The CALERIE™ Genomic Data Resource.

Caloric restriction (CR) slows biological aging and prolongs healthy lifespan in model organisms. Findings from CALERIE-2™ - the first ever randomized, controlled trial of long-term CR in healthy, non-obese humans - broadly supports a similar pattern of effects in humans. To expand our understanding of the molecular pathways and biological processes underpinning CR effects in humans, we generated a series of genomic datasets from stored biospecimens collected from n=218 participants during the trial. These data constitute the first publicly-accessible genomic data resource for a randomized controlled trial of an intervention targeting the biology of aging. Datasets include whole-genome SNP genotypes, and three-timepoint-longitudinal DNA methylation, mRNA, and small RNA datasets generated from blood, skeletal muscle, and adipose tissue samples (total sample n=2327). The CALERIE Genomic Data Resource described in this article is available from the Aging Research Biobank. This mult-itissue, multi-omic, longitudinal data resource has great potential to advance translational geroscience.

Cognitive Polygenic Index is Associated with Occupational Complexity over and above Brain Morphometry.

Although the impact of occupation on cognitive skills has been extensively studied, there is limited research examining if genetically predicted cognitive score may influence occupation. We examined the association between Cognitive Polygenic Index (PGI) and occupation, including the role of brain measures. Participants were recruited for the Reference Ability Neural Network and the Cognitive Reserve studies. Occupational complexity ratings for Data, People, or Things came from the Dictionary of Occupational Titles. A previously-created Cognitive PGI and linear regression models were used for the analyses. Age, sex, education, and the first 20 genetic Principal Components (PCs) of the sample were covariates. Total cortical thickness and total gray matter volume were further covariates. We included 168 white-ethnicity participants, 20-80 years old. After initial adjustment, higher Cognitive PGI was associated with higher Data complexity (B=-0.526, SE = 0.227, Beta= -0.526 p = 0.022, R2 = 0.259) (lower score implies higher complexity). Associations for People or Things were not significant. After adding brain measures, association for Data remained significant (B=-0.496, SE: 0.245, Beta= -0.422, p = 0.045, R2 = 0.254). Similarly, for a further, fully-adjusted analysis including all the three occupational complexity measures (B=-0.568, SE = 0.237, Beta= -0.483, p = 0.018, R2 = 0.327). Cognitive genes were associated with occupational complexity over and above brain morphometry. Working with Data occupational complexity probably acquires higher cognitive status, which can be significantly genetically predetermined.

Pace of Aging in older adults matters for healthspan and lifespan.

As societies age, policy makers need tools to understand how demographic aging will affect population health and to develop programs to increase healthspan. The current metrics used for policy analysis do not distinguish differences caused by early-life factors, such as prenatal care and nutrition, from those caused by ongoing changes in people's bodies due to aging. Here we introduce an adapted Pace of Aging method designed to quantify differences between individuals and populations in the speed of aging-related health declines. The adapted Pace of Aging method, implemented in data from N=13,626 older adults in the US Health and Retirement Study, integrates longitudinal data on blood biomarkers, physical measurements, and functional tests. It reveals stark differences in rates of aging between population subgroups and demonstrates strong and consistent prospective associations with incident morbidity, disability, and mortality. Pace of Aging can advance the population science of healthy longevity.

Effect of long-term caloric restriction on DNA methylation measures of biological aging in healthy adults from the CALERIE trial.

The geroscience hypothesis proposes that therapy to slow or reverse molecular changes that occur with aging can delay or prevent multiple chronic diseases and extend healthy lifespan1-3. Caloric restriction (CR), defined as lessening caloric intake without depriving essential nutrients4, results in changes in molecular processes that have been associated with aging, including DNA methylation (DNAm)5-7, and is established to increase healthy lifespan in multiple species8,9. Here we report the results of a post hoc analysis of the influence of CR on DNAm measures of aging in blood samples from the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE) trial, a randomized controlled trial in which n = 220 adults without obesity were randomized to 25% CR or ad libitum control diet for 2 yr (ref. 10). We found that CALERIE intervention slowed the pace of aging, as measured by the DunedinPACE DNAm algorithm, but did not lead to significant changes in biological age estimates measured by various DNAm clocks including PhenoAge and GrimAge. Treatment effect sizes were small. Nevertheless, modest slowing of the pace of aging can have profound effects on population health11-13. The finding that CR modified DunedinPACE in a randomized controlled trial supports the geroscience hypothesis, building on evidence from small and uncontrolled studies14-16 and contrasting with reports that biological aging may not be modifiable17. Ultimately, a conclusive test of the geroscience hypothesis will require trials with long-term follow-up to establish effects of intervention on primary healthy-aging endpoints, including incidence of chronic disease and mortality18-20.

