Cardiovascular variability, sociodemographics, and biomarkers of disease: the MIDUS study.

Introduction: Like heart rate, blood pressure (BP) is not steady but varies over intervals as long as months to as short as consecutive cardiac cycles. This blood pressure variability (BPV) consists of regularly occurring oscillations as well as less well-organized changes and typically is computed as the standard deviation of multiple clinic visit-to-visit (VVV-BP) measures or from 24-h ambulatory BP recordings (ABPV). BP also varies on a beat-to-beat basis, quantified by methods that parse variation into discrete bins, e.g., low frequency (0.04-0.15 Hz, LF). However, beat-to-beat BPV requires continuous recordings that are not easily acquired. As a result, we know little about the relationship between LF-BPV and basic sociodemographic characteristics such as age, sex, and race and clinical conditions. Methods: We computed LF-BPV during an 11-min resting period in 2,118 participants in the Midlife in the US (MIDUS) study. Results: LF-BPV was negatively associated with age, greater in men than women, and unrelated to race or socioeconomic status. It was greater in participants with hypertension but unrelated to hyperlipidemia, hypertriglyceridemia, diabetes, elevated CRP, or obesity. LF-diastolic BPV (DBPV), but not-systolic BPV (SBPV), was negatively correlated with IL-6 and s-ICAM and positively correlated with urinary epinephrine and cortisol. Finally, LF-DBPV was negatively associated with mortality, an effect was rendered nonsignificant by adjustment by age but not other sociodemographic characteristics. Discussion: These findings, the first from a large, national sample, suggest that LF-BPV differs significantly from VVV-BP and ABPV. Confirming its relationship to sociodemographic risk factors and clinical outcomes requires further study with large and representative samples.

Dietary flavanols restore hippocampal-dependent memory in older adults with lower diet quality and lower habitual flavanol consumption.

Dietary flavanols are food constituents found in certain fruits and vegetables that have been linked to cognitive aging. Previous studies suggested that consumption of dietary flavanols might specifically be associated with the hippocampal-dependent memory component of cognitive aging and that memory benefits of a flavanol intervention might depend on habitual diet quality. Here, we tested these hypotheses in the context of a large-scale study of 3,562 older adults, who were randomly assigned to a 3-y intervention of cocoa extract (500 mg of cocoa flavanols per day) or a placebo [(COcoa Supplement and Multivitamin Outcomes Study) COSMOS-Web, NCT04582617]. Using the alternative Healthy Eating Index in all participants and a urine-based biomarker of flavanol intake in a subset of participants [n = 1,361], we show that habitual flavanol consumption and diet quality at baseline are positively and selectively correlated with hippocampal-dependent memory. While the prespecified primary end point testing for an intervention-related improvement in memory in all participants after 1 y was not statistically significant, the flavanol intervention restored memory among participants in lower tertiles of habitual diet quality or habitual flavanol consumption. Increases in the flavanol biomarker over the course of the trial were associated with improving memory. Collectively, our results allow dietary flavanols to be considered in the context of a depletion-repletion paradigm and suggest that low flavanol consumption can act as a driver of the hippocampal-dependent component of cognitive aging.

Multivitamin Supplementation Improves Memory in Older Adults: A Randomized Clinical Trial.

BACKGROUND: Maintenance of cognitive abilities is of critical importance to older adults, yet few effective strategies to slow cognitive decline currently exist. Multivitamin supplementation is used to promote general health; it is unclear whether it favorably affects cognition in older age. OBJECTIVES: To examine the effect of daily multivitamin/multimineral supplementation on memory in older adults. METHODS: The COcoa Supplement and Multivitamin Outcomes Study Web (COSMOS-Web) ancillary study (NCT04582617) included 3562 older adults. Participants were randomly assigned to a daily multivitamin supplement (Centrum Silver) or placebo and evaluated annually with an Internet-based battery of neuropsychological tests for 3 y. The prespecified primary outcome measure was change in episodic memory, operationally defined as immediate recall performance on the ModRey test, after 1 y of intervention. Secondary outcome measures included changes in episodic memory over 3 y of follow-up and changes in performance on neuropsychological tasks of novel object recognition and executive function over 3 y. RESULTS: Compared with placebo, participants randomly assigned to multivitamin supplementation had significantly better ModRey immediate recall at 1 y, the primary endpoint (t(5889) = 2.25, P = 0.025), as well as across the 3 y of follow-up on average (t(5889) = 2.54, P = 0.011). Multivitamin supplementation had no significant effects on secondary outcomes. Based on cross-sectional analysis of the association between age and performance on the ModRey, we estimated that the effect of the multivitamin intervention improved memory performance above placebo by the equivalent of 3.1 y of age-related memory change. CONCLUSIONS: Daily multivitamin supplementation, compared with placebo, improves memory in older adults. Multivitamin supplementation holds promise as a safe and accessible approach to maintaining cognitive health in older age. This trial was registered at clinicaltrials.gov as NCT04582617.

