Manipulating the exposome to enable better ageing.

The sum total of life course exposures creates an exposome that has a significant impact on age-related health. Understanding the interplay between exposome factors and the (epi) genome, offers pertinent insights into the ageing process and its relationship with the accumulation of allostatic load. We propose to exploit this to develop a biomimetic approach that will provide insight into how evolution through natural selection in other species has solved many age related human health issues. In particular, we will emphasise the need to reconnect a more mechanistic approach to medical science with a broader natural sciences approach, using biomimetics to mitigate the global burden of age related ill health. In particular, we will discuss how such an approach indicates leverage of the activities of the Nrf 2 gene to enhance health span via reintroduction of the classical 'Food as Medicine' concept, including modulation of the microbiome and the creation of more salutogenic and biophilic environments. Additionally, we will discuss how this approach integrates with novel and developing senotherapies.

Allostatic overload in patients with essential hypertension.

The role of psychosocial stress in the development of essential hypertension has attracted increasing attention in the last decades, even though research findings have been often inconclusive. We specifically investigated allostatic overload (AO) in hypertensive patients using a clinimetric approach. Allostatic overload was assessed by a semi-structured research interview based on clinimetric criteria in 80 consecutive outpatients with essential hypertension (46.3 % females; mean age 62.18 ±â€¯8.59 years; age range 47-74 years) and 80 normotensive matched controls. Three clinical interviews and two self-rating questionnaires for assessing psychological distress and well-being were also administered. Cardiac variables were collected. AO was present in 26 (32.5 %) of the hypertensive patients based on clinical interviewing, and in only 6 normotensive controls (p < .001). Hypertensive patients with AO had significantly higher levels of psychological distress than those without. Further, patients with AO displayed significantly lower levels of well-being and quality of life (p < .001). A significantly greater prevalence of psychosomatic syndromes was found to be associated with the presence of AO (p < .05), whereas no significant association was detected as to psychiatric diagnoses. Significantly greater cardiovascular risk was found among hypertensive patients reporting AO compared to those without (p < .05). The results of this study support the clinical relevance of a psychological assessment of hypertensive patients, with important implications for the non-pharmacological management of hypertension.

Educational attainment and allostatic load in later life: Evidence using genetic markers.

Education is strongly correlated with health outcomes in older adulthood. Whether the impact of education expansion improves health remains unclear due to a lack of clarity over the causal relationship. Previous health research within the social sciences has tended to use specific activities of daily living or self-reported health status. This study uses a broader and objective health measure - allostatic load (AL) - to take into consideration the exposures that accumulate throughout the life course. This paper applies a Mendelian Randomization (MR) approach to identify causality in relation to education on health as measured by AL. Using the Health and Retirement Study 2008 (N=3935), we adopt a polygenic score built from genetic variants associated with years of education. To test whether our analyses violate the exclusion assumption, we further run MR Egger regressions to test for bias from pleiotropy. We also explore the potential pathways between education and AL, including smoking, drinking, marital length, health insurance, etc. Using this genetic instrument, we find a 0.3 unit (19% of a standard deviation) reduction in AL per year of schooling. The effect is mainly driven by BMI and Hba1c. Smoking and marital stability are two potential pathways that also causally influenced by education. If our main and sensitivity analyses are valid, the results find support that a higher level of education is causally related to better health in older adulthood.

Decline in telomere length by age and effect modification by gender, allostatic load and comorbidities in National Health and Nutrition Examination Survey (1999-2002).

BACKGROUND: This study aims to assess the decline in telomere length (TL) with age and evaluate effect modification by gender, chronic stress, and comorbidity in a representative sample of the US population. METHODS: Cross-sectional data on 7826 adults with a TL measurement, were included from the National Health and Nutrition Examination Survey, years 1999-2002. The population rate of decline in TL across 10-year age categories was estimated using crude and adjusted regression. RESULTS: In an adjusted model, the population rate of decline in TL with age was consistent and linear for only three age categories: 20-29 (ß = -0.0172, 95% CI: -0.0342, -0.0002), 50-59 (ß = -0.0182, 95% CI: -0.0311, -0.0054) and 70-79 (ß = -0.0170, 95% CI: -0.0329, -0.0011) years. The population rate of decline in TL with age was significantly greater for males and those with high allostatic load and a history of comorbidities. When the population rate of decline in TL was analyzed by gender in 10-year age bins, a fairly consistent yet statistically non-significant decline for males was observed; however, a trough in the rate was observed for females in the age categories 20-29 years (ß = -0.0284, 95% CI: -0.0464, -0.0103) and 50-59 years (ß = -0.0211, 95% CI: -0.0391, -0.0032). To further elucidate the gender difference observed in the primary analyses, secondary analyses were conducted with reproductive and hormonal status; a significant inverse association was found between TL and parity, menopause, and age at menopause. CONCLUSIONS: TL was shorter with increasing age and this decline was modified by gender, chronic stress and comorbidities; individuals with chronic morbidity and/or chronic stress and females in their twenties and fifties experienced greater decline. Female reproductive factors, i.e., parity and menopause, were associated with TL.

