Improving human healthspan in our rapidly aging population has never been more imperative. Telomeres, protective \"caps\" at the ends of linear chromosomes, are essential for maintaining genome stability of eukaryotic genomes. Due to their physical location and the \"end-replication problem\" first envisioned by Dr. Alexey Olovnikov, telomeres shorten with cell division, the implications of which are remarkably profound. Telomeres are hallmarks and molecular drivers of aging, as well as fundamental integrating components of the cumulative effects of genetic, lifestyle, and environmental factors that erode telomere length over time. Ongoing telomere attrition and the resulting limit to replicative potential imposed by cellular senescence serves a powerful tumor suppressor function, and also underlies aging and a spectrum of age-related degenerative pathologies, including reduced fertility, dementias, cardiovascular disease and cancer. However, very little data exists regarding the extraordinary stressors and exposures associated with long-duration space exploration and eventual habitation of other planets, nor how such missions will influence telomeres, reproduction, health, disease risk, and aging. Here, we briefly review our current understanding, which has advanced significantly in recent years as a result of the NASA Twins Study, the most comprehensive evaluation of human health effects associated with spaceflight ever conducted. Thus, the Twins Study is at the forefront of personalized space medicine approaches for astronauts and sets the stage for subsequent missions. We also extrapolate from current understanding to future missions, highlighting potential biological and biochemical strategies that may enable human survival, and consider the prospect of longevity in the extreme environment of space.

Research into clinical applications of speech-based emotion recognition (SER) technologies has been steadily increasing over the past few years. One such potential application is the automatic recognition of expressed emotion (EE) components within family environments. The identification of EE is highly important as they have been linked with a range of adverse life events. Manual coding of these events requires time-consuming specialist training, amplifying the need for automated approaches. Herein we describe an automated machine learning approach for determining the degree of warmth, a key component of EE, from acoustic and text natural language features. Our dataset of 52 recorded interviews is taken from recordings, collected over 20 years ago, from a nationally representative birth cohort of British twin children, and was manually coded for EE by two researchers (inter-rater reliability 0.84-0.90). We demonstrate that the degree of warmth can be predicted with an F1-score of 64.7% despite working with audio recordings of highly variable quality. Our highly promising results suggest that machine learning may be able to assist in the coding of EE in the near future.

Cognitive decline and spinal pain (back pain [BP] and neck pain [NP]) represent a major public health challenge, yet the potential relationship between them remains elusive. A retrospective analysis of the Longitudinal Study of Ageing Danish Twins was performed to determine any potential relationships between BP/NP and cognitive function adjusting for age, sex, educational and socioeconomic status. A total of 4731 adults (2788 females/1943 males) aged 78 ± 6 (SD) years were included in the analysis. We observed a 1-month prevalence of 25% with BP, 21% with NP and 11% for combined BP/NP. While there were no differences in cognition scores for males and females reporting combined BP/NP, compared to those without combined BP/NP (34.38 points [95% confidence interval (CI) = 31.88, 36.88] vs. 35.72 points [95% CI = 35.19, 36.26]; P = 0.180; and 35.72 points [95% CI = 35.19, 36.26] vs. 35.85 points [95% CI = 35.39, 36.31]; P = 0.327; for male and females, respectively), an adjusted analysis revealed that males with combined BP/NP presented with lower cognitive scores compared to males without combined BP/NP (81.26 points [95% CI = 73.80, 88.72] vs. 79.48 points [95% CI = 70.31, 88.66]; P = 0.043). The findings of this hypothesis-generating study may highlight a potential sex-specific association between spinal pain and later-life neurodegeneration.

Recent state-of-the-art sequencing technologies enable the investigation of challenging regions in the human genome and expand the scope of variant benchmarking datasets. Herein, we sequence a Chinese Quartet, comprising two monozygotic twin daughters and their biological parents, using four short and long sequencing platforms (Illumina, BGI, PacBio, and Oxford Nanopore Technology).
The long reads from the monozygotic twin daughters are phased into paternal and maternal haplotypes using the parent-child genetic map and for each haplotype. We also use long reads to generate haplotype-resolved whole-genome assemblies with completeness and continuity exceeding that of GRCh38. Using this Quartet, we comprehensively catalogue the human variant landscape, generating a dataset of 3,962,453 SNVs, 886,648 indels (< 50 bp), 9726 large deletions (≥ 50 bp), 15,600 large insertions (≥ 50 bp), 40 inversions, 31 complex structural variants, and 68 de novo mutations which are shared between the monozygotic twin daughters. Variants underrepresented in previous benchmarks owing to their complexity-including those located at long repeat regions, complex structural variants, and de novo mutations-are systematically examined in this study.
In summary, this study provides high-quality haplotype-resolved assemblies and a comprehensive set of benchmarking resources for two Chinese monozygotic twin samples which, relative to existing benchmarks, offers expanded genomic coverage and insight into complex variant categories.

