of off-gassing from museum construction materials. While many of these characteristics are now well documented, the objectivity of the instrumental result is arguable. While the detection of volatiles and semi-volatiles by GC–MS can confidently yield a list of potential pollutants, “chemical intuition” must be used to predict whether many of the emitted compounds can in fact adversely affect artwork. In this study, evolved gas analysis (EGA) coupled to GC–MS is used to predict the suitability of a small sample set of plastics for use in a museum. The potential impact of volatiles observed in the EGA chromatogram was assessed using chemical reactivity principles and the sparse literature data on the material damages caused by a small group of known pollutants. These same plastics were then tested using the British Museum’s 3-in-1 Oddy test. The prediction based on an educated chemical assessment of the compounds identified through instrumental analysis shows good correlation with pooled results from the Oddy test. In one of the two instances of disagreement, the EGA analysis was actually overly conservative and leaned toward prohibiting or restricting a material that passed the Oddy test. In the other, a material that failed the Oddy test but was passed by instrumental analysis was later shown to contain VOCs that could be considered corrosive. This trial suggests that with practice and experience instrumental approaches may be useful to supplement and perhaps one day supplant traditional accelerated corrosion testing of museum construction materials.

Extreme longevity in humans is known to be a heritable trait. In a well‐established twin erythrocyte metabolomics and proteomics database, we identified the longevity factor spermidine and a cluster of correlated molecules with high heritability estimates. Erythrocyte spermidine is 82% heritable and significantly correlated with 59 metabolites and 22 proteins. Thirty‐eight metabolites and 19 proteins were >20% heritable, with a mean heritability of 61% for metabolites and 49% for proteins. Correlated metabolites are concentrated in energy metabolism, redox homeostasis, and autophagy pathways. Erythrocyte mean cell volume (MCV), an established heritable trait, was consistently negatively correlated with the top 25 biomolecules most strongly correlated with spermidine, indicating that smaller MCVs are associated with higher concentrations of spermidine and correlated molecules. Previous studies have linked larger MCVs with poorer memory, cognition, and all‐cause mortality. Analysis of 432,682 unique patient records showed a linear increase in MCV with age but a significant deviation toward smaller than expected MCVs above age 86, suggesting that smaller MCVs are associated with extreme longevity. Consistent with previous reports, a subset of 78,158 unique patient records showed a significant skewing toward larger MCV values in a deceased cohort compared to an age‐matched living cohort. Our study supports the existence of a complex, heritable phenotype in erythrocytes associated with health and longevity. A classic twin study revealed heritable biomolecule cohorts. High spermidine levels and upregulation of autophagy/glycolysis result in increased erythrocyte lifespan.

By the year 2060, the number of Americans aged 65 or older is expected to nearly double. In order to support this rapidly aging population, there is an immediate need to better understand the biology of aging and age-related diseases like Alzheimer’s disease (AD), the most common cause of dementia in the aging population. To advance both aging and AD research, this dissertation uses mass spectrometry (MS) as a tool to perform both targeted and untargeted analyses of the human metabolome and lipidome. Untargeted biomarker discovery studies analyzing both erythrocytes and brain of AD patients and controls were conducted; with these studies, we were able to further explore AD brain metabolic changes, while also determining whether erythrocytes are a suitable source of biomarkers. Targeted analysis of whole blood spermidine, a polyamine associated with healthy aging, was performed using three methodological approaches: chemical derivatization, mixed mode liquid chromatography (LC) separation, and microfluidic capillary electrophoresis (mCE), coupled with mass spectrometry. Overall, this dissertation advances aging and AD research through both the discovery of new potential biomarker targets and the development of methods for analyzing previously established molecules of interest, while also highlighting the utility of less commonly studied biomarker sources like whole blood.

can transiently or persistently colonize the human gut, posing a risk factor for infections. This colonization is influenced by complex molecular and ecological interactions with human gut microbiota. By investigating dynamics in human gut communities over hundreds of generations, we show patterns of stable coexistence, instability, or competitive exclusion. Lowering carbohydrate concentration shifted a community containing and the prevalent human gut symbiont from competitive exclusion to coexistence, facilitated by increased cross-feeding. In this environment, adapted via single-point mutations in key metabolic genes, altering its metabolic niche from proline to glucose utilization. These metabolic changes substantially impacted inter-species interactions and reduced disease severity in the mammalian gut. In sum, human gut microbiota interactions are crucial in shaping the long-term growth dynamics and evolutionary adaptations of , offering key insights for developing anti- strategies.

Ether lipids play critical roles in membrane dynamics, antioxidant defense, and signaling. They comprise ∼20% of mammalian phospholipids, and disruptions in their metabolism cause severe genetic disorders and are associated with neurodegenerative and metabolic diseases. Ether lipids are synthesized de novo from glycolytic intermediates or salvaged from the diet. While the products of these pathways are known, several key enzymes remain unidentified, including the 1-O-alkylglycerol kinase and the 1-O-alkyl-2-acetyl-sn-glycero-3-phosphate phosphatase. Here, we show that acyl-CoA dehydrogenase member 10 (ACAD10) catalyzes the phosphorylation of 1-O-alkylglycerols and the dephosphorylation of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphate. Worms and mice lacking ACAD10 have reduced ether lipid levels and cannot salvage dietary alkylglycerols. Furthermore, individuals from the Akimel O’odham (Pima) tribe carrying ACAD10 polymorphisms also show decreased plasma ether lipid levels. Collectively, our findings resolve two long-standing gaps in ether lipid biochemistry and reveal a mechanistic link between ether lipid metabolism and a population-associated risk factor for type 2 diabetes.