Common and rare variant associations with clonal haematopoiesis phenotypes.

Clonal haematopoiesis involves the expansion of certain blood cell lineages and has been associated with ageing and adverse health outcomes. Here we use exome sequence data on 628,388 individuals to identify 40,208 carriers of clonal haematopoiesis of indeterminate potential (CHIP). Using genome-wide and exome-wide association analyses, we identify 24 loci (21 of which are novel) where germline genetic variation influences predisposition to CHIP, including missense variants in the lymphocytic antigen coding gene LY75, which are associated with reduced incidence of CHIP.

A rare human centenarian variant of SIRT6 enhances genome stability and interaction with Lamin A.

Sirtuin 6 (SIRT6) is a deacylase and mono-ADP ribosyl transferase (mADPr) enzyme involved in multiple cellular pathways implicated in aging and metabolism regulation. Targeted sequencing of SIRT6 locus in a population of 450 Ashkenazi Jewish (AJ) centenarians and 550 AJ individuals without a family history of exceptional longevity identified enrichment of a SIRT6 allele containing two linked substitutions (N308K/A313S) in centenarians compared with AJ control individuals. Characterization of this SIRT6 allele (centSIRT6) demonstrated it to be a stronger suppressor of LINE1 retrotransposons, confer enhanced stimulation of DNA double-strand break repair, and more robustly kill cancer cells compared with wild-type SIRT6.

The Emergency Medicine Group Standardized Letter of Evaluation as a Workplace-based Assessment: The Validity Is in the Detail.

Introduction: Interest is growing in specialty-specific assessments of student candidates based on clinical clerkship performance to assist in the selection process for postgraduate training. The most established and extensively used is the emergency medicine (EM) Standardized Letter of Evaluation (SLOE), serving as a substitute for the letter of recommendation. Typically developed by a program's leadership, the group SLOE strives to provide a unified institutional perspective on performance.

Therapeutic targeting of Notch signaling and immune checkpoint blockade in a spontaneous, genetically heterogeneous mouse model of T-cell acute lymphoblastic leukemia.

T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive hematologic cancer derived from the malignant transformation of T-cell progenitors. Outcomes remain poor for T-ALL patients who have either primary resistance to standard-of-care chemotherapy or disease relapse. Notably, there are currently no targeted therapies available in T-ALL.

LINE1 Derepression in Aged Wild-Type and SIRT6-Deficient Mice Drives Inflammation.

Mice deficient for SIRT6 exhibit a severely shortened lifespan, growth retardation, and highly elevated LINE1 (L1) activity. Here we report that SIRT6-deficient cells and tissues accumulate abundant cytoplasmic L1 cDNA, which triggers strong type I interferon response via activation of cGAS. Remarkably, nucleoside reverse-transcriptase inhibitors (NRTIs), which inhibit L1 retrotransposition, significantly improved health and lifespan of SIRT6 knockout mice and completely rescued type I interferon response.

Relationship Between Institutional Standardized Letter of Evaluation Global Assessment Ranking Practices, Interviewing Practices, and Medical Student Outcomes.

Background: Emergency medicine (EM) program directors rely largely on the standardized letter of evaluation (SLOE) to help determine which applicants to interview in the face of an increasing number of applications. To further characterize the SLOE's role in the EM application process, particularly the global assessment (GA) ranking and its effect on interviewing practices and medical student outcomes, the leaders of EM programs were surveyed regarding their experiences in both generating and utilizing the SLOE.

Methods: Individuals on the Council of Emergency Medicine Residency Directors (CORD) and Clerkship Directors in Emergency Medicine (CDEM) Academy listservs were anonymously surveyed from March 21-30, 2015, with 18 questions in multiple-choice and fill-in-the-blank formats.

Effects of an unusual poison identify a lifespan role for Topoisomerase 2 in .

A progressive loss of genome maintenance has been implicated as both a cause and consequence of aging. Here we present evidence supporting the hypothesis that an age-associated decay in genome maintenance promotes aging in (yeast) due to an inability to sense or repair DNA damage by topoisomerase 2 (yTop2). We describe the characterization of LS1, identified in a high throughput screen for small molecules that shorten the replicative lifespan of yeast.

