Genetic Determinants of Amidating Enzyme Activity and its Relationship with Metal Cofactors in Human Serum

Abstract BACKGROUND: α-amidation is a final, essential step in the biosynthesis of about half of all peptide hormones and neurotransmitters. Peptidylglycine α-amidating monooxygenase (PAM), with enzymatic domains that utilize Cu and Zn, is the only enzyme that catalyzes this reaction. PAM activity is detected in serum, but its significance and utility as a clinical biomarker remain unexplored. METHODS: We used well-established enzymatic assays specific for the peptidylglycine-α -hydroxylating monooxygenase (PHM) and peptidyl-α-hydroxyglycine α-amidating lyase (PAL) domains of PAM to quantify amidating activity in the sera of 144 elderly men. Relationships between PHM and PAL activity and serum levels of their respective active-site metals, Cu and Zn, were analyzed. Study participants were also genotyped for eight non-coding single nucleotide polymorphisms (SNPs) in PAM, and relationships between genotype and serum enzyme activity and metal levels were analyzed. RESULTS: Serum PHM and PAL activities were normally distributed and correlated linearly with each other. Serum PAL activity, but not serum PHM activity, correlated with serum Cu; neither activity correlated with serum Zn. Study subjects possessing the minor alleles for rs32680 had lower PHM and PAL activities, and subjects with minor alleles for rs11952361 and rs10515341 had lower PHM activities. CONCLUSIONS: Our results characterize large variation in serum amidating activity and provide unique insight into its potential origin and determinants. Common non-coding polymorphisms affect serum amidating activity and Cu levels. Serum amidating activity should be explored as a biomarker for functionality in the elderly and in additional study groups

Are Baby Boomers Who Care for their Older Parents Planning for their Own Future Long-Term Care Needs?

A rapidly expanding number of baby boomers provide care to aging parents. This study examines associations between caregiver status and outcomes related to awareness and anticipation of future long-term care (LTC) needs using 2007 Connecticut Long-Term Care Needs Assessment survey data. Baby boomers who were adult child caregivers (n = 353) vs. baby boomers who were not (n = 1242) were more likely to anticipate some future LTC needs and to have considered certain financing strategies. Although baby boomer adult child caregivers more readily anticipate some future LTC needs, they are not taking specific actions. It is important to address the need for public education directed towards those who are currently (or have recently completed) caring for aging parents

The 6-Minute Walk is Associated With Frailty and Predicts Mortality in Older Adults With Heart Failure

Heart failure is the most rapidly increasing cardiovascular disease in the US and the primary discharge diagnosis for Medicare recipients. There are approximately 5.7 million people who have the diagnosis of HF in the US.1 Heart failure constitutes the most common cause for re-hospitalization and has been identified by the Medicare Payment Advisory Commission as the highest cost to the healthcare system.2, 3 Hospitalizations of older patients can result in functional deterioration leading to dependency and disability.4, 5 Due to the unpredictable trajectory of heart failure exacerbations it is difficult to discern which patients are at the greatest risk for repeat hospitalizations, functional decline and mortality. The frailty syndrome defined as a poor ability to cope with physiological stress, has demonstrated a strong association with a diagnosis of heart failure in observational studies.5–9 Frail patients with or without heart failure often experience functional decline and have an increased risk of death compared to their more robust counterparts. The difficulty has been to identify patients who are frail in order to increase resources available to these patients in hopes of improving health outcomes. There is no direct clinical test to measure frailty, and the challenge is to identify proxy measures which can serve as an indicator of this vulnerable state. Since heart failure and frailty have an association, patients with heart failure are an ideal population to study to further understand frailty. We have previously found an association between frailty, poor endurance, vitamin D, and C-reactive protein in a cross-sectional analysis of patients with heart failure.10 This study is a 4 year follow up of the original cohort of patients to determine if measures of frailty and endurance are useful predictors of outcomes in older patients with heart failure

Effects of Varenicline, Nicotine or Placebo on Depressive Symptoms in Postmenopausal Smokers