Signaling by adenosine receptors-Homeostatic or allostatic control?

Adenosine modulation is considered both a paracrine signal coordinating different cells in a tissue and a stress signal. Both functions are ensured by 4 types of adenosine receptors (ARs), which have been studied individually. Mice with knockout of all ARs (quad-AR-KO) now allow enquiring the overall function of the adenosine modulation system. The observed "normal" physiology of quad-AR-KO mice indicates that ARs do not regulate homeostasis and are likely recruited to selectively control allostasis.

How does socio-economic position (SEP) get biologically embedded? A comparison of allostatic load and the epigenetic clock(s).

Individuals of lower socio-economic position (SEP) carry a heavier burden of disease and morbidity and live shorter lives on average compared with their more advantaged counterparts. This has sparked research interest in the processes and mechanisms via which social adversity gets biologically embedded. The present study directly compares the empirical worth of two candidate mechanisms: Allostatic Load (AL) and the Epigenetic Clock(s) for advancing our understanding of embodiment using a sub-sample of 490 individuals from the Irish Longitudinal Study (TILDA) who were explicitly selected for this purpose based on their inter-generational life course social class trajectory. A battery of 14 biomarkers representing the activity of 4 different physiological systems: Immunological, Cardiovascular, Metabolic, and Renal was used to construct the AL score. Biomarkers were dichotomised into high and low risk groups according to sex-specific quartiles of risk and summed to create a count ranging from 0-14. Three measures of epigenetic age acceleration were computed according to three sets of age-associated Cytosine-phosphate-Guanine (CpG) sites described by Horvath, Hannum and Levine. AL was strongly socially patterned across a number of measures of SEP, while the epigenetic clocks were not. AL partially mediated the association between measures of SEP and an objective measure of physiological functioning: performance on the Timed Up and Go (TUG test). We conclude that AL may represent the more promising candidate for understanding the pervasive link between SEP and health.

Linking Race, Cancer Outcomes, and Tissue Repair.

The burden of cancer in the United States is unevenly spread across its different populations, with stark differences in both disease prevalence and outcome on the basis of race and ethnicity. Although a large portion of these differences can be explained by a variety of sociobehavioral and socioeconomic factors, even after these exposures are taken into consideration, considerable disparities persist. In this review, we explore a conceptual framework of biological theories and unifying concepts, based on an evolutionary perspective, that may help better define common guiding principles for exploration of underlying causes of cancer health disparities. The ultimate goal of this conceptual perspective is to outline approaches that may aid in establishing integrated pathway and processes analyses to provide useful insights to guide the development of future interventions. These interventions will improve outcome, increase prevention, and ultimately eliminate all disparities.

Youth temperament, harsh parenting, and variation in the oxytocin receptor gene forecast allostatic load during emerging adulthood.

An association has been found between receipt of harsh parenting in childhood and adult health problems. However, this research has been principally retrospective, has treated children as passive recipients of parental behavior, and has overlooked individual differences in youth responsivity to harsh parenting. In a 10-year multiple-wave prospective study of African American families, we addressed these issues by focusing on the influence of polymorphisms in the oxytocin receptor gene (OXTR), variants of which appear to buffer or amplify responses to environmental stress. The participants were 303 youths, with a mean age of 11.2 at the first assessment, and their parents, all of whom were genotyped for variations in the rs53576 (A/G) polymorphism. Teachers rated preadolescent (ages 11 to 13) emotionally intense and distractible temperaments, and adolescents (ages 15 and 16) reported receipt of harsh parenting. Allostatic load was assessed during young adulthood (ages 20 and 21). Difficult preadolescent temperament forecast elevated receipt of harsh parenting in adolescence, and adolescents who experienced harsh parenting evinced high allostatic load during young adulthood. However, these associations emerged only among children and parents who carried A alleles of the OXTR genotype. The results suggest the oxytocin system operates along with temperament and parenting to forecast young adults' allostatic load.

Resilience to adversity and the early origins of disease.

