Daniel Eisenberg, Ph.D. - US grants

Telomeres are DNA sequences at chromosome ends that shorten with age and are required for proper cell division. This shortening is associated with diminished cell proliferation capacity, which is believed to contribute to aging. Leukocyte telomere length (LTL) is thought to reflect previous immune system activation and current/reserved immune function. It has also been proposed that catch-up growth accelerates telomere depletion. Despite the evolutionary and health-related significance of telomeres, they have been little examined in non-western environments or from an anthropological/evolutionary perspective. The researchers are examining population variation in LTL in mothers and their offspring across nine populations from around the world. They combine the breadth of this cross-population data with 26 years of multi-generational longitudinal data from the Philippines, providing complementary insights into several related hypotheses. Specifically, they are testing hypotheses linking infectious and nutritional stressors known to influence cellular proliferation with LTL. This study will provide some of the first comparative data on LTL in populations varying widely in ecological conditions, and will be the first to our knowledge to use longitudinal data to link measures of early life immune activation with adult LTL. By modulating expenditure on cellular and tissue maintenance, telomere length may be an important life-history allocation mechanism. By tracking the developmental responses of telomere lengths to ecological stressors, the study contributes insights into a possible mechanism linking early life environment with programming of later-life physiology.

This grant will be used to train a PhD student, while also helping foster collaborations with Filipino researchers. Further, LTLs are associated with cardiovascular disease, the number one global killer. By clarifying developmental predictors of LTL using longitudinal data, this study will contribute new insights into the rapidly-expanding literature linking early life experiences with adult chronic disease in societies experiencing rapid economic and lifestyle transitions.

In the U.S. and many other countries people are increasingly putting off starting families until later in life. Correspondingly there is growing concern about the effects of mothers' and fathers' ages on the biology of their offspring. This research examines an important genetic marker of aging, telomere length, that is thought to be influenced by paternal age. Telomeres are DNA that cap the ends of chromosomes, and that shorten with cell replication, oxidative stress, and age. Contrary to other findings, older paternal age might have positive influences on telomere length that promote offspring longevity. This proposal will collect family tree histories and measure telomere lengths in order to better discern whether paternal age actually influences telomere length, and whether this effect persists across generations (e.g. whether grandfather's age or great-grandfather's age at reproduction influences descendants' telomere lengths). Additionally this proposal will examine whether telomere length influences early life immune function in addition to aging. These investigations will therefore contribute to the larger understanding of the evolution of human life history. Broader impacts include the production of a valuable shared dataset that will be relevant to human biologists and public health researchers, and integration of the project analysis and data into student training, mentoring and curricula.

Models for the evolution of senescence assume that when individuals reproduce at advanced ages, selection will favor increased maintenance effort and a corresponding slowing of senescence. Inter-specific comparisons and selection experiments in model organisms have demonstrated that lower mortality/later ages of reproduction are associated with lifespan extension, broadly supporting these theoretical expectations. While natural selection operating on gene frequencies is assumed to form the basis of much of this variation, recent work in telomere biology provides evidence for a mechanism of intergenerational plasticity that could lead to rapid changes in maintenance effort in response to shifts in reproductive scheduling. Telomere shortening places limits on cell division, and is thought to contribute to impairment of cell proliferation-dependent traits such as immunity and tissue repair, and thereby to accelerate senescence. Unlike the telomere length (TL) attrition that occurs with age in most tissues, sperm are the only cell type in which TL increases with age. Because telomeres are DNA, any lengthening of sperm TL due to delayed reproduction should be passed on to offspring with high fidelity, leading to the hypothesis that multi-generational secular trends towards older paternal age at conception (PAC) will result in cumulative and rapid lengthening of inherited TL. Although PAC in any one generation will vary due to birth order and other factors, the cumulative multi-generational character of the PAC effect could lead to a more stable, and thus reliable, indicator of age at reproduction in recent ancestors--thus providing a useful signal from which to calibrate patterns of resource allocation that influence the pace of aging. Recent pilot data demonstrated this cumulative PAC effect across two generations living in Cebu, the Philippines. However, it remains unclear how many generations the PAC effect on TL persists, and thus, how deep and integrative the historical demographic signal conveyed via TL is. This project will therefore 1) examine the intergenerational stability of the PAC effect on descendants' TL across four generations; 2) characterize the sex-specific heritability patterns of TL; and 3) assess possible fitness impacts of inherited TL as reflected in early life infectious disease related morbidity and mortality.

