Idan Shalev

Pennsylvania State University | Penn State · Department of Biobehavioral Health

Epigenetic clocks are a common group of tools used to measure biological aging—the progressive deterioration of cells, tissues, and organs. Epigenetic clocks have been trained almost exclusively using blood‐based tissues, but there is growing interest in estimating epigenetic age using less‐invasive oral‐based tissues (i.e., buccal or saliva) in bo...

In recent decades, grandparents have taken more active caregiving roles, with over 10% of U.S. grandparents raising a grandchild for 6+ months. Role theory postulates grandparent caregivers face unique strain due to complex roles as second-time parents, and physical demandingness of caring for children. Given grandparents are already vulnerable to...

Accurately measuring the process of biological aging – the progressive deterioration of cells, tissues and organs – is crucial in studying the effects of aging interventions. A common group of tools used to measure the process of biological aging are epigenetic clocks (i.e., algorithms that take advantage of the age-related changes observed in the...

Older parental age at birth is associated with increased risk of autism spectrum disorders (ASD) in offspring. Independently, shorter telomere length (TL) has also been shown to be associated with ASD in children. However, older paternal age at birth, with or without controlling for maternal age, has been associated with longer TL, a seemingly cont...

Epigenetic clocks are a common group of tools used to measure biological aging – the progressive deterioration of cells, tissues and organs. Epigenetic clocks have been trained almost exclusively using blood-based tissues but there is growing interest in estimating epigenetic age using less-invasive oral-based tissues (i.e., buccal or saliva) in bo...

A regulated stress response is essential for healthy child growth and development trajectories. We conducted a cluster-randomized trial in rural Bangladesh (funded by the Bill & Melinda Gates Foundation, ClinicalTrials.gov NCT01590095) to assess the effects of an integrated nutritional, water, sanitation, and handwashing intervention on child healt...

Caloric restriction (CR) modifies lifespan and aging biology in animal models. The Comprehensive Assessment of Long‐Term Effects of Reducing Intake of Energy (CALERIE™) 2 trial tested translation of these findings to humans. CALERIE™ randomized healthy, nonobese men and premenopausal women (age 21–50y; BMI 22.0–27.9 kg/m²), to 25% CR or ad‐libitum...

Telomere length (TL) is an important biomarker of cellular aging, yet its links with health outcomes may be complicated by use of different tissues. We evaluated within- and between-individual variability in TL and quality metrics of DNA across five tissues using a cross-sectional dataset ranging from 8 to 70 years (N = 197). DNA was extracted from...

In this article, we suggest that aging and development are two sides of the same coin, and that developing a comprehensive understanding of health and disease risk requires examining age‐related processes occurring throughout the earliest years of life. Compared to other periods in life, it is during this early period of acute vulnerability, when c...

Background Hundreds of millions of children in low-and middle-income countries are exposed to chronic stressors, such as poverty, poor sanitation and hygiene, and sub-optimal nutrition. These stressors can have physiological consequences for children and may ultimately have detrimental effects on child development. This study explores associations...

Telomere length (TL) is an important biomarker of cellular aging, yet its links with health outcomes may be complicated by use of different tissues. We evaluated within- and between-individual variability in TL and quality metrics of DNA across five tissues using a cross-sectional dataset ranging from 8 to 70 years (N=197). DNA was extracted from a...

Telomere attrition is a proposed hallmark of aging. To evaluate the association of telomere length (TL) with chronological age across the human lifespan, we conducted a systematic review and meta-analysis of 414 study samples comprising 743,019 individuals aged 0 to 112 years. We examined both cross-sectional and longitudinal data, and evaluated th...

Identifying factors that influence the stability of DNA methylation measurements across biological replicates is of critical importance in basic and clinical research. Using a within-person between-group experimental design (n = 31, number of observations = 192), we report the stability of biological replicates over a variety of unique temporal sce...

Aging is characterized by functional decline occurring alongside changes to several hallmarks of aging. One of the hallmarks includes attrition of repeated DNA sequences found at the ends of chromosomes called telomeres. While telomere attrition is linked to morbidity and mortality, whether and how it causally contributes to lifelong rates of funct...

Background: Immune cell proportions can be used to detect pathophysiological states and are also critical covariates in genomic analyses. The complete blood count (CBC) is the most common method of immune cell proportion estimation, but immune cell proportions can also be estimated using whole-genome DNA methylation (DNAm). Although the concordanc...