Anatomical biology guides a search for nutrients for the aging brain.

Considerable evidence has established the importance of specific nutrients that have been found vital for the developing brain. We hypothesize that in a similar manner there should be nutrients vital to the aging brain and that based on aging's distinct pathophysiology they should be different than those essential to development. Specific brain networks that govern cognition are particularly vulnerable to the aging process, resulting in what is referred to as 'cognitive aging'. Common late-life disorders, however, such as Alzheimer's disease also target these same brain networks. Studies have disambiguated cognitive aging from late-life disease by isolating regions and biological pathways within each network differentially linked to one or the other. This anatomical biology anchors a framework to identify nutrients and/or dietary bioactives relevant to cognitive aging whose utility is illustrated via a decades-long research program into how dietary bioactive flavanols benefit the brain. As we are living longer in cognitively more demanding lives, the framework's ultimate goal is to generate specific dietary recommendations that will fortify our mind for its golden years.

Obstructive sleep apnea, myocardial perfusion and myocardial blood flow: A study of older male twins.

BACKGROUND: Obstructive sleep apnea (OSA) has been associated with incidence of cardiovascular disease and with nocturnal angina, but evidence of a link with coronary atherosclerosis and myocardial ischemia is limited and previous studies may have been affected by selection bias or unmeasured confounding factors. METHODS: We performed overnight polysomnography in 178 older male twins. The Apnea/Hypopnea Index (AHI) was calculated to assess OSA from the overnight sleep evaluation. AHI ≥15 was used as indicator of moderate/severe OSA. The following day, twins underwent myocardial perfusion imaging with [82Rb]-chloride positron emission tomography. Quantitative and semiquantitative measures of myocardial perfusion and absolute myocardial blood flow were obtained. RESULTS: The mean age was 68 years and 40% of the sample had an AHI≥15, which indicates moderate to severe OSA. Abnormal myocardial perfusion, both with stress and at rest, was more common in twins with elevated AHI. After adjusting for clinical, lifestyle and behavioral factors, and previous history of cardiovascular disease, twins with AHI ≥15 had 3.6 higher odds (95% CI, 1.5-8.9) of an abnormal total severity score, defined as a score ≥100, and for each 5-point increment in AHI, the odds of abnormality increased by 20% (95% CI, 7%-34%). Twin pairs where both twins had OSA exhibited the greatest risk. There were no differences in measures of ischemia and absolute myocardial blood flow and flow reserve by AHI status. CONCLUSIONS: OSA is associated with myocardial perfusion abnormalities that suggest prior subclinical myocardial scarring or infarction. Early environmental factors that affect both twins equally may play a role and should be further explored.

Association of the 2020 US Presidential Election With Hospitalizations for Acute Cardiovascular Conditions.

