Childhood adversity, accelerated GrimAge, and associated health consequences.

Childhood adversity is linked to psychological, behavioral, and physical health problems, including obesity and cardiometabolic disease. Epigenetic alterations are one pathway through which the effects of early life stress and adversity might persist into adulthood. Epigenetic mechanisms have also been proposed to explain why cardiometabolic health can vary greatly between individuals with similar Body Mass Index (BMIs). We evaluated two independent cross-sectional cohorts of adults without known medical illness, one of which explicitly recruited individuals with early life stress (ELS) and control participants (n = 195), and the other a general community sample (n = 477). In these cohorts, we examine associations between childhood adversity, epigenetic aging, and metabolic health. Childhood adversity was associated with increased GrimAge Acceleration (GAA) in both cohorts, both utilizing a dichotomous yes/no classification (both p < 0.01) as well as a continuous measure using the Childhood Trauma Questionnaire (CTQ) (both p < 0.05). Further investigation demonstrated that CTQ subscales for physical and sexual abuse (both p < 0.05) were associated with increased GAA in both cohorts, whereas physical and emotional neglect were not. In both cohorts, higher CTQ was also associated with higher BMI and increased insulin resistance (both p < 0.05). Finally, we demonstrate a moderating effect of BMI on the relationship between GAA and insulin resistance where GAA correlated with insulin resistance specifically at higher BMIs. These results, which were largely replicated between two independent cohorts, suggest that interactions between epigenetics, obesity, and metabolic health may be important mechanisms through which childhood adversity contributes to long-term physical and metabolic health effects.

Greater stress and trauma mediate race-related differences in epigenetic age between Black and White young adults in a community sample.

Black Americans suffer lower life expectancy and show signs of accelerated aging compared to other Americans. While previous studies observe these differences in children and populations with chronic illness, whether these pathologic processes exist or how these pathologic processes progress has yet to be explored prior to the onset of significant chronic illness, within a young adult population. Therefore, we investigated race-related differences in epigenetic age in a cross-sectional sample of young putatively healthy adults and assessed whether lifetime stress and/or trauma mediate those differences. Biological and psychological data were collected from self-reported healthy adult volunteers within the local New Haven area (399 volunteers, 19.8% Black, mean age: 29.28). Stress and trauma data was collected using the Cumulative Adversity Inventory (CAI) interview, which assessed specific types of stressors, including major life events, traumatic events, work, financial, relationship and chronic stressors cumulatively over time. GrimAge Acceleration (GAA), determined from whole blood collected from participants, measured epigenetic age. In order to understand the impact of stress and trauma on GAA, exploratory mediation analyses were then used. We found cumulative stressors across all types of events (mean difference of 6.9 p = 2.14e-4) and GAA (ß = 2.29 years [1.57-3.01, p = 9.70e-10] for race, partial η2 = 0.091, model adjusted R2 = 0.242) were significantly greater in Black compared to White participants. Critically, CAI total score (proportion mediated: 0.185 [0.073-0.34, p = 6e-4]) significantly mediated the relationship between race and GAA. Further analysis attributed this difference to more traumatic events, particularly assaultive traumas and death of loved ones. Our results suggest that, prior to development of significant chronic disease, Black individuals have increased epigenetic age compared to White participants and that increased cumulative stress and traumatic events may contribute significantly to this epigenetic aging difference.

The Cutting Edge of Epigenetic Clocks: In Search of Mechanisms Linking Aging and Mental Health.

Individuals with psychiatric disorders are at increased risk of age-related diseases and early mortality. Recent studies demonstrate that this link between mental health and aging is reflected in epigenetic clocks, aging biomarkers based on DNA methylation. The reported relationships between epigenetic clocks and mental health are mostly correlational, and the mechanisms are poorly understood. Here, we review recent progress concerning the molecular and cellular processes underlying epigenetic clocks as well as novel technologies enabling further studies of the causes and consequences of epigenetic aging. We then review the current literature on how epigenetic clocks relate to specific aspects of mental health, such as stress, medications, substance use, health behaviors, and symptom clusters. We propose an integrated framework where mental health and epigenetic aging are each broken down into multiple distinct processes, which are then linked to each other, using stress and schizophrenia as examples. This framework incorporates the heterogeneity and complexity of both mental health conditions and aging, may help reconcile conflicting results, and provides a basis for further hypothesis-driven research in humans and model systems to investigate potentially causal mechanisms linking aging and mental health.

Psychological and biological resilience modulates the effects of stress on epigenetic aging.

