Leukocyte Telomere Length and the Father's Age Enigma: Implications for Population Health and for Life Course

What are the implications for population health of the demographic trend toward increasing paternal age at conception (PAC) in modern societies? We propose that the effects of older PAC are likely to be broad and harmful in some domains of health but beneficial in others. Harmful effects of older PAC have received the most attention. Thus, for example, older PAC is associated with an increased risk of offspring having rare conditions such as achondroplasia and Marfan syndrome, as well as with neurodevelopmental disorders such as autism. However, newly emerging evidence in the telomere field suggests potentially beneficial effects, since older PAC is associated with a longer leukocyte telomere length (LTL) in offspring, and a longer LTL is associated with a reduced risk of atherosclerosis and with increased survival in the elderly. Thus, older PAC may cumulatively increase resistance to atherosclerosis and lengthen lifespan in successive generations of modern humans. In this paper we: (i) introduce these novel findings; (ii) discuss potential explanations for the effect of older PAC on offspring LTL; (iii) draw implications for population health and for life course; (iv) put forth an evolutionary perspective as a context for the multigenerational effects of PAC; and (v) call for broad and intensive research to understand the mechanisms underlying the effects of PAC. We draw together work across a range of disciplines to offer an integrated perspective of this issue

Are social causes so different from all other causes? A comment on Sander Greenland

Sander Greenland's elegant paper raises deep questions about the way in which we choose and evaluate public health actions. We agree with the main thrust of his argument with respect to public health policy. We have some concerns, however, about his treatment of social causes, and on this point we focus our critique

Can Sibling Sex Ratios Be Used as a Valid Test for the Prenatal Androgen Hypothesis of Autism Spectrum Disorders?

Sibling sex ratios have been applied as an indirect test of a hypothesized association between prenatal testosterone levels and risk for autism, a developmental disorder disproportionately affecting males. Differences in sibling sex ratios between those with and without autism would provide evidence of a shared risk factor for autism and offspring sex. Conclusions related to prenatal testosterone, however, require additional assumptions. Here, we used directed acyclic graphs (DAGs) to clarify the elements required for a valid test of the hypothesis that sibling sex ratios differ between children with and without autism. We then conducted such a test using a large, population-based sample of children

Fetal Environment and Schizophrenia

Schizophrenia and related disorders are adult-onset illnesses with no definitively established risk factors. Several studies report that exposures to infection and nutritional deprivation during early development may elevate the risk of later developing schizophrenia, specifically during the prenatal period. Preliminary evidence implicates lead exposure as well, suggesting that chemical exposures during early development may constitute a new class of risk factors for schizophrenia that has not been adequately investigated. Exposure to lead is given as an example of a chemical agent for which some effects have been described throughout the life course on both general neurodevelopmental outcomes and now on a specific psychiatric diagnosis. Findings from prospectively collected birth cohorts are offered as examples of both innovations in methodology and opportunities for future generations of investigators

Telomere Length and the Cancer–Atherosclerosis Trade-Off

Modern humans, the longest-living terrestrial mammals, display short telomeres and repressed telomerase activity in somatic tissues compared with most short-living small mammals. The dual trait of short telomeres and repressed telomerase might render humans relatively resistant to cancer compared with short-living small mammals. However, the trade-off for cancer resistance is ostensibly increased age-related degenerative diseases, principally in the form of atherosclerosis. In this communication, we discuss (a) the genetics of human telomere length, a highly heritable complex trait that is influenced by genetic ancestry, sex, and paternal age at conception, (b) how cancer might have played a role in the evolution of telomere biology across mammals, (c) evidence that in modern humans telomere length is a determinant (rather than only a biomarker) of cancer and atherosclerosis, and (d) the potential influence of relatively recent evolutionary forces in fashioning the variation in telomere length across and within populations, and their likely lasting impact on major diseases in humans. Finally, we propose venues for future research on human telomere genetics in the context of its potential role in shaping the modern human lifespan

Cohort effects explain the increase in autism diagnosis among children born from 1992 to 2003 in California

The incidence and prevalence of autism have dramatically increased over the last 20 years. Decomposition of autism incidence rates into age, period and cohort effects disentangle underlying domains of causal factors linked to time trends. We estimate an age-period-cohort effect model for autism diagnostic incidence overall and by level of functioning

The Disappearing Seasonality of Autism Conceptions in California

Autism incidence and prevalence have increased dramatically in the last two decades. The autism caseload in California increased 600% between 1992 and 2006, yet there is little consensus as to the cause. Studying the seasonality of conceptions of children later diagnosed with autism may yield clues to potential etiological drivers. We searched for seasonality in conceptions of children later diagnosed with autism by applying a one-dimensional scan statistic with adaptive temporal windows on case and control population data from California for 1992 through 2000. We tested for potential confounding effects from known risk factors using logistic regression models. There is a consistent but decreasing seasonal pattern in the risk of conceiving a child later diagnosed with autism in November for the first half of the study period. Temporal clustering of autism conceptions is not an artifact of composition with respect to known risk factors for autism such as socio-economic status. There is some evidence of seasonality in the risk of conceiving a child later diagnosed with autism. Searches for environmental factors related to autism should allow for the possibility of risk factors or etiological drivers that are seasonally patterned and that appear and remain salient for a discrete number of years

An approach to assessment of endocrine disruption in the National Children's Study.

In this article we consider the importance of assessing endocrine disruption in a large new cohort that has been proposed, the National Children's Study (NCS). We briefly review evidence that endocrine disruption is a potentially important hypothesis for human studies and weigh the need to assess endocrine disruption in the NCS. We note the salient features of earlier, similar cohort studies that serve as reference points for the design of the NCS. Finally, we discuss features of the NCS that would allow or enhance assessment of endocrine disruption, even if endocrine disruption were not a primary hypothesis motivating the study. At this time, the evidence supporting endocrine disruption in humans with background-level exposures is not strong. Thus, a compelling rationale for the NCS will probably need to be based on core hypotheses that focus on other issues. Nonetheless, if properly designed, the NCS could serve as an excellent resource for investigating future hypotheses regarding endocrine disruption