Importance: Prior studies found a higher risk of acute cardiovascular disease (CVD) around population-wide psychosocial or environmental stressors. Less is known about acute CVD risk in relation to political events. Objective: To examine acute CVD hospitalizations following the 2020 presidential election. Design, Setting, and Participants: This retrospective cohort study examined acute CVD hospitalizations following the 2020 presidential election. Participants were adult members aged 18 years or older at Kaiser Permanente Southern California and Kaiser Permanente Northern California, 2 large, integrated health care delivery systems. Statistical analysis was performed from March to July 2021. Exposure: 2020 US presidential election. Main Outcomes and Measures: Hospitalizations for acute CVD around the 2020 presidential election were examined. CVD was defined as hospitalizations for acute myocardial infarction (AMI), heart failure (HF), or stroke. Rate ratios (RR) and 95% CIs were calculated comparing rates of CVD hospitalization in the 5 days following the 2020 election with the same 5-day period 2 weeks prior. Results: Among 6 396 830 adults (3 970 077 [62.1%] aged 18 to 54 years; 3 422 479 [53.5%] female; 1 083 128 [16.9%] Asian/Pacific Islander, 2 101 367 [32.9%] Hispanic, and 2 641 897 [41.3%] White), rates of hospitalization for CVD following the election (666 hospitalizations; rate = 760.5 per 100 000 person-years [PY]) were 1.17 times higher (95% CI, 1.05-1.31) compared with the same 5-day period 2 weeks prior (569 hospitalizations; rate = 648.0 per 100 000 PY). Rates of AMI were significantly higher following the election (RR, 1.42; 95% CI, 1.13-1.79). No significant difference was found for stroke (RR, 1.02; 95% CI, 0.86-1.21) or HF (RR, 1.18; 95% CI, 0.98-1.42). Conclusions and Relevance: Higher rates of acute CVD hospitalization were observed following the 2020 presidential election. Awareness of the heightened risk of CVD and strategies to mitigate risk during notable political events are needed.

Association of Depressive Symptoms with Sleep Disturbance: A Co-twin Control Study.

BACKGROUND: Few studies have comprehensively evaluated the association of depression with sleep disturbance using a controlled twin study design. PURPOSE: To cross-sectionally evaluate the association of depression with both objective and subjective sleep disturbance. METHODS: We studied 246 members of the Vietnam Era Twin Registry. We measured depressive symptoms using the Beck Depression Inventory-II (BDI) and assessed major depression using structured clinical interviews. Twins underwent one-night polysomnography and 7-day actigraphy to derive measures of objective sleep and completed the Pittsburgh Sleep Quality Index for subjective sleep. Multivariable mixed-effects models were used to examine the association. RESULTS: Twins were all male, mostly white (97%), with a mean (SD) age of 68 (2). The mean (SD) BDI was 5.9 (6.3), and 49 (20%) met the criteria for major depression. For polysomnography, each 5-unit higher BDI, within-pair, was significantly associated with 19.7 min longer rapid eye movement (REM) sleep latency, and 1.1% shorter REM sleep after multivariable adjustment. BDI was not associated with sleep architecture or sleep-disordered breathing. For actigraphy, a higher BDI, within-pair, was significantly associated with lower sleep efficiency, more fragmentation and higher variability in sleep duration. BDI was associated with almost all dimensions of self-reported sleep disturbance. Results did not differ by zygosity, and remained consistent using major depression instead of BDI and were independent of the presence of comorbid posttraumatic stress disorder and antidepressant use. CONCLUSIONS: Depression is associated with REM sleep disruption in lab and sleep fragmentation and sleep variability at home, but not with sleep architecture or sleep-disordered breathing.

Cognitive impairment and World Trade Centre-related exposures.

On 11 September 2001 the World Trade Center (WTC) in New York was attacked by terrorists, causing the collapse of multiple buildings including the iconic 110-story 'Twin Towers'. Thousands of people died that day from the collapse of the buildings, fires, falling from the buildings, falling debris, or other related accidents. Survivors of the attacks, those who worked in search and rescue during and after the buildings collapsed, and those working in recovery and clean-up operations were exposed to severe psychological stressors. Concurrently, these 'WTC-affected' individuals breathed and ingested a mixture of organic and particulate neurotoxins and pro-inflammogens generated as a result of the attack and building collapse. Twenty years later, researchers have documented neurocognitive and motor dysfunctions that resemble the typical features of neurodegenerative disease in some WTC responders at midlife. Cortical atrophy, which usually manifests later in life, has also been observed in this population. Evidence indicates that neurocognitive symptoms and corresponding brain atrophy are associated with both physical exposures at the WTC and chronic post-traumatic stress disorder, including regularly re-experiencing traumatic memories of the events while awake or during sleep. Despite these findings, little is understood about the long-term effects of these physical and mental exposures on the brain health of WTC-affected individuals, and the potential for neurocognitive disorders. Here, we review the existing evidence concerning neurological outcomes in WTC-affected individuals, with the aim of contextualizing this research for policymakers, researchers and clinicians and educating WTC-affected individuals and their friends and families. We conclude by providing a rationale and recommendations for monitoring the neurological health of WTC-affected individuals.

