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The yeast SIR protein complex has been implicated in transcription silencing and suppression of recombination. The Sir complex represses transcription at telomeres, mating-type loci, and ribosomal DNA. Unlike SIR3 and SIR4 , the SIR2 gene is highly conserved in organisms ranging from archaea to humans. Interestingly, Sir2 is active as an NAD + -dependent deacetylase, which is broadly conserved from bacteria to higher eukaryotes. In this review, we discuss the role of NAD + , the unusual products of the deacetylation reaction, the Sir2 structure, and the Sir2 chemical inhibitors and activators that were recently identified. We summarize the current knowledge of the Sir2 homologs from different organisms, and finally we discuss the role of Sir2 in caloric restriction and aging.

Exercise is effective toward delaying or preventing chronic disease, with a large body of evidence supporting its effectiveness. However, less is known about the specific healthspan-promoting effects of exercise on blood biomarkers in the disease-free population. In this work, we examine 23,237 generally healthy individuals who self-report varying weekly running volumes and compare them to 4,428 generally healthy sedentary individuals, as well as 82 professional endurance runners. We estimate the significance of differences among blood biomarkers for groups of increasing running levels using analysis of variance (ANOVA), adjusting for age, gender, and BMI. We attempt and add insight to our observational dataset analysis via two-sample Mendelian randomization (2S-MR) using large independent datasets. We find that self-reported running volume associates with biomarker signatures of improved wellness, with some serum markers apparently being principally modified by BMI, whereas others show a dose-effect with respect to running volume. We further detect hints of sexually dimorphic serum responses in oxygen transport and hormonal traits, and we also observe a tendency toward pronounced modifications in magnesium status in professional endurance athletes. Thus, our results further characterize blood biomarkers of exercise and metabolic health, particularly regarding dose-effect relationships, and better inform personalized advice for training and performance.

Background The interplay between diet and healthspan is a topic of great interest in biomedical research. Toward this end, consumption of marine omega-3 fatty acids is of particular significance, as reports suggest that diets focused on seafood can prolong the disease-free portion of the human lifespan. Fish consumption has also been linked to reduced biological aging as measured by epigenetic clocks, but there is no conclusive evidence of a causal relationship. Moreover, fish oils reduce triglycerides, and may affect other lipid profiles, as well as systemic inflammation. To investigate further, we used two-sample Mendelian randomization to investigate potential causality between fish intake and healthspan markers. Methods Bidirectional Mendelian randomization was performed in the two-sample setting with publicly available GWAS summary statistics. GWAS data from the UK Biobank for oily fish consumption ( n = 460,443) and fish oil supplementation ( n = 461,384) were used as the primary exposures. First-generation epigenetic clocks Hannum age and intrinsic epigenetic age acceleration (IEAA), as well as second-generation clocks GrimAge and PhenoAge were collected from an independent dataset of individuals of European ancestry ( n = [34,449–34,667]). Finally, data from the Integrative Epidemiology Unit database was used for serum proxies of lipidemia and systemic inflammation ( n = [61,308–78,700]). Additional sensitivity analyses, such as reverse causation testing and the Cochran’s Q test were performed for exposure-outcome pairs where the inverse variance weighted (IVW) method was significant ( p -value < 0.05), and where the MR Egger method indicated an effect in the same direction as the IVW result. Results We report that oily fish consumption appears to decrease PhenoAge acceleration ( p < 0.0086), whereas fish oil supplementation appears to decrease GrimAge ( p = 0.037). Both omega-3 exposures modify the epigenetic clocks in the expected negative, or age-decelerating, direction. For the serum biomarkers, we find evidence that fish oil consumption leads to a reduction in triglycerides ( p = 0.004), although HDL and LDL were not significantly modified. Finally, we also detected a suggestive inverse relationship between oily fish consumption and hsCRP ( p = 0.064). Conclusions Our analysis shows that consuming fish oil, whether through whole food or as a supplement, can have a rejuvenating impact as measured by PhenoAge and GrimAge acceleration. We have also provided evidence further linking fish oil intake and lower triglyceride levels. These results, based on robust MR-based analyses, emphasize the effectiveness of dietary choices in modifying emerging measures of healthspan.

Numerous longevity genes have been discovered in model organisms and altering their function results in prolonged lifespan. In mammals, some have speculated that any health benefits derived from manipulating these same pathways might be offset by increased cancer risk on account of their propensity to boost cell survival. The Sir2/SIRT1 family of NAD(+)-dependent deacetylases is proposed to underlie the health benefits of calorie restriction (CR), a diet that broadly suppresses cancer in mammals. Here we show that CR induces a two-fold increase SIRT1 expression in the intestine of rodents and that ectopic induction of SIRT1 in a beta-catenin-driven mouse model of colon cancer significantly reduces tumor formation, proliferation, and animal morbidity in the absence of CR. We show that SIRT1 deacetylates beta-catenin and suppresses its ability to activate transcription and drive cell proliferation. Moreover, SIRT1 promotes cytoplasmic localization of the otherwise nuclear-localized oncogenic form of beta-catenin. Consistent with this, a significant inverse correlation was found between the presence of nuclear SIRT1 and the oncogenic form of beta-catenin in 81 human colon tumor specimens analyzed. Taken together, these observations show that SIRT1 suppresses intestinal tumor formation in vivo and raise the prospect that therapies targeting SIRT1 may be of clinical use in beta-catenin-driven malignancies.

