Dan Eisenberg | University of Washington (original) (raw)

Papers by Dan Eisenberg

Objectives: Telomeres, emerging biomarkers of aging, are comprised of DNA repeats located at chro... more Objectives: Telomeres, emerging biomarkers of aging, are comprised of DNA repeats located at chromosomal ends that shorten with cellular replication and age in most human tissues. In contrast, spermatocyte telomeres lengthen with age. These changes in telomere length (TL) appear to be heritable, as older paternal ages of conception (PAC) predict longer offspring TL. Mouse-model studies raise questions about the potential for effects of paternal experiences on human offspring TL, as they suggest that smoking, inflammation, DNA damage, and stressors all shorten sperm TL. Here, we examined whether factors from the paternal environment predict offspring TL as well as interact with PAC to predict offspring TL. Materials and Methods: Using data from the Philippines, we tested if smoking, psy-chosocial stressors, or shorter knee height (a measure of early life adversity) predict shorter offspring TL. We also tested if these interacted with PAC in predicting offspring TL. Results: While we did not find the predicted associations, we observed a trend toward fathers with shorter knee height having offspring with longer TL. In addition, we found that knee height interacted with PAC to predict offspring TL. Specifically, fathers with shorter knee heights showed a stronger positive effect of PAC on offspring TL. Discussion: While the reasons for these associations remain uncertain, shorter knee height is characteristic of earlier puberty. Since spermatocyte TL increases with the production of sperm, we speculate that individuals with earlier puberty, and its concomitant commencement of production of sperm, had more time to accumulate longer sperm telomeres. K E Y W O R D S epigenetics, intergenerational effects, intergenerational inertia, intergenerational plasticity, senescence

Telomere length (TL) declines with age in most human tissues, and shorter TL appears to accelerat... more Telomere length (TL) declines with age in most human tissues, and shorter TL appears to accelerate senescence. By contrast, men's sperm TL is positively correlated with age. Correspondingly, in humans, older paternal age at conception (PAC) predicts longer offspring TL. We have hypothesized that this PAC effect could persist across multiple generations, and thereby contribute to a transgenerational genetic plasticity that increases expenditures on somatic maintenance as the average age at reproduction is delayed within a lineage. Here, we examine TL data from 3282 humans together with PAC data across four generations. In this sample, the PAC effect is detectable in children and grandchildren. The PAC effect is transmitted through the matriline and patriline with similar strength and is characterized by a generational decay. PACs of more distant male ancestors were not significant predictors, although statistical power was limited in these analyses. Sensitivity analyses suggest that the PAC effect is linear, not moderated by offspring age, or maternal age, and is robust to controls for income, urbanicity and ancestry. These findings show that TL reflects the age at the reproduction of recent male matrilineal and patrilineal ancestors, with an effect that decays across generations.

Telomeres are repeating DNA found at the ends of chromosomes that, in the absence of restorative ... more Telomeres are repeating DNA found at the ends of chromosomes that, in the absence of restorative processes, shorten with cell replications and are implicated as a cause of senescence. It appears that sperm telomere length (TL) increases with age in humans, and as a result offspring of older fathers inherit longer telomeres. We review possible mechanisms underlying this paternal age at conception (PAC) effect on TL, including sperm telomere extension due to telomerase activity, age-dependent changes in the spermatogonial stem cell population (possibly driven by 'selfish' spermatogonia) and non-causal confounding. In contrast to the lengthening of TL with PAC, higher maternal age at conception appears to predict shorter offspring TL in humans. We review evidence for heterogeneity across species in the PAC effect on TL, which could relate to differences in statistical power, sperm production rates or testicular telomerase activity. Finally, we review the hypothesis that the PAC effect on TL may allow a gradual multi-generational adaptive calibration of maintenance effort, and reproductive lifespan, to local demographic conditions: descendants of males who reproduced at a later age are likely to find themselves in an environment where increased maintenance effort, allowing later reproduction, represents a fitness improving resource allocation. This article is part of the theme issue 'Understanding diversity in telomere dynamics'.

