Association of Advanced Glycation End Products with Cognitive Function: HealthyDance Study.

Background: The current research on advanced glycosylation end products (AGEs) and cognitive function is limited. Objective: We aimed to investigate the relationship between multiple plasma AGEs and cognitive function and mild cognitive impairment (MCI). Methods: Baseline data from The Lifestyle and Healthy Aging of Chinese Square Dancer Study was used in this cross-sectional study. Ultra-high-performance liquid chromatography tandem mass spectrometry was used to determine plasma levels of carboxymethyl lysine (CML), carboxyethyl lysine (CEL), and methyl imidazolinone (MG-H1). Four cognitive tests were used to obtain the four cognitive domain scores and the composite z scores. The Petersen criteria were used to diagnose MCI. The data were analyzed by multivariable linear and logistic regression models. Results: This study included 1,018 participants (median age 61.0 years, 87.3% female). After multivariate adjustment, the ßs of the highest quartile of CML and CEL compared to the lowest quartile were -0.28 (-0.38, -0.17) and -0.13 (-0.23, -0.03), respectively, for the composite z score. For the four cognitive domains, CML was negatively correlated with memory, attention, and executive function, and CEL was negatively associated with memory and language function. In addition, higher CML was associated with a higher odds of MCI. MG-H1 was not associated with cognitive function. Conclusions: High plasma AGE levels were correlated with poorer cognitive function, particularly CML and CEL, higher levels of CML were also associated with higher odds of MCI. To clarify the effects of different AGEs on cognitive function and the underlying mechanisms, further longitudinal and experimental studies are needed.

TMO-Net: an explainable pretrained multi-omics model for multi-task learning in oncology.

Cancer is a complex disease composing systemic alterations in multiple scales. In this study, we develop the Tumor Multi-Omics pre-trained Network (TMO-Net) that integrates multi-omics pan-cancer datasets for model pre-training, facilitating cross-omics interactions and enabling joint representation learning and incomplete omics inference. This model enhances multi-omics sample representation and empowers various downstream oncology tasks with incomplete multi-omics datasets. By employing interpretable learning, we characterize the contributions of distinct omics features to clinical outcomes. The TMO-Net model serves as a versatile framework for cross-modal multi-omics learning in oncology, paving the way for tumor omics-specific foundation models.

High-fat diet induces sarcopenic obesity in natural aging rats through the gut-trimethylamine N-oxide-muscle axis.

INTRODUCTION: The lack of suitable animal models for sarcopenic obesity (SO) limits in-depth research into the disease. Emerging studies have demonstrated that gut dysbiosis is involved in the development of SO. As the importance of microbial metabolites is starting to unveil, it is necessary to comprehend the specific metabolites associated with gut microbiota and SO. OBJECTIVES: We aimed to investigate whether high-fat diet (HFD) causes SO in natural aging animal models and specific microbial metabolites that are involved in linking HFD and SO. METHODS: Young rats received HFD or control diet for 80 weeks, and obesity-related metabolic disorders and sarcopenia were measured. 16S rRNA sequencing and non-targeted and targeted metabolomics methods were used to detect fecal gut microbiota and serum metabolites. Gut barrier function was evaluated by intestinal barrier integrity and intestinal permeability. Trimethylamine N-oxide (TMAO) treatment was further conducted for verification. RESULTS: HFD resulted in body weight gain, dyslipidemia, impaired glucose tolerance, insulin resistance, and systemic inflammation in natural aging rats. HFD also caused decreases in muscle mass, strength, function, and fiber cross-sectional area and increase in muscle fatty infiltration in natural aging rats. 16S rRNA sequencing and nontargeted and targeted metabolomics analysis indicated that HFD contributed to gut dysbiosis, mainly characterized by increases in deleterious bacteria and TMAO. HFD destroyed intestinal barrier integrity and increased intestinal permeability, as evaluated by reducing levels of colonic mucin-2, tight junction proteins, goblet cells and elevating serum level of fluorescein isothiocyanate-dextran 4. Correlation analysis showed a positive association between TMAO and SO. In addition, TMAO treatment aggravated the development of SO in HFD-fed aged rats through regulating the ROS-AKT/mTOR signaling pathway. CONCLUSION: HFD leads to SO in natural aging rats, partially through the gut-microbiota-TMAO-muscle axis.