The causes of obsessive-compulsive disorder (OCD) remain unknown. Gene-searching efforts are well underway, but the identification of environmental risk factors is at least as important and should be a priority because some of them may be amenable to prevention or early intervention strategies. Genetically informative studies, particularly those employing the discordant monozygotic (MZ) twin design, are ideally suited to study environmental risk factors. This protocol paper describes the study rationale, aims, and methods of OCDTWIN, an open cohort of MZ twin pairs who are discordant for the diagnosis of OCD.
OCDTWIN has two broad aims. In Aim 1, we are recruiting MZ twin pairs from across Sweden, conducting thorough clinical assessments, and building a biobank of biological specimens, including blood, saliva, urine, stool, hair, nails, and multimodal brain imaging. A wealth of early life exposures (e.g., perinatal variables, health-related information, psychosocial stressors) are available through linkage with the nationwide registers and the Swedish Twin Registry. Blood spots stored in the Swedish phenylketonuria (PKU) biobank will be available to extract DNA, proteins, and metabolites, providing an invaluable source of biomaterial taken at birth. In Aim 2, we will perform within-pair comparisons of discordant MZ twins, which will allow us to isolate unique environmental risk factors that are in the causal pathway to OCD, while strictly controlling for genetic and early shared environmental influences. To date (May 2023), 43 pairs of twins (21 discordant for OCD) have been recruited.
OCDTWIN hopes to generate unique insights into environmental risk factors that are in the causal pathway to OCD, some of which have the potential of being actionable targets.

Twin samples allow to conduct a quasi-experimental co-twin case-control approach that can control for genetic and environmental confounding in brain-cognition associations, being more informative on causality compared with studies in unrelated individuals. We conducted a review of studies that have utilized discordant co-twin design to investigate the associations of brain imaging markers of Alzheimer\'s disease and cognition. Inclusion criteria encompassed twin pairs discordant for cognition or Alzheimer\'s disease imaging markers and reporting of within-twin pair comparison on the association between cognition and brain measures. Our PubMed search (2022 April 23, updated 2023 March 9) resulted in 18 studies matching these criteria. Alzheimer\'s disease imaging markers have been addressed only by few studies, most with small sample size. Structural magnetic resonance imaging studies have indicated greater hippocampal volume and thicker cortex in co-twins with better cognitive performance compared with their co-twins with poorer cognitive performance. No studies have looked at cortical surface area. Positron emission tomography imaging studies have suggested that lower cortical glucose metabolism rate and higher cortical neuroinflammation, amyloid, and tau accumulations are related to poorer episodic memory in within-twin pair comparisons. Thus far, only cross-sectional within-twin pair associations of cortical amyloid and hippocampal volume with cognition have been replicated.

Although epigenome-wide association studies (EWAS) have been successful in identifying DNA methylation (DNAm) patterns associated with disease states, any further characterization of etiologic mechanisms underlying disease remains elusive. This knowledge gap does not originate from a lack of DNAm-trait associations, but rather stems from study design issues that affect the interpretability of EWAS results. Despite known limitations in predicting the function of a particular CpG site, most EWAS maintain the broad assumption that altered DNAm results in a concomitant change of transcription at the most proximal gene. This study integrated DNAm and gene expression (GE) measurements in two cohorts, the Adolescent and Young Adult Twin Study (AYATS) and the Pregnancy, Race, Environment, Genes (PREG) study, to improve the understanding of epigenomic regulatory mechanisms. CpG sites associated with GE in cis were enriched in areas of transcription factor binding and areas of intermediate-to-low CpG density. CpG sites associated with trans GE were also enriched in areas of known regulatory significance, including enhancer regions. These results highlight issues with restricting DNAm-transcript annotations to small genomic intervals and question the validity of assuming a cis DNAm-GE pathway. Based on these findings, the interpretation of EWAS results is limited in studies without multi-omic support and further research should identify genomic regions in which GE-associated DNAm is overrepresented. An in-depth characterization of GE-associated CpG sites could improve predictions of the downstream functional impact of altered DNAm and inform best practices for interpreting DNAm-trait associations generated by EWAS.