Objectives: Telomere length (TL) is a biomarker of aging and age-related decline. Although venous... more Objectives: Telomere length (TL) is a biomarker of aging and age-related decline. Although venous blood is considered the " gold standard " for TL measurement, its collection is often not feasible or desired in nonclinical settings. Saliva and dried blood spots (DBS) have been used as alternatives when venipuncture cannot be performed. However, it is not known whether these sample types yield TL measurements comparable to those obtained from venous blood. We sought to determine whether different samples from the same individual yield comparable TL measurements. Methods: We extracted DNA from matched buffy coat, saliva (Oragene and Oasis), and DBS (venous and capillary) samples from 40 women aged 18-77 years. We used the monochrome multiplex qPCR (MMQPCR) assay to measure TL in all sample types for each participant and applied quality control measures to retain only high-quality samples for analysis. We then compared TL from buffy coat and saliva to examine how these measurements differ and to test if TL is correlated across sample types. Results: TL differed significantly across buffy coat, Oragene saliva, and Oasis saliva samples. TL from buffy coat and Oragene saliva was moderately correlated (q 5 0.48, P 5 .002) and the most similar in size. Oasis saliva TL was not correlated with buffy coat or Oragene saliva TL, and was the shortest. DBS DNA yields were inadequate for TL measurement using the MMQPCR assay. Conclusions: Using a matched dataset we demonstrate that sample type significantly influences the TL measurement obtained using the MMQPCR assay.

Objectives: The androgen receptor (AR) mediates expression of androgen-associated somatic traits ... more Objectives: The androgen receptor (AR) mediates expression of androgen-associated somatic traits such as muscle mass and strength. Within the human AR is a highly variable glutamine short-tandem repeat (AR-CAGn), and CAG repeat number has been inversely correlated to AR transcrip-tional activity in vitro. However, evidence for an attenuating effect of long AR-CAGn on androgen-associated somatic traits has been inconsistent in human populations. One possible explanation for this lack of consistency is that the effect of AR-CAGn on AR bioactivity in target tissues likely varies in relation to circulating androgen levels. Materials and Methods: We tested whether relationships between AR-CAGn and several androgen-associated somatic traits (waist circumference, lean mass, arm muscle area, and grip strength) were modified by salivary (waking and pre-bed) and circulating (total) testosterone (T) levels in young adult males living in metropolitan Cebu, Philippines (n 5 675).

Objectives: Telomeres are repetitive DNA at chromosomes ends that shorten with age due to cellula... more Objectives: Telomeres are repetitive DNA at chromosomes ends that shorten with age due to cellular replication and oxidative stress. As telomeres shorten, this can eventually place limits on cell replication and contribute to senescence. Infections are common during early development and activate cellular immune responses that involve clonal expansion and oxidative stress. As such, a high infectious disease burden might shorten blood telomere length (BTL) and accelerate the pace of immune senescence. Methods: To test this, BTL measured in young adults (21.7 6 0.3 years old) from the Philippines (N 5 1,759) were linked to prospectively collected early life data on infectious burden. Results: As predicted, increased early life diarrheal prevalence was associated with shorter adult BTL. The association was most marked for infections experienced from 6 to 12 months, which corresponds with weaning and maximal diarrheal burden. A standard deviation increase in infections at 6–12 m predicts a 45 bp decrease in BTL, equivalent to 3.3 years of adult telomeric aging in this population. Contrary to expectations, breastfeeding duration was not associated with BTL, nor did effects vary by sex. Conclusions: These findings show that infancy diarrheal disease predicts a marker of cellular aging in adult immune cells. These findings suggest that early life infectious burden may influence late life health, or alternatively, that short TL in early life increases infectious disease susceptibility.