Our society is experiencing more stress than ever before, leading to both negative psychiatric and physical outcomes. Chronic stress is linked to negative long-term health consequences, raising the possibility that stress is related to accelerated aging. In this study, we examine whether resilience factors affect stress-associated biological age acceleration. Recently developed "epigenetic clocks" such as GrimAge have shown utility in predicting biological age and mortality. Here, we assessed the impact of cumulative stress, stress physiology, and resilience on accelerated aging in a community sample (N = 444). Cumulative stress was associated with accelerated GrimAge (P = 0.0388) and stress-related physiologic measures of adrenal sensitivity (Cortisol/ACTH ratio) and insulin resistance (HOMA). After controlling for demographic and behavioral factors, HOMA correlated with accelerated GrimAge (P = 0.0186). Remarkably, psychological resilience factors of emotion regulation and self-control moderated these relationships. Emotion regulation moderated the association between stress and aging (P = 8.82e-4) such that with worse emotion regulation, there was greater stress-related age acceleration, while stronger emotion regulation prevented any significant effect of stress on GrimAge. Self-control moderated the relationship between stress and insulin resistance (P = 0.00732), with high self-control blunting this relationship. In the final model, in those with poor emotion regulation, cumulative stress continued to predict additional GrimAge Acceleration even while accounting for demographic, physiologic, and behavioral covariates. These results demonstrate that cumulative stress is associated with epigenetic aging in a healthy population, and these associations are modified by biobehavioral resilience factors.

Neuronal Mechanisms that Drive Organismal Aging Through the Lens of Perception.

Sensory neurons provide organisms with data about the world in which they live, for the purpose of successfully exploiting their environment. The consequences of sensory perception are not simply limited to decision-making behaviors; evidence suggests that sensory perception directly influences physiology and aging, a phenomenon that has been observed in animals across taxa. Therefore, understanding the neural mechanisms by which sensory input influences aging may uncover novel therapeutic targets for aging-related physiologies. In this review, we examine different perceptive experiences that have been most clearly linked to aging or age-related disease: food perception, social perception, time perception, and threat perception. For each, the sensory cues, receptors, and/or pathways that influence aging as well as the individual or groups of neurons involved, if known, are discussed. We conclude with general thoughts about the potential impact of this line of research on human health and aging.

Do developmental temperatures affect redox level and lifespan in C. elegans through upregulation of peroxiredoxin?

Lifespan in poikilothermic organisms, such as Caenorhabditis elegans, can be substantially increased simply by decreasing growth temperature. To gain insights into the mechanistic underpinnings of this effect, we investigated the effects of temperature in development and adulthood on C. elegans lifespan. We found that worms exposed to 25°C during development and shifted to 15°C in adulthood exhibited an even longer lifespan than animals constantly kept at 15°C. Analysis of the in vivo redox status demonstrated that at 25°C, C. elegans larvae have a more reduced redox state and higher Prdx-2 expression levels than animals raised at 15°C. Worms lacking prdx-2 fail to show the additional lifespan extension upon shift from 25°C to 15°C and reveal a lifespan similar to prdx-2 worms always kept at 15°C. These results suggest that transiently altering the in vivo redox state during development can have highly beneficial long-term consequences for organisms.

Perceptive costs of reproduction drive ageing and physiology in male Drosophila.

Costs of reproduction are thought to result from natural selection optimizing organismal fitness within putative physiological constraints. Phenotypic and population genetic studies of reproductive costs are plentiful across taxa, but an understanding of their mechanistic basis would provide important insight into the diversity in life-history traits, including reproductive effort and ageing. Here, we dissect the causes and consequences of specific costs of reproduction in male Drosophila melanogaster. We find that key survival and physiological costs of reproduction arise from perception of the opposite sex, and they are reversed by the act of mating. In the absence of pheromone perception, males are free from reproductive costs on longevity, stress resistance and fat storage. The costs of perception and the benefits of mating are both mediated by evolutionarily conserved neuropeptidergic signalling molecules, as well as the transcription factor dFoxo. These results provide a molecular framework in which certain costs of reproduction arise as a result of self-imposed 'decisions' in response to perceptive neural circuits, which then orchestrate the control of life-history traits independently of physical or energetic effects associated with mating itself.

A computational approach to studying ageing at the individual level.

