Cellular senescence is a state of irreversible cellular growth arrest accompanied by distinct changes in gene expression and the acquisition of a complex proinflammatory secretory profile termed the senescence-associated secretory phenotype (SASP). Senescent cells accumulate in aged tissues and contribute to age-related disease in mice. Increasing evidence that selective removal of senescent cells can ameliorate diseases of late life and extend lifespan in mice has given rise to the development of senolytics that target senescent cells as anti-aging therapeutics. To realize the full potential of senolytic medicine, robust biomarkers of senescence must be in place to monitor the in vivo appearance of senescent cells with age, as well as their removal by senolytic treatments. Here we investigate the dynamic changes in expression of the molecular hallmarks of senescence, including p16Ink4a, p21Cip1, and SASP factors in multiple tissues in mice during aging. We show that expression of these markers is highly variable in age- and tissue-specific manners. Nevertheless, Mmp12 represents a robust SASP factor that shows consistent age-dependent increases in expression across all tissues analyzed in this study and p16Ink4a expression is consistently increased with age in most tissues. Likewise, in humans CDKN2A (p16Ink4a) is one of the top genes exhibiting elevated expression in multiple tissues with age as revealed by data analysis of the Genotype-Tissue Expression (GTEx) project. These results support the targeting of p16Ink4a expressing-cells in senolytic treatments, while emphasizing the need to establish a panel of robust biomarkers of senescence in vivo in both mice and humans.

Impact statementMost signals from genome-wide association studies (GWASs) map to the noncoding genome, and functional interpretation of these associations remained challenging. We reviewed recent progress in methodologies of studying the noncoding genome and argued that no single approach allows one to effectively identify the causal regulatory variants from GWAS results. By illustrating the advantages and limitations of each method, our review potentially provided a guideline for taking a combinatorial approach to accurately predict, prioritize, and eventually experimentally validate the causal variants. AbstractGenome-wide association studies have shown that the far majority of disease-associated variants reside in the non-coding regions of the genome, suggesting that gene regulatory changes contribute to disease risk. To identify truly causal non-coding variants and their affected target genes remains challenging but is a critical step to translate the genetic associations to molecular mechanisms and ultimately clinical applications. Here we review genomic/epigenomic resources and in silico tools that can be used to identify causal non-coding variants and experimental strategies to validate their functionalities.

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. Surprisingly, centSIRT6 displayed weaker deacetylase activity, but stronger mADPr activity, over a range of NAD+ concentrations and substrates. Additionally, centSIRT6 displayed a stronger interaction with Lamin A/C (LMNA), which was correlated with enhanced ribosylation of LMNA. Our results suggest that enhanced SIRT6 function contributes to human longevity by improving genome maintenance via increased mADPr activity and enhanced interaction with LMNA.

No abstract

Aberrant shifts in DNA methylation have long been regarded as an early marker for cancer onset and progression. To chart DNA methylation changes that occur during the transformation from normal healthy colon tissue to malignant colorectal cancer (CRC), we collected over 50 samples from 15 familial adenomatous polyposis (FAP) and non-FAP colorectal cancer patients, and generated 30-70x whole-genome methylation sequencing (WGMS) runs via the novel Ultima Genomics ultra high-throughput sequencing platform. We observed changes in DNA methylation that occur early in the malignant transformation process, in gene promoters and in distal regulatory elements. Among these changes are events of hyper-methylation which are associated with a bivalent "poised" chromatin state at promoters and are CRC-specific. Distal enhancers show nonlinear dynamics, lose methylation in the progression from normal mucosa to dysplastic polyps but regain methylation in the adenocarcinoma state. Enhancers that gain chromatin accessibility in the adenocarcinoma state and are enriched with HOX transcription factor binding sites, a marker of developmental genes. This work demonstrates the feasibility of generating large high-quality WGMS data using the Ultima Genomics platform and provides the first detailed view of methylation dynamics during CRC formation and progression in a model case.