Does the National Resident Match Program Rank List Predict Success in Emergency Medicine Residency Programs?

Background: Emergency medicine (EM) residency programs use nonstandardized criteria to create applicant rank lists. One implicit assumption is that predictive associations exist between an applicant's rank and their future performance as a resident. To date, these associations have not been sufficiently demonstrated.

JNK Phosphorylates SIRT6 to Stimulate DNA Double-Strand Break Repair in Response to Oxidative Stress by Recruiting PARP1 to DNA Breaks.

The accumulation of damage caused by oxidative stress has been linked to aging and to the etiology of numerous age-related diseases. The longevity gene, sirtuin 6 (SIRT6), promotes genome stability by facilitating DNA repair, especially under oxidative stress conditions. Here we uncover the mechanism by which SIRT6 is activated by oxidative stress to promote DNA double-strand break (DSB) repair.

SIRT6 rescues the age related decline in base excision repair in a PARP1-dependent manner.

In principle, a decline in base excision repair (BER) efficiency with age should lead to genomic instability and ultimately contribute to the onset of the aging phenotype. Although multiple studies have indicated a negative link between aging and BER, the change of BER efficiency with age in humans has not been systematically analyzed. Here, with foreskin fibroblasts isolated from 19 donors between 20 and 64 y of age, we report a significant decline of BER efficiency with age using a newly developed GFP reactivation assay.

SIRT6 represses LINE1 retrotransposons by ribosylating KAP1 but this repression fails with stress and age.

L1 retrotransposons are an abundant class of transposable elements that pose a threat to genome stability and may have a role in age-related pathologies such as cancer. Recent evidence indicates that L1s become more active in somatic tissues during the course of ageing; however the mechanisms underlying this phenomenon remain unknown. Here we report that the longevity regulating protein, SIRT6, is a powerful repressor of L1 activity.

SIRT6: a promising target for cancer prevention and therapy.

Many of the pathologies associated with the aging process also contribute to tumor initiation, growth or metastasis. Insights from biogerontology may be instrumental for developing new therapies for cancer. This chapter highlights the rationale for combining biogerontology and cancer research to generate new strategies for cancer treatment.

IGF1R levels in the brain negatively correlate with longevity in 16 rodent species.

The insulin/insulin-like growth factor signaling (IIS) pathway is a major conserved regulator of aging. Nematode, fruit fly and mouse mutants with reduced IIS signaling exhibit extended lifespan. These mutants are often dwarfs leading to the idea that small body mass correlates with longevity within species.

Sirtuin 6 (SIRT6) rescues the decline of homologous recombination repair during replicative senescence.

Genomic instability is a hallmark of aging tissues. Genomic instability may arise from the inefficient or aberrant function of DNA double-stranded break (DSB) repair. DSBs are repaired by homologous recombination (HR) and nonhomologous DNA end joining (NHEJ).

Repairing split ends: SIRT6, mono-ADP ribosylation and DNA repair.

The sirtuin gene family comprises an evolutionarily ancient set of NAD+ dependent protein deacetylase and mono-ADP ribosyltransferase enzymes. Found in all domains of life, sirtuins regulate a diverse array of biological processes, including DNA repair, gene silencing, apoptosis and metabolism. Studies in multiple model organisms have indicated that sirtuins may also function to extend lifespan and attenuate age-related pathologies.

SIRT6 overexpression induces massive apoptosis in cancer cells but not in normal cells.

Emerging evidence suggests that Sirtuin 6 (SIRT6) functions as a longevity assurance gene by promoting genomic stability, regulating metabolic processes and attenuating inflammation. Here, we examine the effect of SIRT6 activation on cancer cells. We show that SIRT6 overexpression induces massive apoptosis in a variety of cancer cell lines but not in normal, non-transformed cells.

SIRT6 promotes DNA repair under stress by activating PARP1.

Sirtuin 6 (SIRT6) is a mammalian homolog of the yeast Sir2 deacetylase. Mice deficient for SIRT6 exhibit genome instability. Here, we show that in mammalian cells subjected to oxidative stress SIRT6 is recruited to the sites of DNA double-strand breaks (DSBs) and stimulates DSB repair, through both nonhomologous end joining and homologous recombination.