Parasympathetic neural activity and the reciprocal regulation of innate antiviral and inflammatory genes in the human immune system.

The vagus nerve mediates parasympathetic nervous system control of peripheral physiological processes including cardiovascular activity and immune response. In mice, tonic vagal activation down-regulates inflammation via nicotinic acetylcholine receptor-mediated inhibition of the pro-inflammatory transcription factor NF-κB in monocyte/macrophages. Because Type I interferon and pro-inflammatory genes are regulated reciprocally at the level of transcription factor activation and cell differentiation, we hypothesized that vagal activity would up-regulate Type I interferon response genes concurrently with inflammatory downregulation in human immune cells. We mapped empirical individual differences in the circulating leukocyte transcriptome and vagal activity indexed by high frequency (0.15-0.40 Hz) heart rate variability (HF-HRV) in 380 participants in the Midlife in the US study. Here we show that promoter-based bioinformatics analyses linked greater HF-HRV to reduced NF-κB activity and increased activity of IRF transcription factors involved in Type I interferon response (independent of ß-antagonists, BMI, smoking, heavy alcohol consumption, and demographic factors). Transcript origin analyses implicated myeloid lineage immune cells as targets, representing per-cell alterations in gene transcription as HF-HRV was not associated with differential prevalence of leukocyte subsets. These findings support the concept of parasympathetic inhibition of pro-inflammatory gene expression in humans and up-regulation of Type I interferons that could augment host defense against viral infections.

Effect of Aerobic Exercise on White Matter Tract Microstructure in Young and Middle-Aged Healthy Adults.

Recent evidence suggests that being physically active can mitigate age-related white matter (WM) changes. In a randomized clinical trial, the effect of 6-month aerobic exercise (AE) or stretching/toning interventions on measures of WM microstructure (WMM) was assessed in a sample of 74 adults aged 20-67 years. Major WM pathways were reconstructed. No significant group-level change in WM tract microstructure following an AE training was observed. Without adjustment for multiple comparisons, an increase in fractional anisotropy (FA) and a decrease in mean diffusivity (MD) of the uncinate fasciculus were observed post-intervention in the AE group in comparison with the stretching group. In the AE group, a significant increase in cardiorespiratory fitness was measured but did not correlate with FA and MD change. The present results of this study are in accordance with similar studies in healthy adults that did not show significant benefit on WMM after participating in an AE program. Clinical Trial Registration: Clinicaltrials.gov identifier, NCT01179958.

Heart Rate Variability and Circulating Inflammatory Markers in Midlife.

Theoretical perspectives and empirical evidence suggest that the parasympathetic nervous system engages in active monitoring and moderating of inflammatory processes. A clearer understanding of the bidirectional communication between the parasympathetic nervous system and the immune system could lead to novel clinical interventions for inflammatory illnesses. The current study used a large (N = 836) nationally representative sample of adults in the United States to investigate the relations between resting parasympathetic modulation of the heart, indexed through both high frequency heart rate variability (HF-HRV) and low frequency heart rate variability (LF-HRV), and six markers of circulating inflammation. Statistical analyses revealed robust inverse relations between HF-HRV and interleukin-6 (IL6), C-reactive protein (CRP), and fibrinogen, with or without covariate adjustment. Similar inverse relations were observed between LF-HRV and IL6 and CRP. No significant relations were observed between HRV and either inflammatory adhesion molecules (E-selectin, intracellular adhesion molecule-1) or soluble IL6 receptor. Results are consistent with the cholinergic anti-inflammatory pathway and suggest that parasympathetic modulation of inflammation through the vagus nerve may act on specific inflammatory molecules more than others.