Because longitudinal studies of aging typically lack cognitive data from earlier ages, it is unclear how general cognitive ability (GCA) changes throughout the life course. In 1173 Vietnam Era Twin Study of Aging (VETSA) participants, we assessed young adult GCA at average age 20 and current GCA at 3 VETSA assessments beginning at average age 56. The same GCA index was used throughout. Higher young adult GCA and better GCA maintenance were associated with stronger specific cognitive abilities from age 51 to 73. Given equivalent GCA at age 56, individuals who had higher age 20 GCA outperformed those whose GCA remained stable in terms of memory, executive function, and working memory abilities from age 51 to 73. Thus, paradoxically, despite poorer maintenance of GCA, high young adult GCA still conferred benefits. Advanced predicted brain age and the combination of elevated vascular burden and APOE-ε4 status were associated with poorer maintenance of GCA. These findings highlight the importance of distinguishing between peak and current GCA for greater understanding of cognitive aging.

Lens and skin fluorescence are related to the systemic accumulation of advanced glycation end products, which is accelerated in diabetes. We have examined lens fluorescence and skin fluorescence in healthy adult twins. The study enrolled twins aged median 59 years from a national population-based registry. Diabetic individuals were excluded from analysis. The interrelatedness between fluorescence parameters and relations between fluorescence and age, current HbA1c and smoking pack years were examined using correlation tests and mixed model linear regression analyses. Broad-sense heritability was analyzed and compared for lens fluorescence, skin fluorescence and HbA1c. Lens fluorescence and skin fluorescence were crudely interrelated (R = 0.38). In linear regression analyses, age explained a larger fraction of the variance in lens fluorescence (R2 = 32%) than in skin fluorescence (R2 = 20%), whereas HbA1c explained smaller variance fractions (R2 = 3% and 8%, respectively) followed by smoking pack years (4% and 3%, respectively). In multivariate analyses, age, HbA1c and smoking pack years combined explained more of the variance in lens fluorescence (R2 = 35%) than in skin fluorescence (R2 = 21%), but the influence of HbA1c on lens fluorescence was not statistically significant (p = .2). Age-adjusted broad-sense heritability was 85% for lens fluorescence, 53% for skin fluorescence and 71% for HbA1c in best fitting heritability models. Both fluorescence parameters increased with age, current glycemia and cumulative smoking. Lens fluorescence was found to be a predominantly heritable trait, whereas skin fluorescence was more influenced by environmental factors and closer related to current glycemia. The results suggest that skin fluorophores have a faster turn-over than lens fluorophores.

The gut microbiome is hypothesised to be related to insulin resistance and other metabolic variables. However, data from population-based studies are limited. We investigated associations between serologic measures of metabolic health and the gut microbiome in the Northern Finland Birth Cohort 1966 (NFBC1966) and the TwinsUK cohort.
Among 506 individuals from the NFBC1966 with available faecal microbiome (16S rRNA gene sequence) data, we estimated associations between gut microbiome diversity metrics and serologic levels of HOMA for insulin resistance (HOMA-IR), HbA1c and C-reactive protein (CRP) using multivariable linear regression models adjusted for sex, smoking status and BMI. Associations between gut microbiome diversity measures and HOMA-IR and CRP were replicated in 1140 adult participants from TwinsUK, with available faecal microbiome (16S rRNA gene sequence) data. For both cohorts, we used general linear models with a quasi-Poisson distribution and Microbiome Regression-based Kernel Association Test (MiRKAT) to estimate associations of metabolic variables with alpha- and beta diversity metrics, respectively, and generalised additive models for location scale and shape (GAMLSS) fitted with the zero-inflated beta distribution to identify taxa associated with the metabolic markers.
In NFBC1966, alpha diversity was lower in individuals with higher HOMA-IR with a mean of 74.4 (95% CI 70.7, 78.3) amplicon sequence variants (ASVs) for the first quartile of HOMA-IR and 66.6 (95% CI 62.9, 70.4) for the fourth quartile of HOMA-IR. Alpha diversity was also lower with higher HbA1c (number of ASVs and Shannon\'s diversity, p < 0.001 and p = 0.003, respectively) and higher CRP (number of ASVs, p = 0.025), even after adjustment for BMI and other potential confounders. In TwinsUK, alpha diversity measures were also lower among participants with higher measures of HOMA-IR and CRP. When considering beta diversity measures, we found that microbial community profiles were associated with HOMA-IR in NFBC1966 and TwinsUK, using multivariate MiRKAT models, with binomial deviance dissimilarity p values of <0.001. In GAMLSS models, the relative abundances of individual genera Prevotella and Blautia were associated with HOMA-IR in both cohorts.
Overall, higher levels of HOMA-IR, CRP and HbA1c were associated with lower microbiome diversity in both the NFBC1966 and TwinsUK cohorts, even after adjustment for BMI and other variables. These results from two distinct population-based cohorts provide evidence for an association between metabolic variables and gut microbial diversity. Further experimental and mechanistic insights are now needed to provide understanding of the potential causal mechanisms that may link the gut microbiota with metabolic health.