Genotypic-phenotypic landscape computation based on first principle and deep learning.

The relationship between genotype and fitness is fundamental to evolution, but quantitatively mapping genotypes to fitness has remained challenging. We propose the Phenotypic-Embedding theorem (P-E theorem) that bridges genotype-phenotype through an encoder-decoder deep learning framework. Inspired by this, we proposed a more general first principle for correlating genotype-phenotype, and the P-E theorem provides a computable basis for the application of first principle. As an application example of the P-E theorem, we developed the Co-attention based Transformer model to bridge Genotype and Fitness model, a Transformer-based pre-train foundation model with downstream supervised fine-tuning that can accurately simulate the neutral evolution of viruses and predict immune escape mutations. Accordingly, following the calculation path of the P-E theorem, we accurately obtained the basic reproduction number (${R}_0$) of SARS-CoV-2 from first principles, quantitatively linked immune escape to viral fitness and plotted the genotype-fitness landscape. The theoretical system we established provides a general and interpretable method to construct genotype-phenotype landscapes, providing a new paradigm for studying theoretical and computational biology.

Lipid-lowering, antihypertensive, and antithrombotic effects of nattokinase combined with red yeast rice in patients with stable coronary artery disease: a randomized, double-blinded, placebo-controlled trial.

Nattokinase (NK) and red yeast rice (RYR) are both indicated for their potential in cardiovascular disease prevention and management, but their combined effects especially in coronary artery disease (CAD) are scarcely examined. This 90-day randomized, double-blind trial aims to investigate the effect of NK and RYR supplementations on cardiometabolic parameters in patients with stable CAD. 178 CAD patients were randomized to four groups: NK + RYR, NK, RYR, and placebo. No adverse effects due to the interventions were reported. In comparisons across groups, NK + RYR showed the maximum effect in reducing triglyceride (-0.39 mmol), total cholesterol (-0.66 mmol/L), diastolic blood pressure (-7.39 mmHg), and increase in high-density lipoprotein cholesterol (0.195 mmol/L) than other groups (all p for multiple groups comparison<0.01). Both NK + RYR and NK groups had significantly better-improved lactate dehydrogenase than the others (-29.1 U/L and - 26.4 U/L). NK + RYR group also showed more potent reductions in thromboxane B2 and increases in antithrombin III compared to placebo (both p < 0.01). These improved markers suggest that combined NK and RYR may preferably alter antithrombin and COX-1 pathways, potentially reducing thrombosis risks in CAD patients. Overall, the combined NK and RYR supplementation is safe and more effective than separately in improving cardiometabolic markers among CAD patients with multiple heart medications use.

Association of aquatic food consumption, long-chain polyunsaturated n-3 fatty acid intake, and blood mercury levels with cognitive function in middle-aged and older adults.

BACKGROUND & AIMS: Aquatic food is rich in nutrients which benefit the human brain and cognitive health; however, concerns about heavy metal accumulation in aquatic food remain. This study evaluated the associations between aquatic food consumption, long-chain n-3 polyunsaturated fatty acids (LC n-3 PUFAs) intake, and blood mercury levels with cognition in middle-aged and older adults. METHODS: This cross-sectional study used baseline data from the Lifestyle and Healthy Aging of Chinese Square Dancer Study. Aquatic food consumption and LC n-3 PUFAs intake were obtained from a food frequency questionnaire. Blood mercury levels were measured using inductively coupled plasma mass spectrometry. A composite z-score was developed to represent global cognition by averaging the z-scores for each cognitive domain. Participants with mild cognitive impairment (MCI) were diagnosed according to Petersen's criteria. Multivariate linear and logistic regression models were used to examine the association between the exposure factors and cognitive performance including cognitive scores and MCI. RESULTS: Of 2621 middle-aged and older adults, the mean (SD) age was 63.71 (5.15) years, and 85.73% were females. Compared with the lowest quartile, those in the highest quartile for aquatic food consumption were associated with higher composite z-scores (ß = 0.156, 95% CI: 0.088-0.225) and lower MCI odds (OR = 0.598, 95% CI: 0.425-0.841). A similar positive relationship between LC n-3 PUFAs intake and composite z-score and an inverse association between LC n-3 PUFAs intake and MCI were also observed. In addition, the participants in the highest quartile for blood mercury levels had higher composite z-scores than those in the lowest quartile. CONCLUSIONS: In this cross-sectional study, higher aquatic food consumption, LC n-3 PUFAs intake, and blood mercury levels were related to better cognitive function. Further studies in Chinese populations are required to confirm these findings.

