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.

Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE Phase 2) screening and recruitment: methods and results.

The Comprehensive Assessment of the Long-term Effects of Reducing Intake of Energy Phase 2 (CALERIE) study is a systematic investigation of sustained 25% calorie restriction (CR) in non-obese humans. CALERIE is a multicenter (3 clinical sites, one coordinating center), parallel group, randomized controlled trial. Participants were recruited, screened, and randomized to the CR or control group with a 2:1 allocation. Inclusion criteria included ages 21-50 years for men and 21-47 years for women, and a body mass index (BMI) of 22.0 ≤ BMI < 28.0 kg/m(2). Exclusion criteria included abnormal laboratory markers, significant medical conditions, psychiatric/behavioral problems, and an inability to adhere to the rigors of the evaluation/intervention schedule. A multi-stage screening process (telephone screen and 3 in-clinic visits) was applied to identify eligible participants. Recruitment was effective and enrollment targets were met on time. 10,856 individuals contacted the clinical sites, of whom 9787 (90%) failed one or more eligibility criteria. Of the 1069 volunteers who started the in-clinic screening, 831 (78%) were either ineligible or dropped. 238 volunteers were enrolled (i.e., initiated the baseline evaluations), 220 were randomized, and 218 started the assigned intervention (2% from the first screening step). This study offered lessons for future multi-center trials engaging non-disease populations. Recruitment strategies must be tailored to specific sites. A multi-disciplinary screening process should be applied to address medical, physical, and psychological/behavioral suitability of participants. Finally, a multi-step screening process with simple criteria first, followed by more elaborate procedures has the potential to reduce the use of study resources.

Predictors of 90-day outcome in patients stabilized after acute coronary syndromes.

AIMS: We investigated predictors of 90-day risk among patients surviving the early period after an acute coronary syndrome (ACS). METHODS AND RESULTS: The study population included 15 904 stabilized ST-segment elevation or non-ST-segment elevation ACS patients randomized in SYMPHONY and 2nd SYMPHONY. We developed risk models for death, death or myocardial infarction (MI), and death, MI, or severe recurrent ischaemia (SRI) using Cox proportional-hazards techniques. Demographic, history, and pre-randomization clinical and medication variables were tested. Validation techniques included development of individual trial models, backward elimination and bootstrapping. Of 118 variables, 17 independently predicted mortality. The strongest associations included greater age (chi(2)=31.1), higher randomization heart rate (chi(2)=27.4), and heart failure (HF) variables (HF between qualifying event and randomization, chi(2)=21.8; history of HF, chi(2)=12.2). Higher creatinine clearance (chi(2)=17.7) and percutaneous coronary intervention between qualifying event and randomization (chi(2)=11.1) most strongly predicted lower risk. Similar characteristics entered the double and triple composite models, but HF variables and age less strongly predicted these end-points. CONCLUSIONS: In patients stabilized after ACS, those at highest risk over the next 90 days can be identified. Typical clinical markers are better at identifying risk of death than non-fatal MI or SRI. Novel risk markers are needed for these outcomes.

Prediction of cardiac mortality after myocardial infarction: the role of maximal treadmill stress echocardiography.

Patients frequently undergo low-level exercise treadmill testing after acute myocardial infarction (MI) and, in the absence of inducible ischemia, a maximal test several weeks later. This study examines 203 patients who had 2-dimensional echocardiography before and after a maximal Bruce protocol exercise treadmill test performed 4 to 6 weeks after MI. The subjects were followed for a mean of 43 months (range 1 to 77 months). Predictors of cardiac mortality by multivariate or univariate analysis included an ejection fraction < or =40%, diabetes, age > or=70 years, and ischemia by exercise echocardiography but not by electrocardiography. Therefore, standard electrocardiographic monitoring during exercise treadmill testing 6 weeks after MI fails to predict cardiac mortality. The addition of pre-exercise and post-exercise treadmill stress echocardiography to readily available clinical parameters identifies those patients at greatest risk for cardiac death (resting ejection fraction < or=40%) and detects residual exercise-induced ischemia that may be of additional prognostic value.

Secondary sexual characteristics and menses in young girls seen in office practice: a study from the Pediatric Research in Office Settings network.

OBJECTIVE: To determine the current prevalence and mean ages of onset of pubertal characteristics in young girls seen in pediatric practices in the United States. METHODS: A cross-sectional study was conducted by 225 clinicians in pediatric practices belonging to Pediatric Research in Office Settings, a practice-based research network. After standardized training in the assessment of pubertal maturation, practitioners rated the level of sexual maturation on girls 3 through 12 years who were undergoing complete physical examinations. RESULTS: Data were analyzed for 17,077 girls, of whom 9.6% were African-American and 90.4% white. At age 3, 3% of African-American girls and 1% of white girls showed breast and/or pubic hair development, with proportions increasing to 27.2% and 6.7%, respectively, at 7 years of age. At age 8, 48.3% of African-American girls and 14.7% of white girls had begun development. At every age for each characteristic, African-American girls were more advanced than white girls. The mean ages of onset of breast development for African-American and white girls were 8.87 years (SD, 1.93) and 9.96 years (SD, 1.82), respectively; and for pubic hair development, 8.78 years (SD, 2.00) and 10.51 years (SD, 1.67), respectively. Menses occurred at 12.16 years (SD, 1.21) in African-American girls and 12.88 years (SD, 1.20) of age in white girls. CONCLUSIONS: These data suggest that girls seen in a sample of pediatric practices from across the United States are developing pubertal characteristics at younger ages than currently used norms. Practitioners may need to revise their criteria for referral of girls with precocious puberty, with attention to racial differences.