Psychosis risk individuals show poor fitness and discrepancies with objective and subjective measures.

Exercise is a promising intervention for individuals at clinical high-risk for psychosis (CHR). However, these youth may not be reliable reporters on fitness. There have been no investigations that utilized objective fitness assessment in this population. The present study objectively characterizes the level of fitness in CHR youth, compares the accuracy of self-report measures to objective fitness indices, and explores clinical factors that may influence the accuracy of self-reported measures of fitness. Forty CHR individuals completed an exercise survey and objective indices of fitness (i.e., VO2max and BMI). Forty healthy volunteers completed objective indices of fitness and a structured clinical interview ruling out the presence of psychiatric illness. CHR youth showed greater BMI and lowered VO2max compared to healthy volunteers. In the CHR group, self-report items (perceived fitness) did not reflect objective indices of fitness, whereas specific exercise behaviors (intensity of exercise) showed stronger correlations with objective fitness measurements. Exploratory analyses suggested that symptoms (grandiosity and avolition) related to errors in self-perception. Results indicate that CHR individuals are less fit than controls as indexed by objective measures of fitness and that it is important to consider unique population clinical characteristics when employing self-report data.

Insights into the role of diet and dietary flavanols in cognitive aging: results of a randomized controlled trial.

With the world's population aging, age-related memory decline is an impending cognitive epidemic. Assessing the impact of diet on cognitive aging, we conducted a controlled, randomized, parallel-arm dietary intervention with 211 healthy adults (50-75 years) investigating effects of either a placebo or 260, 510 and 770 mg/day of cocoa flavanols for 12-weeks followed by 8-weeks washout. The primary outcome was a newly-developed object-recognition task localized to the hippocampus' dentate gyrus. Secondary outcomes included a hippocampal-dependent list-learning task and a prefrontal cortex-dependent list-sorting task. The alternative Healthy Eating Index and a biomarker of flavanol intake (gVLM) were measured. In an MRI substudy, hippocampal cerebral blood volume was mapped. Object-recognition and list-sorting performance did not correlate with baseline diet quality and did not improve after flavanol intake. However, the hippocampal-dependent list-learning performance was directly associated with baseline diet quality and improved after flavanol intake, particularly in participants in the bottom tertile of baseline diet quality. In the imaging substudy, a region-of-interest analysis was negative but a voxel-based-analysis suggested that dietary flavanols target the dentate gyrus. While replication is needed, these findings suggest that diet in general, and dietary flavanols in particular, may be associated with memory function of the aging hippocampus and normal cognitive decline.

A Workshop on Cognitive Aging and Impairment in the 9/11-Exposed Population.

The terrorist attacks on 11 September 2001 potentially exposed more than 400,000 responders, workers, and residents to psychological and physical stressors, and numerous hazardous pollutants. In 2011, the World Trade Center Health Program (WTCHP) was mandated to monitor and treat persons with 9/11-related adverse health conditions and conduct research on physical and mental health conditions related to the attacks. Emerging evidence suggests that persons exposed to 9/11 may be at increased risk of developing mild cognitive impairment. To investigate further, the WTCHP convened a scientific workshop that examined the natural history of cognitive aging and impairment, biomarkers in the pathway of neurodegenerative diseases, the neuropathological changes associated with hazardous exposures, and the evidence of cognitive decline and impairment in the 9/11-exposed population. Invited participants included scientists actively involved in health-effects research of 9/11-exposed persons and other at-risk populations. Attendees shared relevant research results from their respective programs and discussed several options for enhancements to research and surveillance activities, including the development of a multi-institutional collaborative research network. The goal of this report is to outline the meeting's agenda and provide an overview of the presentation materials and group discussion.

Taking context to heart: Momentary emotions, menstrual cycle phase, and cardiac autonomic regulation.