Associations of socioeconomic disparities with buccal DNA-methylation measures of biological aging.

BACKGROUND: Individuals who are socioeconomically disadvantaged are at increased risk for aging-related diseases and perform less well on tests of cognitive function. The weathering hypothesis proposes that these disparities in physical and cognitive health arise from an acceleration of biological processes of aging. Theories of how life adversity is biologically embedded identify epigenetic alterations, including DNA methylation (DNAm), as a mechanistic interface between the environment and health. Consistent with the weathering hypothesis and theories of biological embedding, recently developed DNAm algorithms have revealed profiles reflective of more advanced aging and lower cognitive function among socioeconomically-at-risk groups. These DNAm algorithms were developed using blood-DNA, but social and behavioral science research commonly collect saliva or cheek-swab DNA. This discrepancy is a potential barrier to research to elucidate mechanisms through which socioeconomic disadvantage affects aging and cognition. We therefore tested if social gradients observed in blood DNAm measures could be reproduced using buccal-cell DNA obtained from cheek swabs. RESULTS: We analyzed three DNAm measures of biological aging and one DNAm measure of cognitive performance, all of which showed socioeconomic gradients in previous studies: the PhenoAge and GrimAge DNAm clocks, DunedinPACE, and Epigenetic-g. We first computed blood-buccal cross-tissue correlations in n = 21 adults (GEO111165). Cross-tissue correlations were low-to-moderate (r = .25 to r = .48). We next conducted analyses of socioeconomic gradients using buccal DNAm data from SOEP-G (n = 1128, 57% female; age mean = 42 yrs, SD = 21.56, range 0-72). Associations of socioeconomic status with DNAm measures of aging were in the expected direction, but were smaller as compared to reports from blood DNAm datasets (r = - .08 to r = - .13). CONCLUSIONS: Our findings are consistent with the hypothesis that socioeconomic disadvantage is associated with DNAm indicators of worse physical health. However, relatively low cross-tissue correlations and attenuated effect sizes for socioeconomic gradients in buccal DNAm compared with reports from analysis of blood DNAm suggest that in order to take full advantage of buccal DNA samples, DNAm algorithms customized to buccal DNAm are needed.

Polygenic indices for cognition in healthy aging; the role of brain measures.

Background: Genome-wide association studies (GWAS) have identified large numbers of genetic variants associated with cognition. However, little is known about how these genetic discoveries impact cognitive aging. Methods: We conducted polygenic-index (PGI) analysis of cognitive performance in n = 168 European-ancestry adults aged 20-80. We computed PGIs based on GWAS of cognitive performance in young/middle-aged and older adults. We tested associations of the PGI with cognitive performance, as measured through neuropsychological evaluation. We explored whether these associations were accounted for by magnetic resonance imaging (MRI) measures of brain-aging phenotypes: total gray matter volume (GM), cortical thickness (CT), and white matter hyperintensities burden (WMH). Results: Participants with higher PGI values performed better on cognitive tests (B = 0.627, SE = 0.196, p = 0.002) (age, sex, and principal components as covariates). Associations remained significant with inclusion of covariates for MRI measures of brain aging; B = 0.439, SE: 0.198, p = 0.028). PGI associations were stronger in young and middle-aged (age<65) as compared to older adults. For further validation, linear regression for Cog PGI and cognition in the fully adjusted model and adding the interaction between age group and Cog PGI, showed significant results (B = 0.892, SE: 0.325, p = 0.007) driven by young and middle-aged adults (B = -0.403, SE: 0.193, p = 0.039). In ancillary analysis, the Cognitive PGI was not associated with any of the brain measures. Conclusions: Genetics discovered in GWAS of cognition are associated with cognitive performance in healthy adults across age, but most strongly in young and middle-aged adults. Associations were not explained by brain-structural markers of brain aging. Genetics uncovered in GWAS of cognitive performance may contribute to individual differences established relatively early in life and may not reflect genetic mechanisms of cognitive aging.