Telomeres are repeating DNA at chromosome ends. Telomere length (TL) declines with age in most hu... more Telomeres are repeating DNA at chromosome ends. Telomere length (TL) declines with age in most human tissues, and shorter TL is thought to accelerate senescence. In contrast, older men have sperm with longer TL; correspondingly, older paternal age at conception (PAC) predicts longer TL in offspring. This PAC-effect could be a unique form of transgenerational genetic plasticity that modifies somatic maintenance in response to cues of recent ancestral experience. The PAC-effect has not been examined in any non-human mammals. Objectives: Here, we examine the PAC-effect in chimpanzees (Pan troglodytes). The PAC-effect on TL is thought to be driven by continual production of sperm—the same process that drives increased de novo mutations with PAC. As chimpanzees have both greater sperm production and greater sperm mutation rates with PAC than humans, we predict that the PAC-effect on TL will be more pronounced in chimpanzees. Additionally we examine whether PAC predicts TL of grandchildren. Materials and methods: TL were measured using qPCR from DNA from blood samples from 40 captive chimpanzees and 144 humans. Results: Analyses showed increasing TL with PAC in chimpanzees (p 5 .009) with a slope six times that in humans (p 5 .026). No associations between TL and grandpaternal ages were found in humans or chimpanzees—although statistical power was low. Discussion: These results suggest that sperm production rates across species may be a determinant of the PAC-effect on offspring TL. This raises the possibility that sperm production rates within species may influence the TL passed on to offspring.

The International Journal of Epidemiology continues to be an important forum for discussions of b... more The International Journal of Epidemiology continues to be an important forum for discussions of both methodological 1-7 and theoretical 8,9 issues in telomere epidemiology. The recent commentary by Verhulst and colleagues 2 helped me realize some critical issues that should be a part of this continuing dialogue.

Human sperm are approximately 6000 th of a centimeter long, a small fraction of a man's total bod... more Human sperm are approximately 6000 th of a centimeter long, a small fraction of a man's total body length. By contrast, fruit fly (Drosophila spp.) sperm can reach nearly 6 cm, roughly twenty times the total length of their bodies. This dramatic variation in male reproductive biology is explored in a recent paper from the journal Nature . [1] While the literature on sperm competition has for decades emphasized the fitness benefit males of many species accrue by producing small gametes in large quantities, understanding species whose males produce large gametes in small quantities while remaining competitive for fertilizations has until recently proven more difficult. Stefan Lüpold and colleagues suggest a solution to this "big-sperm paradox."

Objectives: Testosterone (T), the primary androgenic hormone in males, is stimulated through puls... more Objectives: Testosterone (T), the primary androgenic hormone in males, is stimulated through pulsatile secretion of LH and regulated through negative feedback inhibition at the hypothalamus and pituitary. The hypothalamic-pituitary-gonadal (HPG) axis also controls sperm production through the secretion of follicle-stimulating hormone (FSH). Negative feedback in the HPG axis is achieved in part through the binding of T to the androgen receptor (AR), which contains a highly variable trinucleotide repeat polymorphism (AR-CAGn). The number of repeats in the AR-CAGn inversely correlates with transcriptional activity of the AR. Thus, we predicted longer AR-CAGn to be associated with higher T, LH, and FSH levels. Methods: We examined the relationship between AR-CAGn and total plasma T, LH, and FSH, as well as " bioavailable " morning (AM-T) and evening (PM-T) testos-terone in 722 young (21.5 6 0.5 years) Filipino males. Results: There was no relationship between AR-CAGn and total T, AM-T, or LH (P > .25 for all). We did observe a marginally non-significant (P 5 .066) correlation between AR-CAGn and PM-T in the predicted direction, and a negative correlation between AR-CAGn and FSH (P 5 .005). Conclusions: Our results both support and differ from previous findings in this area, and study parameters that differ between our study and others, such as participant age, sample time, and the role of other hormones should be considered when interpreting our findings. While our data point to a modest effect of AR-CAGn on HPG regulation at best, the AR-CAGn may still affect somatic traits by regulating andro-genic activity at peripheral tissues.