PROJECT SUMMARY/ABSTRACT The prevalence of mental health problems among college populations has risen steadily in recent decades, with one-third of college students struggling with anxiety, depression, or an eating disorder. Yet, only 20-40% of college students with mental disorders receive treatment. Inadequacies in mental health care delivery result in prolonged illness, disease progression, poorer prognosis, and greater likelihood of relapse, highlighting the need for a new approach for detecting mental health problems and engaging college students in services. We have developed a transdiagnostic, low-cost mobile health targeted prevention and intervention platform that uses population-level screening for engaging college students in tailored services that address common mental health problems. This care delivery system represents an ideal model for service delivery given its use of our promising, evidence-based mobile programs, a transdiagnostic approach that addresses comorbid mental health issues, and personalized screening and intervention to increase service uptake, enhance engagement, and improve outcomes. Further, our service delivery model harnesses the expertise of our team of leaders in behavioral science, college student mental health, technology, and health economics, and bridges our team's work over the past 25 years in successfully implementing a population-based screening program in over 160 colleges and demonstrating the effectiveness of Internet-based programs for targeted prevention and intervention for anxiety, depression, and eating disorders in over 40 colleges. We propose to test the impact of this mobile mental health platform for service delivery in a large-scale trial across 20 colleges. Students who screen positive or at high-risk for clinical anxiety, depression, or eating disorders (excluding anorexia nervosa, for which more intensive medical monitoring is warranted), which account for a substantial proportion of the mental health burden on college campuses, and who are not currently engaged in mental health services (N=7,884; of 146,000 initially screened) will be randomly assigned to: 1) intervention via the mobile mental health platform; or 2) referral to usual care (i.e., campus health or counseling center). We will test whether the mobile mental health platform, compared to usual care, is associated with improved uptake (i.e., individuals beginning treatment) (Aim 1), reduced clinical cases and disorder-specific symptoms (Aims 2a, 2b), and improved quality of life and functioning (Aim 2c). We will also test putative targets/mechanisms, other mediators, predictors, and moderators of improved mental health outcomes (Aim 3) as well as stakeholder- relevant outcomes, including cost-effectiveness and academic performance (Aim 4). Our comprehensive mental health care platform can yield clinical benefit to students, appeal to university stakeholders, minimize barriers to implementation sustainability on campuses, and produce an economic return on investment compared to usual care. This population-level approach to service engagement has the potential to improve mental health outcomes for the 20+ million students enrolled in U.S. colleges and universities.

The COVID-19 pandemic has resulted in untold challenges to personal and public health, largely because scientists and clinicians know very little about the virus that causes it and how transmission occurs. Whereas respiratory droplets are known to be a major mode of transmission, it is very likely that there are other sources. One understudied possibility is transmission from mother to infant via breastfeeding. Although researchers know that some viruses can be passed from mother to infant in this fashion, almost nothing is known about SARS-CoV-2 (the virus that causes COVID-19). For this reason, there is substantial confusion as to whether breastfeeding is safe and/or beneficial when a mother is known to be infected. This study will provide fundamental information about this basic biological property of SARS-CoV-2, information that will be immediately usable by women, healthcare providers, and public policy makers. This study will investigate whether SARS-CoV-2 and anti-SARS-CoV-2 antibodies can be detected in breast milk produced by infected women. Results will provide needed information about potential spread of the disease between breastfeeding mothers and infants as compared to formula-feeding mothers and infants. This topic is urgent because women continue to give birth and breastfeed during the pandemic, and guidance is critically needed. The Broader Impacts of this project include both outreach to the public to inform breastfeeding mothers about breast-feeding choices, and education of an undergraduate and graduate student.

Although respiratory droplets are a known source of SARS-CoV-2 transmission, other modes likely exist. One such possibility is SARS-CoV-2 vertical transmission during breastfeeding, but little is known about this type of transfer for any coronaviruses. For SARS-CoV-2, there are only a handful of studies that report analysis of milk produced by COVID-19+ women; all but three report no evidence of virus in milk. There is similarly limited research on the effects of maternal milk antibodies on infant immune responses and severity of symptoms. As a result, there is substantial confusion as to the risks and benefits of breastfeeding for SARS-CoV-2+ mothers. This proposed research is a longitudinal, repeated-measures study of 25 breastfeeding mothers and infants and 25 formula-feeding mothers and infants. Dyads will be recruited within 7 days of maternal COVID-19 diagnosis and followed for 2 months during which time milk and breast swabs will be repeatedly collected (from breastfeeding mothers) and analyzed for SARS-CoV-2 RNA using an RT-qPCR; milk will also be analyzed for SARS-CoV-2-specific antibodies. Stool samples will also be collected and analyzed to assess viral exposure/shedding; and dried blood spots collected and analyzed to assess viremia and antibody (IgG and IgA) titers. Results will immediately inform women, healthcare providers, and public policy makers regarding infant feeding choices during the postpartum period. This RAPID award is made by the Physiological and Structural Systems Cluster in the BIO Division of Integrative Organismal Systems, using funds from the Coronavirus Aid, Relief, and Economic Security (CARES) Act.

This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.