Association of plasma advanced glycation end-products and their soluble receptor with type 2 diabetes among Chinese adults.

AIMS: Population-based evidence regarding circulating advanced glycation end-products (AGEs) and the risk of type 2 diabetes (T2D) is conflicting and insufficient. We aimed to examine the association of plasma AGEs and plasma soluble receptors for AGEs (sRAGE) with T2D. MATERIALS AND METHODS: We conducted a hospital-based case-control study including 1072 pairs (53.9 ± 9.7 years, 56.0% male) of newly diagnosed T2D and age- and sex-matched controls. We further performed a nested case-control study within an ongoing prospective cohort consisting of 127 incident T2D cases and 381 well-matched controls (62.2 ± 5.1 years, 71.7% male). Plasma AGEs were detected using liquid chromatography-tandem mass spectrometry, and plasma sRAGE was measured by enzyme-linked immunosorbent assay. Conditional logistic regression was used to evaluate the association of plasma AGEs and sRAGE concentrations with T2D. RESULTS: Higher plasma AGEs and lower sRAGE concentrations were associated with higher odds of T2D. The multivariable-adjusted odds ratios of T2D comparing the highest with the lowest quartile levels were 3.28 (95% CI: 2.14, 5.02) for plasma AGEs and 0.25 (95% CI: 0.16, 0.39) for plasma sRAGE. Participants in the highest quartile of plasma AGEs and the lowest quartile of sRAGE concentrations had the greatest odds of T2D. The positive association of AGEs and inverse association of sRAGE with T2D risk was confirmed in the replication-nested case-control study. CONCLUSIONS: Increased circulating AGEs and decreased sRAGE concentrations were associated with elevated T2D risk. Our findings may have implications for the strategies of T2D prevention and management.

Silibinin Inhibits Cell Ferroptosis and Ferroptosis-Related Tissue Injuries.

Ferroptosis is involved in various tissue injuries including neurodegeneration, ischemia-reperfusion injury, and acute liver injury. Ferroptosis inhibitors exhibit promising clinical potential in the treatment of various diseases. As a traditional chemical, silymarin has been widely used in healthcare and clinical applications to treat liver injuries in which ferroptosis is involved. Silibinin is the main active ingredient of silymarin. However, the effect of silibinin on ferroptosis and ferroptosis-related diseases remains unclear. Here, we found that silibinin inhibited death in different kinds of cells caused by ferroptosis inducers including RSL3 and erastin. Moreover, silibinin alleviated lipid peroxidation induced by RSL3 without affecting the labile iron pool. Next, the antioxidant activity of silibinin was demonstrated by the DPPH assay. In vivo, silibinin strikingly relieved tissue injuries and ferroptosis in the liver and kidney of glutathione peroxidase 4 (GPX4) knockout C57 BL/6J mice. Moreover, silibinin effectively rescued renal ischemia-reperfusion, a well-known ferroptosis-related disease. In conclusion, our study revealed that silibinin effectively inhibits cell ferroptosis and ferroptosis-related tissue injuries, implicating silibinin as a potential chemical to treat ferroptosis-related diseases.

Vaccinium as Potential Therapy for Diabetes and Microvascular Complications.