For the past quarter century, scientists at the Center for Family Research at the University of Georgia have conducted research designed to promote understanding of normative developmental trajectories among low socioeconomic status African American children, youths, and young adults. In this paper, we describe a recent expansion of this research program using longitudinal, epidemiological studies and randomized prevention trials to test hypotheses about the origins of disease among rural African American youths. The contributions of economic hardship, downward mobility, neighborhood poverty, and racial discrimination to allostatic load and epigenetic aging are illustrated. The health benefits of supportive family relationships in protecting youths from these challenges are also illustrated. A cautionary set of studies is presented showing that some psychosocially resilient youths demonstrate high allostatic loads and accelerated epigenetic aging, suggesting that, for some, "resilience is just skin deep." Finally, we end on an optimistic note by demonstrating that family-centered prevention programs can have health benefits by reducing inflammation, helping to preserve telomere length, and inhibiting epigenetic aging.

Sociodemographic, behavioral and genetic determinants of allostatic load in a Swiss population-based study.

Allostatic load (AL) is a marker of physiological dysregulation which reflects exposure to chronic stress. High AL has been related to poorer health outcomes including mortality. We examine here the association of socioeconomic and lifestyle factors with AL. Additionally, we investigate the extent to which AL is genetically determined. We included 803 participants (52% women, mean age 48±16years) from a population and family-based Swiss study. We computed an AL index aggregating 14 markers from cardiovascular, metabolic, lipidic, oxidative, hypothalamus-pituitary-adrenal and inflammatory homeostatic axes. Education and occupational position were used as indicators of socioeconomic status. Marital status, stress, alcohol intake, smoking, dietary patterns and physical activity were considered as lifestyle factors. Heritability of AL was estimated by maximum likelihood. Women with a low occupational position had higher AL (low vs. high OR=3.99, 95%CI [1.22;13.05]), while the opposite was observed for men (middle vs. high OR=0.48, 95%CI [0.23;0.99]). Education tended to be inversely associated with AL in both sexes(low vs. high OR=3.54, 95%CI [1.69;7.4]/OR=1.59, 95%CI [0.88;2.90] in women/men). Heavy drinking men as well as women abstaining from alcohol had higher AL than moderate drinkers. Physical activity was protective against AL while high salt intake was related to increased AL risk. The heritability of AL was estimated to be 29.5% ±7.9%. Our results suggest that generalized physiological dysregulation, as measured by AL, is determined by both environmental and genetic factors. The genetic contribution to AL remains modest when compared to the environmental component, which explains approximately 70% of the phenotypic variance.

The Great Recession and health risks in African American youth.

In the present study, we investigated associations of macro-economic conditions - the Great Recession - with cellular epigenetic aging, allostatic load, and self-reported health, in a group that experiences significant health disparities, African Americans. A sample of 330 African American adolescents in Georgia was followed from pre-recession (2007, M age=16.6) to post-recession (2010, M age=19.3). Economic data were collected in both 2007 and 2010. Three groups were formed to represent economic trajectories across the period of the Great Recession (stable low economic hardship, downward mobility, and stable high economic hardship). At age 19, measures of cellular epigenetic aging (derived from leukocyte DNA methylation profiles, reflecting the disparity between a person's biological and chronological age), allostatic load (composite of blood pressure, C reactive protein, cortisol, epinephrine, norepinephrine, and body mass index), and adolescent self-report of health were obtained. Linear trend analyses documented significant differences across all outcomes. The more time adolescents spent under economic hardship, the higher their epigenetic aging [estimate=1.421, SE=0.466, p=.002] and allostatic load [estimate=1.151, SE=0.375, p=.002] scores, and the worse their self-report of health [estimate=4.957, SE=1.800, p=.006]. Specific group comparisons revealed that adolescents in the downward mobility group had higher levels of allostatic load than adolescents in the stable low hardship group [p<.05]. Overall, these findings suggest that the health profiles of African American youth may in part be shaped by environmental macro-economic societal conditions, and that effects on biological markers can be detected relatively early in life.

Diurnal cortisol rhythms in youth from risky families: effects of cumulative risk exposure and variation in the serotonin transporter gene-linked polymorphic region (5-HTTLPR) [corrected].

