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In this Tools of the Trade article, Kejun Ying describes epigenome-wide Mendelian randomization, which integrates Mendelian randomization into a DNA-methylation-based epigenetic clock to identify CpG sites with potential causal links to lifespan and healthspan.

DNA methylation (DNAm) is one of the most reliable biomarkers of aging across mammalian tissues. While the age-dependent global loss of DNAm has been well characterized, DNAm gain is less characterized. Studies have demonstrated that CpGs which gain methylation with age are enriched in Polycomb Repressive Complex 2 (PRC2) targets. However, whole-genome examination of all PRC2 targets as well as determination of the pan-tissue or tissue-specific nature of these associations is lacking. Here, we show that low-methylated regions (LMRs) which are highly bound by PRC2 in embryonic stem cells (PRC2 LMRs) gain methylation with age in all examined somatic mitotic cells. We estimated that this epigenetic change represents around 90% of the age-dependent DNAm gain genome-wide. Therefore, we propose the “PRC2-AgeIndex,” defined as the average DNAm in PRC2 LMRs, as a universal biomarker of cellular aging in somatic cells which can distinguish the effect of different anti-aging interventions. DNA methylation (DNAm) is a key biomarker of aging, with age-related DNAm changes being well-characterized. Here, the authors show that low-methylated regions (LMRs) bound by PRC2 in embryonic stem cells gain methylation with age in somatic cells, proposing the “PRC2-AgeIndex” as a universal biomarker of cellular aging.

Epigenetic Clocks have been trained to predict chronological age, healthspan and lifespan. Such clocks are often analysed in relation to disease outcomes – typically using small datasets and a limited number of clocks. Here, we present a large-scale ( n  = 18,859), unbiased comparison of 14 widely used clocks as predictors of 174 incident disease outcomes and all-cause mortality over 10-years of follow up. Second- and third-generation clocks significantly outperform first-generation clocks, which have limited applications in disease settings. Of the 176 Bonferroni significant (P < 0.05/174) associations from fully-adjusted Cox regression models controlling for lifestyle and socioeconomic measures, there are 27 diseases (including primary lung cancer and diabetes) where the hazard ratio for the clock exceeds the clock’s association with all-cause mortality. Furthermore, for 32 of the 176 findings, adding the clock to a null classification model with traditional risk factors significantly increases the classification accuracy by >1%. However, there is minimal evidence for interactions between the clocks and sex or smoking (ever/never) status. Second- and third-generation epigenetic clocks show promise for disease risk prediction, particularly in relation to respiratory and liver-based conditions. Epigenetic clocks estimate biological age and health risks. Here, the authors compare 14 clocks in 18,859 individuals, showing second-generation clocks better predict disease incidence and mortality, particularly for respiratory and liver-related conditions.

Quantifying the overall magnitude of every single locus’ genetic effect on the widely measured human phenome is of great challenge. We introduce a unified modelling technique that can consistently provide a total genetic contribution assessment (TGCA) of a gene or genetic variant without thresholding genetic association signals. Genome-wide TGCA in five UK Biobank phenotype domains highlights loci such as the HLA locus for medical conditions, the bone mineral density locus WNT16 for physical measures, and the skin tanning locus MC1R and smoking behaviour locus CHRNA3 for lifestyle. Tissue-specificity investigation reveals several tissues associated with total genetic contributions, including the brain tissues for mental health. Such associations are driven by tissue-specific gene expressions, which share genetic basis with the total genetic contributions. TGCA can provide a genome-wide atlas for the overall genetic contributions in each particular domain of human complex traits. Quantifying the effects of individual loci on the human phenome is a challenging task. Here, the authors introduce a modelling technique, TGCA, that assesses total genetic contribution per locus and apply this to UK Biobank phenotype domains, revealing top loci and links to tissue-specific gene expression.

Specialized ribosomes help determine which proteins are synthesized, however, the influence of age on ribosome heterogeneity and whether dysregulation of this process drives organismal aging is unknown. Here we examined the role of ribosomal RNA (rRNA) methylation in maintaining appropriate translation as organisms age. In a directed RNAi screen, we identified 18S rRNA N6’-dimethyl adenosine (m 6,2 A) methyltransferase, dimt-1 , as a regulator of C. elegans lifespan and stress resistance. We demonstrate that DIMT-1 functions in the germline after mid-life to regulate lifespan. Depletion of dimt-1 leads to selective translation of transcripts important for stress resistance and lifespan regulation in the C. elegans germline including the cytochrome P450 daf-9 , which synthesizes a steroid that signals from the germline to the soma. dimt-1 induced lifespan extension is dependent on the daf-9 signaling pathway. Our findings highlight ribosome heterogeneity, and specific rRNA modifications, in maintaining appropriate translation later in life to promote healthy aging. Here the authors show that rRNA methylase DIMT-1 regulates aging by acting after mid-life in the germline, regulating specialized ribosomes that perform selective translation of mRNAs important for longevity. Thus revealing an additional layer of proteome dysfunction as an aging regulator.