Diabetes mellitus is one of the most critical global health concerns, with a fast-growing prevalence. The incidence of diabetic vascular complications is also rapidly increasing, exacerbating the burden on individuals with diabetes and the consumption of public medical resources. Despite the overall improvements in the prevention, diagnosis, and treatment of diabetic microvascular complications in recent years, safe and effective alternative or adjunctive therapies are urgently needed. The mechanisms underlying diabetic vascular complications are complex, with hyperglycemia-induced oxidative stress and inflammation being the leading causes. Therefore, glycemic control, antioxidation, and anti-inflammation are considered the main targets for the treatment of diabetes and its vascular comorbidities. Vaccinium L. (Ericaceae) is a genus of plants enriched with polyphenolic compounds in their leaves and fruits. Vaccinium and its extracts have demonstrated good bioactivity in reducing blood glucose, oxidative stress, and inflammation, making them excellent candidates for the management of diabetes and diabetic vascular complications. Here, we review recent preclinical and clinical studies on the potential effect of Vaccinium on ameliorating diabetes and diabetic complications, particularly diabetic kidney disease and diabetic retinopathy.

Relationship between Whole-Blood Magnesium and Cognitive Performance among Chinese Adults.

OBJECTIVE: To explore the association between magnesium levels and the odds of mild cognitive impairment (MCI). METHOD: In this cross-sectional study of 1006 participants (≥55 years) from China, whole-blood magnesium concentration was measured using inductively coupled plasma mass spectrometry. MCI was diagnosed according to Petersen criteria using self-reported cognitive decline and a neuropsychological test battery, including the trail-making test-part B (TMT-B), auditory verbal learning test (AVLT), digit symbol substitution test (DSST), and verbal fluency test (VFT), which measured the assessment of executive, memory, attention, and language functioning, respectively. A logistic regression was used to assess the relationship between magnesium levels and MCI, and linear regression analyses were performed for the association between magnesium and cognitive function score. RESULTS: The MCI group had a significantly lower concentration of magnesium compared to the Non-MCI group (34.7 ± 9.8 vs. 36.7 ± 9.7, p = 0.017). After adjusting for covariates, a negative association was observed between magnesium levels and MCI. Compared with the lowest quartile (median: 25.4 mg/L), the odds ratio for MCI was 0.53 (95%CI 0.32-0.90) for the highest quartile (median: 48.4 mg/L), and there was an inverse dose-response relationship (p for trend = 0.009). In addition, higher levels of magnesium were positively correlated with VFT scores (ß = 0.37, 95%CI = 0.11-0.62) and DSST scores (ß = 0.50, 95%CI = 0.01~0.98) and negatively correlated with TMT scores (ß = -1.73, 95%CI = -3.40--0.07) in the middle-aged and older adults. CONCLUSIONS: Whole-blood magnesium was inversely associated with the occurrence of MCI and positively associated with performance in neuropsychological tests assessing attention, executive, and language ability in middle-aged and older adults.

Comprehensive functional evaluation of a novel collagen for the skin protection in human fibroblasts and keratinocytes.

The collagen had been widely used as a promising source of functional food supplements for skin care. Here, we developed a novel animal-derived collagen that displayed multiple functions for protecting the human skin cells under UV irradiation. Different evaluations were performed to explore the protective effects of this collagen on human skin fibroblasts and keratinocytes. Specifically, we found that our collagen could induce the production of collagen I, elastin, and hyaluronic acid in fibroblasts and could also enhance the skin wound healing ability. Besides, it could elevate the expression of aquaporin-3 and cluster of differentiation 44 in keratinocytes. Moreover, this collagen had been demonstrated to alleviate the generation of reactive oxygen species and the malondialdehyde content in UVA-treated fibroblasts, as well as the secretion of inflammation factors in keratinocytes. These data indicated that the novel animal-derived collagen was a hopeful material for the comprehensive protection of the skin cells and the prevention of skin aging.

Genetic and molecular analysis of the anthocyanin pigmentation pathway in Epimedium.