Building on research on cumulative risk and psychopathology, this study examines how cumulative risk exposure is associated with altered diurnal cortisol rhythms in an ethnically diverse, low-income sample of youth. In addition, consistent with a diathesis-stress perspective, this study explores whether the effect of environmental risk is moderated by allelic variation in the promoter region of the serotonin transporter gene-linked polymorphic region (5-HTTLPR). Results show that youth with greater cumulative risk exposure had flatter diurnal cortisol slopes, regardless of 5-HTTLPR genotype. However, the association of cumulative risk with average cortisol output (area under the curve [AUC]) was moderated by the 5-HTTLPR genotype. Among youth homozygous for the long allele, greater cumulative risk exposure was associated with lower cortisol AUC, driven by significant reductions in cortisol levels at waking. In contrast, there was a trend-level association between greater cumulative risk and higher cortisol AUC among youth carrying the short allele, driven by a trend-level increase in bedtime cortisol levels. Findings are discussed with regard to the relevance of dysregulated diurnal cortisol rhythms for the development of psychopathology and the implications of genetically mediated differences in psychophysiological adaptations to stress.

Genome-wide expressional and functional analysis of calcium transport elements during abiotic stress and development in rice.

Ca²âº homeostasis is required to maintain a delicate balance of cytosolic Ca²âº during normal and adverse growth conditions. Various Ca²âº transporters actively participate to maintain this delicate balance especially during abiotic stresses and developmental events in plants. In this study, we present a genome-wide account, detailing expression profiles, subcellular localization and functional analysis of rice Ca²âº transport elements. Exhaustive in silico data mining and analysis resulted in the identification of 81 Ca²âº transport element genes, which belong to various groups such as Ca²âº-ATPases (pumps), exchangers, channels, glutamate receptor homologs and annexins. Phylogenetic analysis revealed that different Ca²âº transporters are evolutionarily conserved across different plant species. Comprehensive expression analysis by gene chip microarray and quantitative RT-PCR revealed that a substantial proportion of Ca²âº transporter genes were expressed differentially under abiotic stresses (salt, cold and drought) and reproductive developmental stages (panicle and seed) in rice. These findings suggest a possible role of rice Ca²âº transporters in abiotic stress and development triggered signaling pathways. Subcellular localization of Ca²âº transporters from different groups in Nicotiana benthamiana revealed their variable localization to different compartments, which could be their possible sites of action. Complementation of Ca²âº transport activity of K616 yeast mutant by Ca²âº-ATPase OsACA7 and involvement in salt tolerance verified its functional behavior. This study will encourage detailed characterization of potential candidate Ca²âº transporters for their functional role in planta.

Cumulative socioeconomic status risk, allostatic load, and adjustment: a prospective latent profile analysis with contextual and genetic protective factors.

The health disparities literature has identified a common pattern among middle-aged African Americans that includes high rates of chronic disease along with low rates of psychiatric disorders despite exposure to high levels of cumulative socioeconomic status (SES) risk. The current study was designed to test hypotheses about the developmental precursors to this pattern. Hypotheses were tested with a representative sample of 443 African American youths living in the rural South. Cumulative SES risk and protective processes were assessed at ages 11-13 years; psychological adjustment was assessed at ages 14-18 years; genotyping at the 5-HTTLPR was conducted at age 16 years; and allostatic load (AL) was assessed at age 19 years. A latent profile analysis identified 5 profiles that evinced distinct patterns of SES risk, AL, and psychological adjustment, with 2 relatively large profiles designated as focal profiles: a physical health vulnerability profile characterized by high SES risk/high AL/low adjustment problems, and a resilient profile characterized by high SES risk/low AL/low adjustment problems. The physical health vulnerability profile mirrored the pattern found in the adult health disparities literature. Multinomial logistic regression analyses indicated that carrying an s allele at the 5-HTTLPR and receiving less peer support distinguished the physical health vulnerability profile from the resilient profile. Protective parenting and planful self-regulation distinguished both focal profiles from the other 3 profiles. The results suggest the public health importance of preventive interventions that enhance coping and reduce the effects of stress across childhood and adolescence.

Supportive family environments, genes that confer sensitivity, and allostatic load among rural African American emerging adults: a prospective analysis.

The purpose of this study was to investigate interactions between exposure to supportive family environments and genetic characteristics, which were hypothesized to forecast variations in allostatic load (AL) in a representative sample of 315 rural African American youths. Data on family environments were gathered when youths were 11-13, and genetic data were collected when they were 16, years of age. Data on AL were obtained at the beginning of emerging adulthood, age 19 years. The data analyses revealed that, as predicted, emerging adults exposed to less supportive family environments across preadolescence manifested higher levels of AL when they carried the short (s) allele at the 5-HTTLPR and an allele of DRD4 with seven or more repeats. This is an E(family environment) × G(5-HTTLPR status) × G(DRD4 status) interaction. These data suggest that African American youths carrying genes that confer sensitivity who are exposed to less supportive family environments may be at greater risk for adverse physical health consequences that AL presages.