Emotions have long been discussed in conjunction with the autonomic nervous system. Most research on emotion-autonomic linkages does not consider sex differences or an evident underlying mechanism for sex differences: menstrual cycle phase. Further, most research is limited to cross-sectional and laboratory studies. The degree to which emotion-autonomic associations manifest in everyday life may be different and may vary by sex and, for women, by menstrual cycle phase. This study employs the ambulatory monitoring of cardiovascular measures (e.g., heart rate and heart rate variability; HRV) and concurrent emotional states (e.g., sadness, stress, anxiety, anger, and happiness) in everyday life to better characterize emotion-autonomic associations as a function of sex and menstrual cycle phase. Participants (N = 174; 87 female) ages 18 to 46 (31.23 ± 6.49) were monitored over a 5-day observation period (one 2- and one 3-day session), using an ambulatory 24-hour electrocardiogram to monitor heart rate and ecological momentary assessment to record emotions every ~30 min. Women were monitored in both the early to mid-follicular and -luteal phases and men in two comparably distanced sessions. Multilevel models indicated that across sex, negative emotions and happiness were associated with elevated heart rate. Relative to men, women exhibited an elevated heart rate and reduced HRV during reports of anger. For women, during the luteal phase, but not follicular phase, momentary sadness, stress, and anxiety predicted increased heart rate and reduced HRV. These findings demonstrate the importance of considering sex and menstrual cycle phase in research investigating emotion-autonomic linkages.

The Impact of Aerobic Training on Cardiovascular Reactivity to and Recovery From Psychological and Orthostatic Challenge.

OBJECTIVE: Elevated cardiovascular reactivity to, and reduced recovery from, challenging events may increase the risk of cardiovascular disease, and exercise training may reduce this reactivity. However, in a randomized controlled trial of aerobic versus strength training in sedentary, healthy young adults, we found no training group differences in reactivity or recovery. Because strength training also may have a reactivity-reducing effect, we conducted a secondary analysis of data from another trial, this time with a wait-list control condition. METHODS: One hundred nineteen healthy, young, sedentary adults were randomized to a 12-week aerobic training program or wait-list control. Before (T1) and after (T2) training and after 4 weeks of sedentary deconditioning (T3), we measured heart rate (HR), heart rate variability, and blood pressure at rest and in response to and recovery from psychological and orthostatic challenge. Data were analyzed using a group (aerobic versus wait-list) by session (T1, T2, and deconditioning) and by period (baseline, psychological challenge, recovery, standing) three-way analysis of variance with prespecified contrasts. RESULTS: Aerobic capacity significantly increased at T2 and decreased at T3 only in the aerobic training group. The groups did not differ on HR, heart rate variability, or blood pressure reactivity to or recovery from challenge. Without baseline adjustment, there were no significant treatment differences in response to challenges. With baseline adjustment, there were significant treatment by session effects for HR (Cohen d = 0.54, p = .002), systolic blood pressure (d = 0.44, p = .014), diastolic blood pressure (d = 0.74, p = .002), and root mean squared successive difference (d = 0.48, p = .006) reactivity from T1 to T2 only for orthostatic challenge: at T2, reactivity in the aerobic group was nonsignificantly reduced, compared with T1. In the wait-list group, reactivity significantly increased after T1. CONCLUSIONS: This study raises further doubt about attenuation of cardiovascular reactivity or enhancement of recovery as a cardioprotective mechanism of aerobic exercise training.Clinical Trial Registration:ClinicalTrials.gov Unique identifier: NCT01335737.

Anterolateral entorhinal cortex volume is associated with memory retention in clinically unimpaired older adults.