Biological aging in maltreated children followed up into middle adulthood.

BACKGROUND: Childhood adversity has been linked to many indicators of shorter healthy lifespan, including earlier onset of disease and disability as well as early mortality. These observations suggest the hypothesis that childhood maltreatment may accelerate aging. OBJECTIVE: To characterize the relationship between childhood maltreatment and accelerated biological aging in a prospective cohort of 357 individuals with documented cases of childhood maltreatment and 250 controls matched on demographic and socioeconomic factors. METHODS: Cases were drawn from juvenile and adult court records from the years 1967 through 1971 in a large Midwest metropolitan geographic area. Cases were defined as having court-substantiated cases of childhood physical or sexual abuse, or neglect occurring at age 11 or younger. Controls were selected from the same schools and hospitals of birth and matched on age, sex, race, and approximate socioeconomic status. We compared biological aging in these two groups using two blood-chemistry algorithms, the Klemera-Doubal method Biological Age (KDM BA) and the PhenoAge. Algorithms were developed and validated in data from the National Health and Nutrition Examination Surveys (NHANES) using published methods and publicly available software. RESULTS: Participants (55% women, 49% non-White) had mean age of 41 years (SD=4). Those with court substantiated childhood maltreatment history exhibited more advanced biological aging as compared with matched controls, although this difference was statistically different for only the KDM BA measure (KDM BA Cohen's D=0.20, 95% CI=[0.03,0.36], p = 0.02; PhenoAge Cohen's D=0.09 95% CI=[-0.08,0.25], p = 0.296). In subgroup analyses, maltreatment effect sizes were larger for women as compared to men and for White participants as compared to non-White participants, although these differences were not statistically significant at the α= 0.05 level. CONCLUSIONS AND RELEVANCE: As of midlife, effects of childhood maltreatment on biological aging are small in magnitude but discernible. Interventions to treat psychological and behavioral sequelae of exposure to childhood maltreatment, including in midlife adults, have potential to protect survivors from excess burden of disease, disability, and mortality in later life.

Association between genetic and socioenvironmental risk for schizophrenia during upbringing in a UK longitudinal cohort.

BACKGROUND: Associations of socioenvironmental features like urbanicity and neighborhood deprivation with psychosis are well-established. An enduring question, however, is whether these associations are causal. Genetic confounding could occur due to downward mobility of individuals at high genetic risk for psychiatric problems into disadvantaged environments. METHODS: We examined correlations of five indices of genetic risk [polygenic risk scores (PRS) for schizophrenia and depression, maternal psychotic symptoms, family psychiatric history, and zygosity-based latent genetic risk] with multiple area-, neighborhood-, and family-level risks during upbringing. Data were from the Environmental Risk (E-Risk) Longitudinal Twin Study, a nationally-representative cohort of 2232 British twins born in 1994-1995 and followed to age 18 (93% retention). Socioenvironmental risks included urbanicity, air pollution, neighborhood deprivation, neighborhood crime, neighborhood disorder, social cohesion, residential mobility, family poverty, and a cumulative environmental risk scale. At age 18, participants were privately interviewed about psychotic experiences. RESULTS: Higher genetic risk on all indices was associated with riskier environments during upbringing. For example, participants with higher schizophrenia PRS (OR = 1.19, 95% CI = 1.06-1.33), depression PRS (OR = 1.20, 95% CI = 1.08-1.34), family history (OR = 1.25, 95% CI = 1.11-1.40), and latent genetic risk (OR = 1.21, 95% CI = 1.07-1.38) had accumulated more socioenvironmental risks for schizophrenia by age 18. However, associations between socioenvironmental risks and psychotic experiences mostly remained significant after covariate adjustment for genetic risk. CONCLUSION: Genetic risk is correlated with socioenvironmental risk for schizophrenia during upbringing, but the associations between socioenvironmental risk and adolescent psychotic experiences appear, at present, to exist above and beyond this gene-environment correlation.