The APOA1/C3/A4/A5 cluster and markers of allostatic load in the Boston Puerto Rican Health Study.

BACKGROUND AND AIMS: The APOA1/C3/A4/A5 cluster encodes key regulators of plasma lipids. Interactions between dietary factors and single nucleotide polymorphisms (SNPs) in the cluster have been reported. Allostatic load, or physiological dysregulation in response to stress, has been implicated in shaping health disparities in ethnic groups. We aimed to determine the association between polymorphisms in the APOA1/C3/A4/A5 cluster with allostatic load parameters, alone, and in interaction with dietary fat intake in Puerto Ricans adults. METHODS AND RESULTS: Data on demographic and anthropometric measures, lifestyle behaviors, and medication use, as well as blood and urine samples for biomarker analysis, were obtained from participants of the Boston Puerto Rican Health Study (n=821, age 45-75 y). The 12 polymorphisms analyzed were not associated with allostatic load parameters. Significant interactions were observed between dietary fat intake and APOA1-75 in association with waist circumference (WC), (P=0.005), APOC3-640 with diastolic blood pressure (DBP), (P=0.003), and APOA4 N147S and APOA5 S19W with systolic blood pressure (SBP), (P=0.001 and P=0.002, respectively). Puerto Ricans homozygous for the common allele of APOA1-75, APOA4 N147S and APOA5 S19W had lower WC and SBP when consuming <31% of total fat from energy, than participants with the minor allele. Participants heterozygous for APOC3-640 had lower DBP at total fat intake ≥31% from energy. CONCLUSION: SNPs in APOA1/C3/A4/A5, as modulated by dietary fat intake, appear to influence allostatic load parameters in Puerto Ricans.

Allostasis and the human brain: Integrating models of stress from the social and life sciences.

We draw on the theory of allostasis to develop an integrative model of the current stress process that highlights the brain as a dynamically adapting interface between the changing environment and the biological self. We review evidence that the core emotional regions of the brain constitute the primary mediator of the well-established association between stress and health, as well as the neural focus of wear and tear due to ongoing adaptation. This mediation, in turn, allows us to model the interplay over time between context, current stressor exposure, internal regulation of bodily processes, and health outcomes. We illustrate how this approach facilitates the integration of current findings in human neuroscience and genetics with key constructs from stress models from the social and life sciences, with implications for future research and the design of interventions targeting individuals at risk.

An angiotensin-1 converting enzyme polymorphism is associated with allostatic load mediated by C-reactive protein, interleukin-6 and cortisol.

Allostatic load (AL) is a theoretical framework that describes the cumulative physiologic effects of adaptation to change or stress throughout the lifespan. AL is operationalized by a composite index of multiple biomarkers. Accordingly, genes, behavior and environment contribute to AL. To determine if individual differences in AL may be influenced by inherent genetic variation, we calculated an allostatic load index (ALI) for 182 Caucasian subjects derived from a population-based study of chronic fatigue syndrome. Nearly 65% of the subjects in this study sample reported fatiguing illness. ALI was calculated based on 11 measures representing metabolic, cardiovascular, inflammatory, hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (SNS) activities. Subjects were dichotomized into high (ALI > or = 3) or low (ALI < 3) AL groups, and the association between high AL and 129 polymorphisms in 32 genes related to the HPA axis, neurotransmission, inflammation, cardiovascular and metabolic functions were evaluated. Polymorphisms in angiotensin-1 converting enzyme (ACE), corticotropin-releasing hormone receptor 1 (CRHR1), and serotonin receptors (HTR3A and HTR4) were associated with AL (p=0.0007-0.0486), but only one polymorphism, rs4968591, in ACE remained significant after correction for multiple comparisons. The T allele of ACE rs4968591 was more common in subjects with high AL (67.5%) than in subjects with low AL (49.3%) (p=0.0007), and this effect appeared independent of age, sex, body mass index and fatigue status. Additionally, high interleukin-6 (IL-6; p(trend)=0.04), and C-reactive protein (CRP; p(trend)=0.01) levels, as well as low urinary cortisol levels in females (p=0.03) were associated with the T allele, which may result in allele-specific binding of the transcription factor, E2F1. Our results suggest a role for ACE in the bidirectional communication between the central nervous and immune systems in response to stress. Further studies will be needed (a) to replicate the association between AL and ACE polymorphisms in population studies designed to differentiate the effects of sex, age and racial/ethnic background, (b) to evaluate the effect of allele-specific binding of E2F1 at rs4968591, and (c) to examine the role of ACE in the co-regulation of CRP, IL-6 and cortisol.