Introduction: Flower color is an ideal trait for studying the molecular basis for phenotypic variations in natural populations of species. Epimedium (Berberidaceae) species exhibit a wide range of flower colors resulting from the varied accumulation of anthocyanins and other pigments in their spur-like petals and petaloid sepals. Methods: In this work, the anthocyanidins of eight different Epimedium species with different floral pigmentation phenotypes were analyzed using HPLC. Twelve genes involved in anthocyanin biosynthesis were cloned and sequenced, and their expression was quantified. Results: The expression levels of the catalytic enzyme genes DFR and ANS were significantly decreased in four species showing loss of floral pigmentation. Complementation of EsF3'H and EsDFR in corresponding Arabidopsis mutants together with overexpression of EsF3'5'H in wild type Arabidopsis analysis revealed that these genes were functional at the protein level, based on the accumulation of anthocyanin pigments. Discussion: These results strongly suggest that transcriptional regulatory changes determine the loss of anthocyanins to be convergent in the floral tissue of Epimedium species.

Metabolomics analysis reveals the accumulation patterns of flavonoids and phenolic acids in quinoa (Chenopodium quinoa Willd.) grains of different colors.

Quinoa grains are gaining increasing popularity owing to their high nutritional merits. However, only limited information is available on the metabolic profiles of quinoa grains. In this study, we determined the metabolic profiles of black, red, and white quinoa grains via an ultraperformance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS)-based metabolomics. A total of 689 metabolites were identified, among which 251, 182, and 317 metabolites displayed different accumulation patterns in the three comparison groups (Black vs Red, Black vs White, and Red vs White), respectively. In particular, flavonoid and phenolic acid contents displayed considerable differences, with 22 flavonoids, 5 phenolic acids, and 1 betacyanin being differentially accumulated among the three quinoa cultivars. Additionally, correlation analysis showed that flavonoids and phenolic acids could act as betanin co-pigments in quinoa grains. In conclusion, this study provides comprehensive insights into the adequate utilization and development of novel quinoa-based functional foods.

Association between Vitamin B and Obesity in Middle-Aged and Older Chinese Adults.

OBJECTIVE: Previous studies have found that obese people have lower levels of vitamin B, but most have focused on obesity as defined by body mass index (BMI), and its relationship with other types of obesity is unclear. The aim of this study was to explore the relationship between vitamin B levels and obesity assessed by different definitions among Chinese middle-aged and older community-dwelling adults. METHODS: This cross-sectional study included 887 participants aged 45 years and older (45-82 years). The concentrations of vitamin B (B1, B2, B6, and B9) were measured by robotic dry blood spot extraction systems in combination with liquid chromatography-tandem mass spectrometry. BMI, body fat percentage (BF%), visceral fat area (VFA), and waist circumference (WC) were used to diagnose obesity. VFA and BF% were assessed by bioelectrical impedance analysis. The logistic regression model was used to assess the associations between vitamin B levels and the odds of obesity. RESULTS: The average age of all participants was 60.77 (SD 6.33) years. The prevalence of obesity varied from 8.6% to 52.4% depending on different diagnostic criteria. After adjusting for covariates, a negative correlation was observed between vitamin B1 level and obesity according to the criteria of WC, VFA, and BF%, and the adjusted odds ratio (OR) was 0.47, 0.52, and 0.46, respectively. When using WC and BF% to define obesity, higher quartiles of vitamin B2 were negatively associated with the odds of obesity (OR: 0.62 and 0.62, respectively). Vitamin B6 was inversely associated with VFA-defined and BF%-defined obesity (OR: 0.64 and 0.64, respectively). When using VFA and BF% to define obesity, a negative correlation was observed in vitamin B9 (OR: 0.61 and 0.67, respectively). CONCLUSIONS: Vitamin B (B1, B2, B6, and B9) level was negatively related to obesity (defined by WC, VFA, or BF%) in Chinese middle-aged and older adults.

Combined probiotics attenuate chronic unpredictable mild stress-induced depressive-like and anxiety-like behaviors in rats.