The entorhinal cortex is subdivided into anterolateral entorhinal cortex (alERC) and posteromedial entorhinal cortex (pmERC) subregions, which are theorized to support distinct cognitive roles. This distinction is particularly important as the alERC is one of the earliest cortical regions affected by Alzheimer's pathology and related neurodegeneration. The relative associations of alERC/pmERC with neuropsychological test performance have not been examined. We examined how alERC/pmERC volumes differentially relate to performance on 1) the Modified Rey Auditory Learning Test (ModRey), a verbal memory test designed to assess normal/preclinical populations, 2) the Montreal Cognitive Assessment (MoCA), and 3) the National Alzheimer's Coordinating Center neuropsychological battery. We also examined whether alERC/pmERC volumes correlate with Alzheimer's disease cerebrospinal fluid (CSF) biomarkers. In 65 cognitively healthy (CDR = 0) older adults, alERC, but not pmERC, volume was associated with ModRey memory retention. Only alERC volume differentiated between participants who scored above and below the MoCA cutoff score for impairment. Evaluating the MoCA subdomains revealed that alERC was particularly associated with verbal recall. On the National Alzheimer's Coordinating Center battery, both alERC and pmERC volumes were associated with Craft story recall and Benson figure copy, but only alERC volume was associated with Craft story retention and semantic fluency. Neither alERC nor pmERC volume correlated with CSF levels of amyloid or tau, and regression analyses showed that alERC volume and CSF amyloid levels were independently associated with ModRey retention performance. Taken together, these results suggest that the alERC is important for memory performance and that alERC volume differences are related to a pattern of neuropsychological test performance (i.e., impairments in episodic memory and semantic fluency) typically seen in clinical Alzheimer's disease.

Childhood Parental Warmth and Heart Rate Variability in Midlife: Implications for Health.

The current study investigated high-frequency heart rate variability (HF-HRV) as a potential mediator between childhood parental warmth and later health and mortality outcomes. Participants were 1,255 adults (56.9% female). Childhood parental warmth was reported retrospectively at mean age 46; resting HF-HRV was measured at mean age 57; cardiovascular health and self-evaluated health were assessed at mean age 57 and 63, and mortality records extracted at mean age 63. Results revealed a positive association between childhood parental warmth and resting HF-HRV, as well as associations between higher HF-HRV and reduced risk of having a later cardiovascular health problem and of mortality by age 63. Mediation analyses revealed a small significant indirect effect of parental warmth, through HF-HRV, on cardiovascular health.

Mitochondrial respiratory capacity modulates LPS-induced inflammatory signatures in human blood.

Mitochondria modulate inflammatory processes in various model organisms, but it is unclear how much mitochondria regulate immune responses in human blood leukocytes. Here, we examine the effect of i) experimental perturbations of mitochondrial respiratory chain function, and ii) baseline inter-individual variation in leukocyte mitochondrial energy production capacity on stimulated cytokine release and glucocorticoid (GC) sensitivity. In a first cohort, whole blood from 20 healthy women and men was stimulated with increasing concentrations of the immune agonist lipopolysaccharide (LPS). Four inhibitors of mitochondrial respiratory chain Complexes I, III, IV, and V were used (LPS + Mito-Inhibitors) to acutely perturb mitochondrial function, GC sensitivity was quantified using the GC-mimetic dexamethasone (DEX) (LPS + DEX), and the resultant cytokine signatures mapped with a 20-cytokine array. Inhibiting mitochondrial respiration caused large inter-individual differences in LPS-stimulated IL-6 reactivity (Cohen's d = 0.72) and TNF-α (d = 1.55) but only minor alteration in EC50-based LPS sensitivity (d = 0.21). Specifically, inhibiting mitochondrial Complex IV potentiated LPS-induced IL-6 levels by 13%, but inhibited TNF-α induction by 72%, indicating mitochondrial regulation of the IL-6/TNF-α ratio. As expected, DEX treatment suppressed multiple LPS-induced pro-inflammatory cytokines (IFN-γ, IL-6, IL-8, IL-1ß, .TNF-α) by >85% and increased the anti-inflammatory cytokine IL-10 by 80%. Inhibiting Complex I potentiated DEX suppression of IL-6 by a further 12% (d = 0.73), indicating partial mitochondrial modulation of glucocorticoid sensitivity. Finally, to examine if intrinsic mitochondrial respiratory capacity may explain a portion of immune reactivity differences across individuals, we measured biochemical respiratory chain enzyme activities and mitochondrial DNA copy number in isolated peripheral blood mononuclear cells (PBMCs) from a second cohort of 44 healthy individuals in parallel with LPS-stimulated IL-6 and TNF-α response. Respiratory chain .function, particularly Complex IV activity, was positively correlated with LPS-stimulated IL-6 levels (r = 0.45, p = 0.002). Overall, these data provide preliminary evidence that mitochondrial behavior modulates LPS-induced inflammatory cytokine signatures in human blood.