American Journal of Human Biology, 2010

The ubiquity and consequences of childhood growth stunting (<22 SD in height-for-age Z score, HAZ... more The ubiquity and consequences of childhood growth stunting (<22 SD in height-for-age Z score, HAZ) in rural areas of low-income nations has galvanized research into the reversibility of stunting, but the shortage of panel data has hindered progress. Using panel data from a native Amazonian society of foragers-farmers in Bolivia (Tsimane'), we estimate rates of catch-up growth for stunted children. One hundred forty-six girls and 158 boys 2 age 7 were measured annually during 2002-2006. Annual D height in cm and in HAZ were regressed separately against baseline stunting and control variables related to attributes of the child, mother, household, and village. Children stunted at baseline had catch-up growth rates 0.11 SD/year higher than their nonstunted age and sex peers, with a higher rate among children farther from towns. The rate of catch up did not differ by the child's sex. A 10% rise in household income and an additional younger sibling lowered by 0.16 SD/year and 0.53 SD/year the rate of growth. Results were weaker when measuring D height in cm rather than in HAZ. Possible reasons for catch-up growth include (a) omitted variable bias, (b) parental reallocation of resources to redress growth faltering, particularly if parents perceive the benefits of redressing growth faltering for child school achievement, and (c) developmental plasticity during this period when growth rates are most rapid and linear growth trajectories have not yet canalized. Am. J. Hum. Biol. 22:336-347, 2010.

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253 Main text: 6,829 Tables (5): 556 Figures (1): 24 References: 1,811 Total (including cover pag... more 253 Main text: 6,829 Tables (5): 556 Figures (1): 24 References: 1,811 Total (including cover page) = 9,465 2 ABSTRACT Evolutionary theory suggests that social interaction and natural selection favor the evolution of brain specialization that allows humans to use facial (and other somatic) cues to assess characteristics of others. Little is know about people's ability to accurately rate objective traits of others based only on facial cues, and to our knowledge few researchers have examined the topic among non-western populations. Our objectives were to test (i) if raters are able to get accurate information about an individual by only looking at his face, and (ii) whether women and men differ in their ratings. To answer the questions we did a study during July-August 2007 among the Tsimane', a native Amazonian society of foragers-farmers in Bolivia. We asked 40 Tsimane' females and 40 Tsimane' males 16-25 years of age to rate four traits in 93 facial photographs of other Tsimane' males. The four traits included health, dominance, sociability, and knowledge. The rating scale for each trait ranged from one (least) to four (most). The average rating for each trait was calculated for each individual shown in the photograph and regressed against measures of the traits. We found that (i) female and male raters were able to identify facial cues related to health, dominance and knowledge (but not sociability) and (ii) females rated sociability more accurately than males and tended to rate knowledge at a higher level. Results support the existence of a human ability to identify objective traits from facial cues.