Increasing evidence indicated that probiotics can be effective in improving behaviors similar to depression and anxiety disorders. However, the underlying mechanisms remain unclear, as is the effects of single vs. combined probiotics on depression and anxiety. This study aimed to determine whether combined probiotics could attenuate depressive-like and anxiety-like behavior induced by chronic unpredictable mild stress (CUMS) and its potential mechanisms. Rats underwent CUMS treatment and then administered Lactobacillus rhamnosus HN001 (HN001) or Bifidobacterium animalis subsp. lactis HN019 (HN019), alone or in combination. Levels of neurotransmitters, inflammatory factors, and the gut microbiota were measured. HN001 and (or) HN019 treatment improved depressive-like and anxiety-like behavior in rats, including increased moving distance and exploratory behavior (p < 0.05). In addition, altered gut microbiota structure induced by CUMS was amended by HN001 and/or HN019 (p < 0.05). HN001 and/or HN019 intervention also remarkably normalized levels of 5-HT, DA, NE, HVA, DOPAC, HIAA, TNF-α, IL-6, IL-18 and IL-1ß in CUMS rats (p < 0.05). Furthermore, the effects of combined probiotics on decreasing inflammation and improved gut microbiota (Chao1 index and ACE index, p < 0.05) were superior to the single probiotics. Moreover, spearman analysis showed a certain correlation between the different microbiota, such as Firmicutes, Bacteroidetes, Verrucomicrobias, Proteobacterias and Actinobacterias, and inflammation and neurotransmitters. These findings suggested that CUMS induced depressive and anxiety-like behaviors can be alleviated by the combination of probiotics, which was possibly associated with the alterations in the gut microbiota composition and increased neurotransmitters and decreased inflammatory factors.

Potential Health-Promoting Effects of Two Candidate Probiotics Isolated from Infant Feces Using an Immune-Based Screening Strategy.

Commensal microorganisms in the human gut are a good source of candidate probiotics, particularly those with immunomodulatory effects that may improve health outcomes by regulating interactions between the gut microbiome and distal organs. Previously, we used an immune-based screening strategy to select two potential probiotic strains from infant feces in China, Bifidobacterium breve 207-1 (207-1) and Lacticaseibacillus paracasei 207-27 (207-27). In this study, the in vitro immunological effects and potential in vivo general health benefits of these two strains were evaluated using Lacticaseibacillus rhamnosus GG (LGG) as the control. The results showed that 207-1 and 207-27 significantly and differentially modulated the cytokine profiles of primary splenic cells, while did not induce abnormal systemic immune responses in healthy mice. They also modulated the gut microbiota composition in a strain-dependent manner, thus decreasing Gram-negative bacteria and increasing health-promoting taxa and short-chain fatty acid levels, particularly butyric acid. Conclusively, 207-1 and 207-27 shaped a robust gut environment in healthy mice in a strain-specific manner. Their potential immunomodulatory effects and other elite properties will be further explored using animal models of disease and subsequent clinical trials. This immune-based screening strategy is promising in efficiently and economically identifying elite candidate probiotics.

Polyphenols in Highland Barley Tea Inhibit the Production of Advanced Glycosylation End-Products and Alleviate the Skeletal Muscle Damage.

SCOPE: Highland barley tea is a kind of caffeine-free cereal tea. Previous studies have shown that it is rich in polyphenol flavonoids. Here, the effect of Highland barley tea polyphenols (HBP) on the production of advanced glycosylation end-products and alleviate the skeletal muscle damage is systematically investigated. METHODS AND RESULTS: HBP effectively inhibits the formation of AGEs in vitro, and 12 phenolic compounds are identified. In addition, d-galactose is used to construct a mouse senescence model and intervenes with different doses of HBP. It is found that high doses of HBP effectively inhibit AGEs in serum and flounder muscle species and increased muscle mass in flounder muscle; also, high doses of HBP increase the expression of the mitochondrial functional protein SIRT3 and decrease the expression of myasthenia-related proteins. Furthermore, cellular experiments show that AGEs can significantly increase oxidative stress in skeletal muscle. CONCLUSION: These data indicate that the relationship between the biological activity and HBP properties is relevant since Highland barley can be a potential functional food to prevent AGEs-mediated skeletal muscle damage.