While previous studies identified common genetic variants associated with longevity in centenarians, the role of the rare loss-of-function (LOF) mutation burden remains largely unexplored. Here, we investigated the burden of rare LOF mutations in Ashkenazi Jewish individuals from the Longevity Genes Project and LonGenity study cohorts using whole-exome sequencing data. We found that centenarians had a significantly lower burden (11-22%) of LOF mutations compared to controls. Similar effects were also observed in their offspring. Gene-level burden analysis identified 35 genes with depleted LOF mutations in centenarians, with 14 of these validated in the UK Biobank. Mendelian randomization and multi-omic analyses on these genes identified RGP1 , PCNX2 , and ANO9 as longevity genes with consistent causal effects on multiple aging-related traits and altered expression during aging. Our findings suggest that a protective genetic background, characterized by a reduced burden of damaging variants, contributes to exceptional longevity, likely acting in concert with specific protective variants to promote healthy aging. Previous studies have identified common genetic variants linked to longevity, but the impact of rare damaging mutations remains unclear. Here, the authors show that centenarians carry fewer harmful loss-of-function mutations and identify genes that may contribute to extreme longevity and healthy aging

Recent epigenome-wide studies have identified a large number of genomic regions that consistently exhibit changes in their methylation status with aging across diverse populations, but the functional consequences of these changes are largely unknown. On the other hand, transcriptomic changes are more easily interpreted than epigenetic alterations, but previously identified age-related gene expression changes have shown limited replicability across populations. Here, we develop an approach that leverages high-resolution multi-omic data for an integrative analysis of epigenetic and transcriptomic age-related changes and identify genomic regions associated with both epigenetic and transcriptomic age-dependent changes in blood. Our results show that these multi-omic aging genes in blood are enriched for adaptive immune functions, replicate more robustly across diverse populations and are more strongly associated with aging-related outcomes compared to the genes identified using epigenetic or transcriptomic data alone. These multi-omic aging genes may serve as targets for epigenetic editing to facilitate cellular rejuvenation. DNA methylation and gene expression data integration identify aging-related genes in blood that predict health outcomes, offering new insights into aging biology and potential therapeutic targets.

BackgroundEpidemiological studies revealed that the elderly and those with comorbidities are most affected by COVID-19, but it is important to investigate shared genetic mechanisms between COVID-19 risk and aging.MethodsWe conducted a multi-instrument Mendelian Randomization analysis of multiple lifespan-related traits and COVID-19. Aging clock models were applied to the subjects with different COVID-19 conditions in the UK-Biobank cohort. We performed a bivariate genomic scan for age-related COVID-19 and Mendelian Randomization analysis of 389 immune cell traits to investigate their effect on lifespan and COVID-19 risk.ResultsWe show that the genetic variation that supports longer life is significantly associated with the lower risk of COVID-19 infection and hospitalization. The odds ratio is 0.31 (P = 9.7 × 10−6) and 0.46 (P = 3.3 × 10−4), respectively, per additional 10 years of life. We detect an association between biological age acceleration and future incidence and severity of COVID-19 infection. Genetic profiling of age-related COVID-19 infection indicates key contributions of Notch signaling and immune system development. We reveal a negative correlation between the effects of immune cell traits on lifespan and COVID-19 risk. We find that lower B-cell CD19 levels are indicative of an increased risk of COVID-19 and decreased life expectancy, which is further validated by COVID-19 clinical data.ConclusionsOur analysis suggests that the factors that accelerate aging lead to an increased COVID-19 risk and point to the importance of Notch signaling and B cells in both. Interventions that target these factors to reduce biological age may reduce the risk of COVID-19.Plain Language SummaryOlder adults and those with comorbidities are more likely to develop severe COVID-19 if infected with SARS-CoV-2. In this study, we investigate the genetic factors underlying the link between aging and COVID-19. Using data on the genetic variation between individuals and statistical methods to allow us to determine causality, we find that genetic variation associated with longer lifespan is associated with reduced risk of COVID-19 infection and hospitalization. We also find that acceleration of biological age (i.e., the age of your body based on physiological measurements rather than time) is associated with future incidence and severity of COVID-19, and identify some of the key cells and molecules involved in aging-related COVID-19 risk. Our study helps to characterize the relationship between aging and COVID-19, which may help to identify strategies to protect or treat older adults.

Mitochondrial diseases represent a spectrum of disorders caused by impaired mitochondrial function, ranging in severity from mortality during infancy to progressive adult-onset disease. Mitochondrial dysfunction is also recognized as a molecular hallmark of the biological ageing process. Rapamycin, a drug that increases lifespan and health during normative ageing, also increases survival and reduces neurological symptoms in a mouse model of the severe mitochondrial disease Leigh syndrome. The Ndufs4 knockout ( Ndufs4 − / − ) mouse lacks the complex I subunit NDUFS4 and shows rapid onset and progression of neurodegeneration mimicking patients with Leigh syndrome. Here we show that another drug that extends lifespan and delays normative ageing in mice, acarbose, also suppresses symptoms of disease and improves survival of Ndufs4 − / − mice. Unlike rapamycin, acarbose rescues disease phenotypes independently of inhibition of the mechanistic target of rapamycin. Furthermore, rapamycin and acarbose have additive effects in delaying neurological symptoms and increasing maximum lifespan in Ndufs4 − / − mice. We find that acarbose remodels the intestinal microbiome and alters the production of short-chain fatty acids. Supplementation with tributyrin, a source of butyric acid, recapitulates some effects of acarbose on lifespan and disease progression, while depletion of the endogenous microbiome in Ndufs4 − / − mice appears to fully recapitulate the effects of acarbose on healthspan and lifespan in these animals. To our knowledge, this study provides the first evidence that alteration of the gut microbiome plays a significant role in severe mitochondrial disease and provides further support for the model that biological ageing and severe mitochondrial disorders share underlying common mechanisms. Alterations in the gut microbiome, as a result of treatment with the anti-diabetic drug acarbose or with antibiotics, are shown to extend healthspan and lifespan in a mouse model of Leigh syndrome.