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 asso...

Past research indicates that an individual’s affective reactivity to daily stressors is associated with elevated levels of inflammatory biomarkers such as interleukin-6 and C-reactive protein. Here, we assessed individuals’ positive and negative affective reactivity to daily stressors, and their association with expression levels of genes in the co...

Measuring telomere length (TL) with high precision is challenging. Currently there is insufficient understanding of the causes of variation in measurement precision, particularly for qPCR-based measurement. To better understand how DNA extraction protocols and laboratory-specific analytical factors influence qPCR-based TL measurement precision, we...

One of the proposed mechanisms linking childhood stressor exposure to negative mental and physical health outcomes in later life is cellular aging. In this prospective, longitudinal, and pre‐registered study, we examined the association between a cumulative pattern of childhood risk exposure from age 6 to age 10 (i.e., poor maternal mental health,...

Evolutionary-developmental psychologists have posited that individuals who grow up in stressful rearing circumstances follow faster life history strategies, thereby increasing their chances of reproduction. This preregistered study tested this stress-acceleration hypothesis in a low-risk longitudinal sample of 193 Dutch mother-child dyads, by inves...

Background: Immune cell proportions can be used to detect pathophysiological states and are also critical covariates in genomic analyses. The complete blood count (CBC) is the most common method of immune cell proportion estimation, but immune cell proportions can also be estimated using whole-genome DNA methylation (DNAm). Although the concordance...

Telomere length (TL) is widely studied as a possible biomarker for stress-related cellular aging and decreased longevity. There have been conflicting findings about the relationship between family caregiving stress and TL. Several initial cross-sectional studies have found associations between longer duration of caregiving or perceived stressfulnes...

New insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association between body mas...

Flexible self-regulation has been shown to be an adaptive ability. This study adapted and validated the adult Flexible Regulation of Emotional Expression (FREE) Scale for use with youth (FREE-Y) in community and maltreatment samples. The FREE-Y measures the ability to flexibly enhance and suppress emotion expression across an array of hypothetical...

Various approaches exist to assess population differences in biological aging. Telomere length (TL) is one such measure, and is associated with disease, disability and early mortality. Yet, issues surrounding precision and reproducibility are a concern for TL measurement. An alternative method to estimate TL using DNA methylation (DNAmTL) was recen...

Early life adversity (ELA) is a risk factor for early onset morbidities and mortality, a relationship that may be driven in part by immune system dysregulation. One mechanism of dysregulation that has yet to be fully examined in the context of ELA is alterations to immune cell dynamics in response to acute stress. Using a within-person between-grou...

Importance: A regulated stress response is essential for healthy trajectories, but the integrated effects of early childhood environmental and nutritional interventions on stress physiology are unknown. Objective: To assess the effects of a combined nutritional, water, sanitation, and handwashing intervention on physiological stress response, oxida...

Background: New insights into mechanisms linking obesity to poor health outcomes suggest a role for cellular aging pathways, casting obesity as a disease of accelerated biological aging. Although obesity has been linked to accelerated epigenetic aging in middle-aged adults, the impact during childhood remains unclear. We tested the association betw...

Acute stress has been found to elicit pro-social, anti-social or null responses in humans. The causes for these contradicting findings are currently poorly understood, and may rise from subjects' characteristics, such as sex or hormonal status, as well as stimuli-based traits, such as group membership. In the current study, 120 subjects performed e...

Calorie restriction (CR) slows aging and increases healthy lifespan in model organisms. We tested if CR slowed biological aging in humans using DNA methylation analysis of blood samples from N=197 participants in the Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE TM ) randomized controlled trial. We quantified C...

Background: Precise determination of amplification efficiency is critical for reliable conversion of within-sample changes in fluorescence occurring on a logarithmic scale to between-sample differences in DNA content occurring on a linear scale. This endeavor is especially challenging for the telomere length (TL) quantitative-PCR (qPCR) assay, wher...

Background Indices quantifying allostatic load (AL) and biological aging (BA) have independently received widespread use in epidemiological literature. However, little attention has been paid to their conceptual and quantitative overlap. By reviewing literature utilizing measures of AL and BA, and conducting comparative analysis, we highlight simil...