Hydroxysafflor yellow A triggered a fast-to-slow muscle fiber-type conversion via regulating FoxO1 in myocytes.

Hydroxysafflor yellow A (HSYA) is the main bioactive component of safflower and has been reported to have significant health-promoting abilities. However, the regulation of HSYA on different types of skeletal myofibers is largely unknown. Here, in vitro experiments found that the water extract of safflower could significantly increase MyHC I, MB and Tnni1 mRNA expression while downregulating MyHC IIb mRNA expression. Furthermore, HSYA triggered fast-to-slow fiber-type switching and increased gene expression related to mitochondrial biosynthesis both in vitro and in vivo. Autodock analyses proved that FoxO1 is a potential target of HSYA, and qRT-PCR and western blotting further showed that HSYA significantly promoted the activation of the FoxO1 signaling pathway. Additionally, the levels of PGC1α, downstream of FoxO1, also significantly increased after HSYA treatment. Together, our findings suggested that HSYA triggered a fast-to-slow myofiber-type shift through the FoxO1 signaling pathway.

The flavonoid procyanidin C1 has senotherapeutic activity and increases lifespan in mice.

Ageing-associated functional decline of organs and increased risk for age-related chronic pathologies is driven in part by the accumulation of senescent cells, which develop the senescence-associated secretory phenotype (SASP). Here we show that procyanidin C1 (PCC1), a polyphenolic component of grape seed extract (GSE), increases the healthspan and lifespan of mice through its action on senescent cells. By screening a library of natural products, we find that GSE, and PCC1 as one of its active components, have specific effects on senescent cells. At low concentrations, PCC1 appears to inhibit SASP formation, whereas it selectively kills senescent cells at higher concentrations, possibly by promoting production of reactive oxygen species and mitochondrial dysfunction. In rodent models, PCC1 depletes senescent cells in a treatment-damaged tumour microenvironment and enhances therapeutic efficacy when co-administered with chemotherapy. Intermittent administration of PCC1 to either irradiated, senescent cell-implanted or naturally aged old mice alleviates physical dysfunction and prolongs survival. We identify PCC1 as a natural senotherapeutic agent with in vivo activity and high potential for further development as a clinical intervention to delay, alleviate or prevent age-related pathologies.

A fully validated high-throughput liquid chromatography tandem mass spectrometry method for automatic extraction and quantitative determination of endogenous nutritional biomarkers in dried blood spot samples.

Dried blood spot (DBS) sampling demonstrates multiple advantages over traditional venous blood collection in terms of quantifying biomarkers for clinical applications. The process is more convenient, less invasive and requires smaller sample size. More importantly, it lowers risk of infection and allows easier sample transportation and storage. In this study, an automated high-throughput DBS-LC-MS/MS method was developed for quantifying endogenous biomarkers in DBS (or 20 µL whole blood) and later applied in riboflavin (i.e. vitamin B2) quantification. The method consists of four steps, including internal standard spraying, high pressure sample extraction, LC-MS/MS sample analysis and automatic extraction module cleaning. The last two steps overlap, thus reducing sample preparation time and shorten the sample analysis cycle to five minutes per sample. The method was validated to be selective and sensitive (LLOQ=2 ng/mL) over a range of 2-120 ng/mL. Matrix effect was compensated by the application of internal standard, while within-run precision, between-run precision, accuracy, stability and ruggedness of the developed method were all assessed to be satisfactory. Quantitative analysis of riboflavin in 133 whole blood samples using the developed method demonstrated strong correlation compared with those quantified using traditional manual sample preparation followed by LC-MS/MS analysis (R = 0.9774). In conclusion, an automated high-throughput DBS-LC-MS/MS method was developed and validated to be sensitive, accurate and robust, suggesting great potential in the quantification of endogenous biomarkers in blood or other biofluids.