Healthy ageing: the natural consequences of good nutrition-a conference report.

Many countries are witnessing a marked increase in longevity and with this increased lifespan and the desire for healthy ageing, many, however, suffer from the opposite including mental and physical deterioration, lost productivity and quality of life, and increased medical costs. While adequate nutrition is fundamental for good health, it remains unclear what impact various dietary interventions may have on prolonging good quality of life. Studies which span age, geography and income all suggest that access to quality foods, host immunity and response to inflammation/infections, impaired senses (i.e., sight, taste, smell) or mobility are all factors which can limit intake or increase the body's need for specific micronutrients. New clinical studies of healthy ageing are needed and quantitative biomarkers are an essential component, particularly tools which can measure improvements in physiological integrity throughout life, thought to be a primary contributor to a long and productive life (a healthy "lifespan"). A framework for progress has recently been proposed in a WHO report which takes a broad, person-centered focus on healthy ageing, emphasizing the need to better understand an individual's intrinsic capacity, their functional abilities at various life stages, and the impact by mental, and physical health, and the environments they inhabit.

Genetics and Crime: Integrating New Genomic Discoveries Into Psychological Research About Antisocial Behavior.

Drawing on psychological and sociological theories of crime causation, we tested the hypothesis that genetic risk for low educational attainment (assessed via a genome-wide polygenic score) is associated with criminal offending. We further tested hypotheses of how polygenic risk relates to the development of antisocial behavior from childhood through adulthood. Across the Dunedin and Environmental Risk (E-Risk) birth cohorts of individuals growing up 20 years and 20,000 kilometers apart, education polygenic scores predicted risk of a criminal record with modest effects. Polygenic risk manifested during primary schooling in lower cognitive abilities, lower self-control, academic difficulties, and truancy, and it was associated with a life-course-persistent pattern of antisocial behavior that onsets in childhood and persists into adulthood. Crime is central in the nature-nurture debate, and findings reported here demonstrate how molecular-genetic discoveries can be incorporated into established theories of antisocial behavior. They also suggest that improving school experiences might prevent genetic influences on crime from unfolding.

Which adolescents develop persistent substance dependence in adulthood? Using population-representative longitudinal data to inform universal risk assessment.

BACKGROUND: To our knowledge, there are no universal screening tools for substance dependence that (1) were developed using a population-based sample, (2) estimate total risk briefly and inexpensively by incorporating a relatively small number of well-established risk factors, and (3) aggregate risk factors using a simple algorithm. We created a universal screening tool that incorporates these features to identify adolescents at risk for persistent substance dependence in adulthood. METHOD: Participants were members of a representative cohort of 1037 individuals born in Dunedin, New Zealand in 1972-1973 and followed prospectively to age 38 years, with 95% retention. We assessed a small set of childhood and adolescent risk factors: family history of substance dependence, childhood psychopathology (conduct disorder, depression), early exposure to substances, frequent substance use in adolescence, sex, and childhood socioeconomic status. We defined the outcome (persistent substance dependence in adulthood) as dependence on one or more of alcohol, tobacco, cannabis, or hard drugs at ⩾3 assessment ages: 21, 26, 32, and 38 years. RESULTS: A cumulative risk index, a simple sum of nine childhood and adolescent risk factors, predicted persistent substance dependence in adulthood with considerable accuracy (AUC = 0.80). CONCLUSIONS: A cumulative risk score can accurately predict which adolescents in the general population will develop persistent substance dependence in adulthood.

Leptin deficiency in maltreated children.