Attention-deficit hyperactivity disorder (ADHD) affects an estimated 8 percent of children (12 pe... more Attention-deficit hyperactivity disorder (ADHD) affects an estimated 8 percent of children (12 percent of boys) and 4.4 percent of adults in the U.S. ADHD has a large heritable component (around 70 percent), suggesting that genes play a role in its etiol-ogy and that it can be modified by natural selection. Thus, ADHD's high prevalence begs the question: Why hasn't natural selection removed the genes that underlie ADHD from the human population? To begin to answer this question, and to better understand the phenomenon of ADHD, we must consider our current social environment, and the likely past environments that we have experienced over our evolutionary history, alongside genetic and molecular evidence. We live in different social and ecological contexts than our ancestors. Widespread formal schooling and formal teaching are recent inventions of the past few hundred years. Before about 10,000 years ago, all humans were nomadic hunter-gatherers, without agriculture or domesticated animals. While our ancestors faced social pressures and needed to focus their attention to learn and practice complex foraging and hunting skills, the nature of the social and educational demands were qualitatively different from those we now face. While today we specialize in narrowly defined skills, hunter-gatherers were likely generalists, needing to acquire and practice a broad variety of subsistence and social skills. From studies of modern hunter-gatherers, we can surmise that learning took place through play, observation, and informal instruction, rather than through the highly regimented classrooms almost all of us have experienced. It is no surprise that ADHD is usually diagnosed in children who have trouble focus-ing " properly " in school, and it continues to be a problem for adults when their work or lifestyle requires focusing in particular , regimented ways. There is good reason to believe that in our evolutionary past, ADHD was often not much of a problem and was perhaps even an asset. Some intriguing evidence for this hypothesis comes from work on the genetics of ADHD. One gene associated with ADHD is called dopamine receptor D4 (DRD4), alleles of which change the sensitivity of a subtype of dopamine receptors that are expressed in the prefrontal cortex. ADHD is a complex trait (regulated by many genes), and the ADHD-associated allele in the DRD4 gene (called DRD4 7R) only accounts for a small portion of the cases of ADHD. Nonetheless, a variation of the DRD4 gene provides a window into the evolutionary forces that shaped our brain. The 7R (ADHD-associated) allele of the DRD4 gene is peculiar in that it seems to have originated about 45,000 years ago and was then positively selected for. That is, the 7R allele conveyed some advantage to those who carried it—it increased their " fitness. " We can infer this based on patterns of " linkage disequilibrium " in the DRD4 gene. Linkage disequilibrium is a well-established technique in genetics that compares the rate of recombination (crossing over) that is expected to occur by chance with that which is actually observed. The deviation in DNA sequences in the population from chance expectations gives evidence about the nature of natural selection that occurred. Based on these linkage disequilibrium patterns, we have good reason to believe that the DRD4 7R allele was selected for in past environments and therefore likely was evolutionarily advantageous. But the story gets more interesting. The frequency of the 7R allele varies dramatically across populations, from less than 1 percent in some populations to more than 70 percent in others. In a study conducted by Chuansheng Chen and colleagues, many of these differences across groups were explained by aspects of the groups' histories. Populations with longer histories of migrating tended to have a greater frequency of DRD4 7R alleles. While we can't be sure why the 7R allele is more prevalent in more migratory populations, it might be that people with be-havioral traits related to ADHD were more likely to want to migrate away from their homes. Or perhaps people with this allele were better at adapting to the new environments they found themselves in once they did migrate. Entering an unfamiliar environment can be overwhelming, and it takes time to learn what is most critical to pay attention to. Perhaps those with what we would now recognize as ADHD were better able to adapt to these new environment by learning different methods of hunting and gathering or negotiating new social and/or cultural norms. Additionally, Chen and colleagues reported that populations that currently practiced a nomadic lifestyle tend to have higher frequencies of the 7R (ADHD-associated) allele than sedentary populations. We have extended Chen's work with evidence gathered from work with a group of pastoralists of Kenya known as the Ariaal. The Ariaal are traditionally herders of camels, cattle, sheep, and goats. They traditionally live in the desert and don't stay in one place for long, because they must keep finding food and water for their herds. While many Ariaal continue to practice this traditional lifestyle, more recently a subgroup of Ariaal have become less nomadic, settling in one location. This settled group practices more agriculture, sells more goods on the market, and their children go to school. We analyzed the DRD4 genotypes of about 150 adult Ariaal men, about half from the nomadic group and half from the settled group. Specifically, we looked to see if we could correlate the presence of the 7R allele with a measure of health (as determined by men being less underweight) of the Ariaal men. We found that