Background Varenicline carries a black box warning for neuropsychiatric adverse events. Objective We examined varenicline use and past history of major depressive disorder (MDD) on depressive symptoms during smoking cessation. Method This is a secondary analysis of two smoking cessation studies in 152 postmenopausal women who received placebo or nicotine patch, or 78 women who received varenicline with relaxation. Lifetime history of MDD (LH-MDD) was assessed at baseline and women with current MDD were excluded. Center for Epidemiologic Study Depression scale (CESD) measured depressive symptoms at baseline, 6 and 12 weeks. Results Baseline CESD scores were 5.3 + 4.4. Those with a LH-MDD reported higher CESD scores (p \u3e.001). Those taking varenicline reported lower scores over all time periods compared to nicotine or placebo (p \u3c.01). The differences between varenicline and the other treatments remained when controlling for LH-MDD, indicating an independent effect. CESD scores were associated with concurrent smoking status (p \u3c.001), and with withdrawal symptoms (p \u3c.001). Conclusion CESD score were lower in those receiving varenicline, whether this is due to an anti-depressant effect, subject selection, use of relaxation or another cause is unknown. Varenicline does not increase depressive symptoms during smoking cessation in postmenopausal women without current MDD. Subjects with a LH-MDD are susceptible to developing depressive symptoms during smoking cessation, regardless of pharmacologic aid

High Serum Cu and Cu/Zn Ratios Correlate with Impairments in Bone Density, Physical Performance and Overall Health in a Population of Elderly Men With Frailty Characteristics

Serum Cu levels rise with age and high Cu/Zn ratios are linked with multiple-cause mortality in the elderly. The relationships of these parameters to measures of musculoskeletal health and frailty have not yet been analyzed. We used inductively coupled mass spectrometry to assess serum levels of Cu and Zn and probed for relationships between serum Cu levels and the Cu/Zn ratio with specific measures of bone, physical and overall health in a cohort of 144 frail elderly men. Subjects were divided into quintiles based on serum metal levels and comparisons for functional measures were made between the reference (middle) group and the low and high groups. Subjects’ serum metal values were normally distributed. We found significant correlations between high Cu/Zn ratios and deficits in femoral bone mineral density, measures of speed and strength, muscle mass and hematocrit. High Cu/Zn ratios were also correlated with decreased triglycerides and increased reliance on ADL assistance. This study identifies specific deficits associated with high Cu/Zn ratios that span multiple organ systems and supports earlier studies indicating that serum Cu levels and the Cu/Zn ratio may serve as useful predictive biomarkers for poor health in the elderly

Adequate Dietary Protein is Associated with Better Physical Performance Among Post-menopausal Women 60–90 years

Objectives Sarcopenia, the involuntary loss of skeletal muscle with age, affects up to one-quarter of older adults. Evidence indicates a positive association between dietary protein intake and lean muscle mass and strength among older persons, but information on dietary protein’s effect on physical performance in older adults has received less attention. Design Cross-sectional observational analysis of the relationship of dietary protein on body composition and physical performance. Setting Clinical research center. Participants 387 healthy women aged 60 – 90 years (mean 72.7 ± 7.0 y). Measurements Measures included body composition (fat-free mass, appendicular skeletal mass and fat mass) via dual x-ray absorptiometry (DXA), physical performance (Physical Performance Test [PPT] and Short Physical Performance Battery [SPPB]), handgrip strength, Physical Activity Scale in the Elderly (PASE), quality of life measure (SF-8), falls, fractures, nutrient and macromolecule intake (four-day food record). Independent samples t-tests determined mean differences between the above or below RDA protein groups. Statistical Analysis Analysis of covariance was used to control for body mass index (BMI) between groups when assessing physical performance, physical activity and health-related quality of life. Results The subjects consumed an average of 72.2 g protein/day representing 1.1 g protein/kg body weight/day. Subjects were categorized as below the recommended daily allowance (RDA) for protein (defined as less than 0.8 g protein/kg) or at or above the RDA (equal to or higher than 0.8 g protein/kg). Ninety-seven subjects (25%) were in the low protein group, and 290 (75%) were in the higher protein group. Women in the higher protein group had lower body mass, including fat and lean mass, and fat-to-lean ratio than those in the lower-protein group (p \u3c0.001). Composite scores of upper and lower extremity strength were impaired in the group with low protein intake; SPPB score was 9.9±1.9 compared to 10.6±1.6 in those with higher protein intake and PPT was 19.8± 2.9 compared to 20.9± 2.1 in the low and higher protein groups, respectively. The results were attenuated by correction for BMI, but remained significant. The physical component of the SF-8 was also lower in the low protein group but did not remain significant when controlling for BMI. No significant differences were found in hand grip strength or reported physical activity. Conclusion Healthy, older postmenopausal women consumed, on average, 1.1 g/kg/d protein, although 25% consumed less than the RDA. Those in the low protein group had higher body fat and fat-to-lean ratio than those who consumed the higher protein diet. Upper and lower extremity function was impaired in those who consumed a low protein diet compared to those with a higher protein intake. Protein intake should be considered when evaluating the multi-factorial loss of physical function in older women