Consistent with findings from experimental research in nonhuman primates exposed to early-life stress, children exposed to maltreatment are at high risk of detrimental physical health conditions, such as obesity and systemic inflammation. Because leptin is a key molecule involved in the regulation of both energy balance and immunity, we investigated abnormalities in leptin physiology among maltreated children. We measured leptin, body mass index and C-reactive protein in 170 12-year-old children members of the Environmental-Risk Longitudinal Twin Study, for whom we had prospectively-collected information on maltreatment exposure. We found that maltreated children exhibited blunted elevation in leptin levels in relation to increasing levels of physiological stimuli, adiposity and inflammation, compared with a group of non-maltreated children matched for gender, zygosity and socioeconomic status. These findings were also independent of key potential artifacts and confounders, such as time of day at sample collection, history of food insecurity, pubertal maturation and depressive symptoms. Furthermore, using birth weight as a proxy measure for leptin, we found that physiological abnormalities were presumably not present at birth in children who went on to be maltreated but only emerged over the course of childhood, after maltreatment exposure. Leptin deficiency may contribute to onset, persistence and progression of physical health problems in maltreated children.

Heavy drinking in early adulthood and outcomes at mid life.

BACKGROUND: Heavy drinking in early adulthood among Blacks, but not Whites, has been found to be associated with more deleterious health outcomes, lower labor market success and lower educational attainment at mid-life. This study analysed psychosocial pathways underlying racial differences in the impact of early heavy alcohol use on occupational and educational attainment at mid-life. METHODS: Outcomes in labor market participation, occupational prestige and educational attainment were measured in early and mid-adulthood. A mixture model was used to identify psychosocial classes that explain how race-specific differences in the relationship between drinking in early adulthood and occupational outcomes in mid-life operate. Data came from Coronary Artery Risk Development in Young Adults, a longitudinal epidemiologic study. RESULTS: Especially for Blacks, heavy drinking in early adulthood was associated with a lower probability of being employed in mid-life. Among employed persons, there was a link between heavy drinking for both Whites and Blacks and decreased occupational attainment at mid-life. We grouped individuals into three distinct distress classes based on external stressors and indicators of internally generated stress. Blacks were more likely to belong to the higher distressed classes as were heavy drinkers in early adulthood. Stratifying the data by distress class, relationships between heavy drinking, race and heavy drinking-race interactions were overall weaker than in the pooled analysis. CONCLUSIONS: Disproportionate intensification of life stresses in Blacks renders them more vulnerable to long-term effects of heavy drinking.

Case report: diabetes mellitus as a predisposing factor in the development of pyomyositis.

Pyomyositis is an uncommon infection in temperate climates, usually resulting from Staphylococcus aureus infection of skeletal muscle. In this report, the authors describe a patient with untreated Type 2 diabetes mellitus who suffered nonpenetrating blunt trauma to his left anterior thigh, and S. aureus pyomyositis and secondary osteomyelitis of his proximal tibia and patella subsequently developed as a result of delayed diagnosis and treatment. Patients with diabetes mellitus are at increased risk for the development of pyomyositis because of more frequent S. aureus colonization of skin, nasal mucosa, and oropharynx; a delay in definitive treatment can lead to significant morbidity in these patients. Computed tomography or magnetic resonance imaging may be helpful in the diagnosis of pyomyositis. An anemia of chronic disease may result from this disorder, which resolves with treatment.

Prenatal care and maternal health during adolescent pregnancy: a review and meta-analysis.

PURPOSE: A meta-analysis and review of pregnancy complications and behavioral risk factors associated with infant low birth weight and other poor outcomes which occur during adolescent pregnancy was undertaken using the published literature. METHODS: Studies were eligible for inclusion if they: 1) utilized a clearly defined sample of teenagers 2) provided numeric data on complications of interest or the proportions needed to compute this information 3) included a control or comparison group. RESULTS: Many behavioral risk factors (smoking, drinking and drug use) appeared to be less prevalent among teenage gravidas, particularly when the young women were ethnic minorities. An increased risk of preterm delivery was associated with young maternal age in both developed and developing countries. In the developed world, risk of cesarean delivery was reduced for teenagers and there was a secular decline in maternal anemia and pregnancy induced hypertension in comparison to the risk sustained by more mature women. Programs of comprehensive prenatal care appeared to have the potential to diminish risk of many complications. In the developing world, teenagers were at increased risk of maternal anemia, preterm birth and cesarean delivery. CONCLUSIONS: Although future research efforts will need to address the issues of bias inherent in much of the published research, the published literature suggests that prenatal care regimens which provide social and behavioral services along with medical care could improve both the health of the mother and the outcome of her pregnancy.