As championed by the work of Ed Zigler, investing in nurturing environments for all children is a chief tenet of primary prevention that will have far-reaching benefits to the health and welfare of all members of society. Children who endure child maltreatment (CM) are among society's most vulnerable. Prospective longitudinal research aimed at a co...

Background Childhood sexual abuse (CSA) confers elevated risks for obesity in females. Mechanisms that explain this link remain unclear. This study tracked serum basal cortisol levels with body mass index (BMI) from childhood into adulthood to test whether hypothalamic-pituitary-adrenal (HPA) axis attenuation accounts for elevated obesity risks for...

Childhood psychiatric symptoms may be associated with advanced biological aging. This study examined whether epigenetic age acceleration (EAA) associates with internalizing and externalizing symptoms that were prospectively collected across childhood in a longitudinal cohort study. At age 6 buccal epithelial cells from 148 children (69 girls) were...

The role of short telomeres as the trigger for genomic instability and changes in cellular phenotype is well documented; however, aging and disease-related cellular changes may be driven by changes in the structure of telomeres, as influenced by their length, prior to reaching a critically short length. This is pertinent to the relationships among...

Epidemiological literature has produced robust associations between telomere length (TL) and health, wherein individuals with shorter TL are at increased risk for chronic disease and death. Even so, technical challenges associated with TL measurement have led some to question their utility as a biomarker of aging. Several pre-analytical factors inf...

Exposure to maltreatment during childhood can lead to increased risk for poor health outcomes in adulthood. Child maltreatment and later poor health may be linked by premature biological aging. We tested whether childhood sexual abuse (CSA) is associated with telomere length (TL) in adult females. We further tested the hypothesis of intergeneration...

Indices quantifying allostatic load (AL) and biological aging (BA) have received widespread use in epidemiological and health science literature. However, little attention has been paid to the conceptual and quantitative overlap between these indicators. By reviewing literature utilizing measures of AL and BA, we highlight differences with respect...

Technical challenges associated with telomere length (TL) measurements have prompted concerns regarding their utility as a biomarker of aging. Several factors influence TL assessment via qPCR, the most common measurement method in epidemiological studies, including storage conditions and DNA extraction method. Here, we tested the impact of power su...

Background Exposure to maltreatment in childhood can lead to increased risk for poor health outcomes in adulthood. Child maltreatment and later poor health may be linked by premature biological aging. We tested whether childhood sexual abuse (CSA) was associated with telomere length (TL) in adult females. We further tested the hypothesis of interge...

Objective Exposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present pilot study outlines a novel...

Telomeres are the protective DNA-protein sequences appearing at the ends of chromosomes; they shorten with each cell division and are considered a biomarker of aging. Shorter telomere length and greater erosion have been associated with compromised physical and mental health and are hypothesized to be affected by early life stress. In the latter ca...

Biological processes of aging are thought to be modifiable causes of many chronic diseases. Measures of biological aging could provide sensitive endpoints for studies of risk factors hypothesized to shorten healthy lifespan and/or interventions that extend it. However, uncertainty remains about how to measure biological aging and if proposed measur...

Although maternal postpartum depressive symptoms (PDS) are associated with child behavior problems, the underlying biological mechanisms are poorly understood. Thus, the current study focused on 193 healthy mother-child dyads and investigated child cortisol and telomere length as potential mediating factors. At 3 and 6 months postpartum, mothers re...

Childhood psychiatric symptoms may be associated with advanced biological aging. This study examined whether epigenetic age acceleration (EAA) associates with internalizing and externalizing symptoms across childhood in a longitudinal cohort study. At age 6 buccal epithelial cells from 148 children (69 girls) were collected to survey genome-wide DN...

Objective Exposure to early-life adversity (ELA) can result in long-term changes to physiological systems, which predispose individuals to negative health outcomes. This biological embedding of stress-responsive systems may operate via dysregulation of physiological resources in response to common stressors. The present study used a novel experimen...

Telomeres, the repetitive nucleoprotein regions at chromosome ends, are hallmarks of biological aging. Deficiencies in the network of proteins and nucleic acids which govern telomere regulation result in their gradual erosion over time, and shorter telomere length is associated with chronic disease as well as all-cause mortality. Telomeres are also...

Background: Biological processes of aging are thought to be modifiable causes of many different chronic diseases. Measures of biological aging could provide sensitive endpoints for studies of risk factors hypothesized to shorten healthy lifespan and/or interventions that extend it. But uncertainty remains about how to measure biological aging and...