The ageing process is actively regulated throughout an organism's life, but studying the rate of ageing in individuals is difficult with conventional methods. Consequently, ageing studies typically make biological inference based on population mortality rates, which often do not accurately reflect the probabilities of death at the individual level. To study the relationship between individual and population mortality rates, we integrated in vivo switch experiments with in silico stochastic simulations to elucidate how carefully designed experiments allow key aspects of individual ageing to be deduced from group mortality measurements. As our case study, we used the recent report demonstrating that pheromones of the opposite sex decrease lifespan in Drosophila melanogaster by reversibly increasing population mortality rates. We showed that the population mortality reversal following pheromone removal was almost surely occurring in individuals, albeit more slowly than suggested by population measures. Furthermore, heterogeneity among individuals due to the inherent stochasticity of behavioural interactions skewed population mortality rates in middle-age away from the individual-level trajectories of which they are comprised. This article exemplifies how computational models function as important predictive tools for designing wet-laboratory experiments to use population mortality rates to understand how genetic and environmental manipulations affect ageing in the individual.

FLIC: high-throughput, continuous analysis of feeding behaviors in Drosophila.

We present a complete hardware and software system for collecting and quantifying continuous measures of feeding behaviors in the fruit fly, Drosophila melanogaster. The FLIC (Fly Liquid-Food Interaction Counter) detects analog electronic signals as brief as 50 µs that occur when a fly makes physical contact with liquid food. Signal characteristics effectively distinguish between different types of behaviors, such as feeding and tasting events. The FLIC system performs as well or better than popular methods for simple assays, and it provides an unprecedented opportunity to study novel components of feeding behavior, such as time-dependent changes in food preference and individual levels of motivation and hunger. Furthermore, FLIC experiments can persist indefinitely without disturbance, and we highlight this ability by establishing a detailed picture of circadian feeding behaviors in the fly. We believe that the FLIC system will work hand-in-hand with modern molecular techniques to facilitate mechanistic studies of feeding behaviors in Drosophila using modern, high-throughput technologies.

Water sensor ppk28 modulates Drosophila lifespan and physiology through AKH signaling.

Sensory perception modulates lifespan across taxa, presumably due to alterations in physiological homeostasis after central nervous system integration. The coordinating circuitry of this control, however, remains unknown. Here, we used the Drosophila melanogaster gustatory system to dissect one component of sensory regulation of aging. We found that loss of the critical water sensor, pickpocket 28 (ppk28), altered metabolic homeostasis to promote internal lipid and water stores and extended healthy lifespan. Additionally, loss of ppk28 increased neuronal glucagon-like adipokinetic hormone (AKH) signaling, and the AKH receptor was necessary for ppk28 mutant effects. Furthermore, activation of AKH-producing cells alone was sufficient to enhance longevity, suggesting that a perceived lack of water availability triggers a metabolic shift that promotes the production of metabolic water and increases lifespan via AKH signaling. This work provides an example of how discrete gustatory signals recruit nutrient-dependent endocrine systems to coordinate metabolic homeostasis, thereby influencing long-term health and aging.

Drosophila life span and physiology are modulated by sexual perception and reward.

Sensory perception can modulate aging and physiology across taxa. We found that perception of female sexual pheromones through a specific gustatory receptor expressed in a subset of foreleg neurons in male fruit flies, Drosophila melanogaster, rapidly and reversibly decreases fat stores, reduces resistance to starvation, and limits life span. Neurons that express the reward-mediating neuropeptide F are also required for pheromone effects. High-throughput whole-genome RNA sequencing experiments revealed a set of molecular processes that were affected by the activity of the longevity circuit, thereby identifying new candidate cell-nonautonomous aging mechanisms. Mating reversed the effects of pheromone perception; therefore, life span may be modulated through the integrated action of sensory and reward circuits, and healthy aging may be compromised when the expectations defined by sensory perception are discordant with ensuing experience.

Friedreich's ataxia (GAA)n•(TTC)n repeats strongly stimulate mitotic crossovers in Saccharomyces cerevisae.

Expansions of trinucleotide GAA•TTC tracts are associated with the human disease Friedreich's ataxia, and long GAA•TTC tracts elevate genome instability in yeast. We show that tracts of (GAA)(230)•(TTC)(230) stimulate mitotic crossovers in yeast about 10,000-fold relative to a "normal" DNA sequence; (GAA)(n)•(TTC)(n) tracts, however, do not significantly elevate meiotic recombination. Most of the mitotic crossovers are associated with a region of non-reciprocal transfer of information (gene conversion). The major class of recombination events stimulated by (GAA)(n)•(TTC)(n) tracts is a tract-associated double-strand break (DSB) that occurs in unreplicated chromosomes, likely in G1 of the cell cycle. These findings indicate that (GAA)(n)•(TTC)(n) tracts can be a potent source of loss of heterozygosity in yeast.