PIP: A meta-analysis of pregnancy complications and behavioral risk factors associated with infant low birth weight during adolescent pregnancy was undertaken using the published literature. Studies were included which 1) utilized a clearly defined sample of teenagers 2) provided numeric data on complications 3) included a control or comparison group. Many behavioral risk factors (smoking, drinking and drug use) appeared to be less prevalent among teenage gravidas, particularly when the young women were ethnic minorities. Teenagers enrolled in comprehensive programs of prenatal care showed a diminished risk of pregnancy-induced hypertension (PIH) in comparison to those enrolled in traditional care programs. The summary relative risk for PIH with comprehensive prenatal care was 0.59. Current publications indicated a slight, but not statistically significant, recent diminution in risk of anemia for those with young maternal age (Summary Relative Risk = 0.80). There was no overall increase in risk of anemia with young maternal age (Summary Relative Risk = 1.13). The overall relative risk for the eight controlled clinical studies reporting information on maternal anemia was 2.00 for a significant overall association between anemia and young maternal age, both currently in developing countries and in the past in the developed world. Apart from disproportion in young black women, other complications of labor and delivery where the relative risk was at least 10% higher in teenagers compared with mature women included fever, seizures, and, for whites, fetal distress. Rates at least 10% lower included those for placenta previa, precipitous labor, breech or malpresentation, and, for blacks, cord prolapse and complications of anaesthesia. Overall, the summary relative risk showed a diminution in preterm delivery with comprehensive care, after adjustment for study and time (Summary Relative Risk = 0.81). The published literature suggests that prenatal care regiments which provide social and behavioral services along with medical care could improve both the health of the mother and the outcome of her pregnancy.

Rate and amount of weight gain during adolescent pregnancy: associations with maternal weight-for-height and birth weight.

This study presents information on the course and rates of weight gain and the associations among weight gain, prepregnancy weight-for-height, and infant birth weight, based on a total sample of 1419 uncomplicated term deliveries to adolescents. The distribution of cumulative weight gain indicates that for adolescents not only is the median gain at term (14.2-15.5 kg) significantly in excess of that reported for adults, but also weight-gain velocity is greater from the beginning of pregnancy. Although the contributions of prepregnancy weight-for-height and weight gain to birth weight may be independent, they are not necessarily additive. Birth weight does not appear improved for the infants of overweight adolescents except when weight gain is low (less than 11.1-12.3 kg at term), and, for Puerto Rican and black adolescents, birth weight is not further improved at any maternal prepregnancy body mass index (weight-for-height) with excessive weight gains (greater than 17.9-19.3 kg at term).

Laparoscopic tubal sterilization. The potential for thermal bowel injury.

One of the most severe complications of laparoscopic tubal sterilization is bowel burns, although they often go undetected at the time of laparoscopy. Controversy remains over whether these injuries are caused directly by operator error or indirectly from a hot oviduct's or instrument's inadvertently touching and burning the intestine. A study was performed to determine the potential for direct or indirect bowel burns using bipolar electrocoagulation in rabbits. The results indicate that neither a hot tube nor hot (recently used) forceps could cause injuries to the serosal surface of the intestine. That was true both of immediate injury and after one to five days of recovery. It was observed that the hot uterine tube caused significant bowel adhesions by five days after the procedure. Direct electrocoagulation of the bowel using 40 W for three seconds caused a minor, noticeable blanch on the bowel that was not detectable with gross or histologic means after one day of recovery. A direct bowel injury did result when 80 W was used for three seconds; the bowel became perforated after one day. These findings indicate that it is unlikely that one can produce a bowel burn indirectly from a hot uterine tube or instrument and that only a direct insult to the bowel appears to cause an injury. However, adhesions could be a complication of the procedure and should be considered.