Telomeres are repeating sequences of DNA found at the ends of chromosomes, that shorten in most p... more Telomeres are repeating sequences of DNA found at the ends of chromosomes, that shorten in most proliferating tissues as we age and our cells replicate. Shortened telomeres result in a reduced capacity for cell proliferation, and in adults have been shown to predict increased morbidity and earlier mortality. Whereas telomeres tend to shorten with cell replications in most tissues, sperm telomere length appears to run counter to this trend by increasing with each cell division, leading to a lengthening of sperm telomeres as men age. 1 As a result, offspring of older fathers have longer telomere lengths. This finding suggests that the age at which a man conceives his offspring might have important influences on his children's health and longevity by altering the length of telomeres that they inherit. Abraham Aviv and Ezra Susser are leaders in considering this paternal age at conception (PAC) effect on offspring telomere lengths, and their article in this issue is an important review of this topic. 2 In addition to discussing the basic molecular biology and health implications of the PAC effect, they also briefly consider some of the evolutionary dynamics that are implied by this unusual phenomenon. Here we elaborate on the evolutionary significance of the PAC effect and note some points where our interpretations of the literature differ slightly from those of Aviv and Susser.

Recent years have seen an explosion of research on the determinants of obesity, mostly in industr... more Recent years have seen an explosion of research on the determinants of obesity, mostly in industrialized nations, but also in industrializing nations (Popkin and . Standard covariates of obesity in industrialized nations include food intake, physical activity, alterations in sleep patterns, and stress (Bell et al.

Evidence from industrial nations suggests that sibling composition is associated with chil-dren's... more Evidence from industrial nations suggests that sibling composition is associated with chil-dren's educational attainment, particularly if parents face resource constraints. If sibling composition is associated with educational attainment, then those associations should be stronger in poor societies of developing nations. We use data from a pre-industrial society of native Amazonians in Bolivia and found that school-age (5–16) girls or boys with an additional older sibling, particularly an older brother, were less likely to enroll in school and had fewer years of completed schooling. Because older siblings affected the school attainment of younger siblings, older siblings lowered a child's academic skills. Unlike their peers in rich households, younger sisters in poor households were less likely to enroll in school if they had an older sibling. The results lend cross-cultural support to the hypothesis that resource constraint is associated with children's human capital accumulation.

Sibling configuration, including birth order, or the number, age, and sex of siblings is associat... more Sibling configuration, including birth order, or the number, age, and sex of siblings is associated with parental resource allocation between children and is thus associated with a person's well-being. Little is known about the association between specific types of siblings and adult health outcomes. Here we test several hypotheses about sibling composition (number of older brothers, older sisters, younger sisters, younger brothers) and adult blood pressure in a foraging-farming society of native Amazonians in Bolivia (Tsimane'). We collected data in 2007 from 374 adults (16-60 years of age) from 196 households in 13 villages. Household random-effects multiple regressions were run using systolic (SBP) or diastolic blood pressure (DBP) as outcomes; covariates included the four sibling categories and control variables (e.g., sex, age, education, body mass index [BMI]). Mean SBP and DBP were 114 (SD = 14) and 66 (SD = 11) mmHg. The prevalence of hypertension was 5.08%. Having an additional younger brother bore a small (3.3-5.9%) positive association with both SBP and DBP, with the effect weakening as people aged. Having an additional younger sister was associated with a small (3.8%) increase in SBP among women, with the magnitude shrinking as people aged. In a large family, the number of younger brothers may exert an impact on an individual's blood pressure.

American Journal of Human Biology, 2010

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MOST OF THE WORLD LACKS QUALIFIED MEDICAL PERSONNEL TO serve the basic needs of patients. A promi... more MOST OF THE WORLD LACKS QUALIFIED MEDICAL PERSONNEL TO serve the basic needs of patients. A prominent network of global health leaders recently concluded that in many countries it is simply not feasible to improve health by increasing the numbers of physicians and nurses. 1 In these countries, nontraditional resources are relied on for much of the needed medical guidance. In many of these countries, medications are available for purchase without prescriptions, and nonprofessionals try their best to use these powerful medications to heal.