Sex hormones are significant regulators of stress reactivity, however, little is known about how genetic variation in hormone receptors contributes to this process. Here we report interactions between biological sex and repeat polymorphisms in genes encoding sex hormone receptors, and their effects on salivary cortisol reactivity in a sample of 100...

he chapters included in this volume represent the bulk of the proceedings from “New Frontiers in the Biology of Stress, Maltreatment and Trauma: Opportunities for translation, resilience and reversibility,” held from September 30 to October 1, 2015.

This study explores the relationship between competitiveness and stress. In Experiment 1, we observe a higher response of cortisol—the primary stress hormone—to the computation task coupled with tournament than to the computation task with piece rate. Moreover, more competitive subjects exhibit higher stress responses than their less competitive co...

Intervention studies in animals suggest molecular changes underlying age-related disease and disability can be slowed or reversed. To speed translation of these so-called “geroprotective” therapies to prevent age-related disease and disability in humans, biomarkers are needed that can track changes in the rate of human aging over the course of inte...

Biological aging measures have been proposed as proxies for extension of healthy lifespan in trials of geroprotective therapies that aim to slow aging. Several methods to measure biological aging show promise; but it is not known if these methods are sensitive to changes caused by geroprotective therapy. We conducted analysis of two proposed method...

Background Impairments in social behavior and cognition, such as the ability to identify others’ emotional state, are important features in schizophrenia. Arginine vasopressin (AVP) and oxytocin (OXT) and are nonapeptides that influence social cognition and behavior. Previous studies have shown that the administration of intranasal AVP or OXT may a...

Objective: This study was designed to examine prospective associations of risky family environments with subsequent levels of negative emotions and peripheral blood mononuclear cell telomere length (TL), a marker of cellular aging. A second purpose was to determine whether negative emotions mediate the hypothesized link between risky family proces...

Purpose: The purpose was to examine whether the timing of puberty, indexed by breast development and pubic hair development, was earlier for sexually abused females compared with a matched comparison group of nonabused females, controlling for key alternative confounds. Methods: A cohort of sexually abused females and matched comparisons was fol...

Two independent lines of inquiry suggest that growing up under conditions of contextual adversity (e.g., poverty and household chaos) accelerates aging and undermines long-term health. Whereas work addressing the developmental origins of health and disease highlights accelerated-aging effects of contextual adversity on telomere erosion, that inform...

Preliminary findings indicate developmental programming in response to early life adversity may occur in a cell specific manner. Gross peripheral blood mononuclear cells show no differences between control and risk groups. However, CD8+ cells (cytotoxic t-cells) have decreased viability in the presence of higher cortisol release by the risk group f...

Child maltreatment is a debilitating problem and a global public health issue.¹ According to the World Health Organization, 1 in 4 adults report having been physically maltreated and 1 in 5 women disclose having been sexually abused in childhood. The extent of the problem is even larger when considering neglect as well as psychological and emotiona...

Significance This paper makes a singular contribution to understanding the association between biological aging indexed by leukocyte telomeres length (LTL) and delay discounting measured in an incentivized behavioral economic task. In a large group of young, healthy undergraduates, steeper delay discounting is significantly associated with shorter...

This study explores the relationship between competitiveness and stress. In Experiment 1, we examine the response of cortisol, the primary stress hormone, during both piece-rate and tournament tasks. We find that the more competitive tournament task induces a higher cortisol response than the less competitive piece-rate task. Moreover, more competi...

Aim: To examine the association between telomere erosion and periodontitis in a longstanding prospective cohort study of New Zealand adults. Specific hypotheses tested were: (1) that exposure to periodontitis at ages 26 and 38 was associated with accelerated leucocyte telomere erosion; and (2) that accelerated leucocyte telomere erosion was associ...

Routine incorporation of blood-based biomarker measurements in population studies has been hampered by challenges in obtaining samples suitable for biomarker assessment outside of laboratory settings. Here, we assessed the suitability of venous blood left unprocessed for 4, 24, or 48 hours post-collection at either room temperature or 4°C for quant...

Empathy is the ability to recognize and share in the emotions of others. It can be considered a multi-faceted concept with cognitive and emotional aspects. Little is known regarding the underlying neurochemistry of empathy and in the current study we used a neurogenetic approach to explore possible brain neurotransmitter pathways contributing to co...