Digital health technologies offer new opportunities for personalized health management and disease prevention. In this retrospective, long-term longitudinal study of over 20,000 users of a digital health platform (DHP), we aimed to determine whether improvements in health-related biomarkers could be observed in users and, if so, how they were maintained over time. We further explored whether genetic predisposition and physiological patterns, such as sleep and activity, were associated with variability in these biomarker responses. The DHP evaluates a user’s individual biological profile, consisting of blood biomarkers, polygenic risk scores (PGS), and fitness tracker data, and provides personalized lifestyle interventions based on knowledge about nutrition, supplements, exercise, and recovery collected from over 7,000 clinical studies. Here, we show improvement in suboptimal levels of the primary outcome, key blood biomarkers that are sustained or increased in the long-term with DHP use. We additionally show the correlation of biomarker improvement with secondary outcomes, including specific sleep and activity patterns in users. Lastly, we find significant correlations between polygenic risk and both baseline levels and longitudinal change in biomarkers, including low-density lipoprotein cholesterol (LDL-c), suggesting that genetic predisposition for a negative trait (e.g., elevated LDL-c) could make it more difficult to improve that trait. This longitudinal, integrated biomarker dataset highlights the potential of digital health tools in fostering improvements in health-related biomarkers through personalized data analytics and targeted behavioral interventions.

Mutations in oncogenes and tumor suppressor genes are critical in the development of cancer. A major pathway for the formation of mutations is the replication of unrepaired DNA lesions. To better understand the mechanism of translesion replication (TLR) in mammals, a quantitative assay for TLR in cultured cells was developed. The assay is based on the transient transfection of cultured cells with a gapped plasmid, carrying a site-specific lesion in the gap region. Filling in of the gap by TLR is assayed in a subsequent bioassay, by the ability of the plasmid extracted from the cells, to transform an Escherichia coli indicator strain. Using this method it was found that TLR through a synthetic abasic site in the adenocarcinoma H1299, the osteogenic sarcoma Saos-2, the prostate carcinoma PC3, and the hepatoma Hep3B cell lines occurred with efficiencies of 92 ± 6%, 32 ± 2%, 72 ± 4%, and 26 ± 3%, respectively. DNA sequence analysis showed that 85% of the bypass events in H1299 cells involved insertion of dAMP opposite the synthetic abasic site. Addition of aphidicolin, an inhibitor of DNA polymerases α, δ, and ε, caused a 4.4-fold inhibition of bypass. Analysis of two XP-V cell lines, defective in DNA polymerase η, showed bypass of 89%, indicating that polymerase η is not essential for bypass of abasic sites. These results suggest that in human cells bypass of abasic sites does not require the bypass-specific DNA polymerase η, but it does require at least one of the replicative DNA polymerases, γ, δ, or ε. The quantitative TLR assay is expected to be useful in the molecular analysis of lesion bypass in a large variety of cultured mammalian cells.

To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-α/γ agonist, aleglitazar, with tesaglitazar (a dual PPAR-α/γ agonist) or a combination of pioglitazone (Pio; PPAR-γ agonist) and fenofibrate (Feno; PPAR-α agonist) in human hepatocytes. Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC(50)-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-α signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect. All treatments were inferred to decrease proliferative signaling. Aleglitazar induces transcriptional signatures related to lipid parameters and stress responses that are unique from other dual PPAR-α/γ treatments. This may underlie observed favorable changes in lipid profiles in animal and clinical studies with aleglitazar and suggests a differentiated gene profile compared with other dual PPAR-α/γ agonist treatments.

Digital health technologies offer new opportunities for personalized health management and disease prevention. In this retrospective, long-term longitudinal study of over 20,000 users of a digital health platform (DHP), we aimed to determine whether improvements in health-related biomarkers could be observed in users and, if so, how they were maintained over time. We further explored whether genetic predisposition and physiological patterns, such as sleep and activity, were associated with variability in these biomarker responses. The DHP evaluates a user's individual biological profile, consisting of blood biomarkers, polygenic risk scores (PGS), and fitness tracker data, and provides personalized lifestyle interventions based on knowledge about nutrition, supplements, exercise, and recovery collected from over 7,000 clinical studies. Here, we show improvement in suboptimal levels of the primary outcome, key blood biomarkers that are sustained or increased in the long-term with DHP use. We additionally show the correlation of biomarker improvement with secondary outcomes, including specific sleep and activity patterns in users. Lastly, we find significant correlations between polygenic risk and both baseline levels and longitudinal change in biomarkers, including low-density lipoprotein cholesterol (LDL-c), suggesting that genetic predisposition for a negative trait (e.g., elevated LDL-c) could make it more difficult to improve that trait. This longitudinal, integrated biomarker dataset highlights the potential of digital health tools in fostering improvements in health-related biomarkers through personalized data analytics and targeted behavioral interventions.

Elevated blood concentration of low-density lipoprotein cholesterol (LDLc) is a primary risk factor for developing cardiovascular disease. Lifestyle interventions including an increase in dietary phytosterols as well as medications have proven effective in lowering LDLc. The primary objective of this randomized, placebo controlled, double blind, crossover study was to determine the impact of a new phytosterol emulsion for dietary supplements (1.5 g/day phytosterol equivalents) on LDLc concentrations. Thirty-two healthy adults were randomly assigned to receive placebo or treatment followed by a washout period, followed by placebo or treatment, each phase lasting one month. Secondary endpoints related to cardiovascular health were also assessed. Study management, including screening, recruitment, monitoring, compliance, and data collection, were done remotely (a siteless clinical trial) utilizing a novel virtual tool. Phytosterol supplementation significantly lowered LDLc concentrations by 10.2% (16.17 mg/dL or 0.419 mmol/L, p = 0.008 by paired t-test, p = 0.014 by Wilcoxon signed rank testing). No secondary biomarkers were found to change significantly. Supplementation with phytosterols in a new dietary supplement formulation efficiently and safely decreases LDLc within one month in a free-living setting.

[This corrects the article DOI: 10.1371/journal.pone.0002020.].