Developmental origins of exceptional health and survival: A four-generation family cohort study

Descendants of longevity-enriched sibships demonstrate a broad health and survival advantage throughout the life course. However, little is known about manifestations during very early life. Here we show a pattern of lower risk of adverse early life outcomes in third-generation grandchildren (N = 5637) of Danish longevity-enriched sibships compared to the general population, including infant mortality (Hazard Ratio = 0.53, 95% CI [0.36, 0.77]) and a range of neonatal health indicators. These associations in fourth-generation great-grandchildren (N = 14,908) were strongly attenuated and less consistent (e.g., infant mortality, Hazard Ratio = 0.90, [0.70, 1.17]). These dilatory patterns across successive generations were independent of stable socioeconomic and behavioural advantages (e.g., parental education and maternal smoking), maternal and paternal lines of transmission, as well as secular trends in the background population. Our findings suggest that exceptional health and survival may have early life developmental components and implicate heritable genetic and or epigenetic factors in their transmission. Background Previous researched has demonstrated potent health and survival advantages across three-generations in longevity-enriched families. However, the survival advantage associated with familial longevity may manifest earlier in life than previously thought. Methods We conducted a matched cohort study comparing early health trajectories in third-generation grandchildren (n = 5,637) and fourth-generation great-grandchildren (n = 14,908) of longevity-enriched sibships to demographically matched births (n = 41,090) in Denmark between 1973 and 2018. Results Lower risk was observed across a range of adverse early life outcomes in the grandchildren, including infant mortality (Hazard Ratio (HR) = 0.53, 95% CI [0.36, 0.77]), preterm birth (Odds Ratio (OR) = 0.82, [0.72, 0.93]), small for gestational age (OR = 0.83, [0.76, 0.90]) and neonatal respiratory disorders (OR = 0.77, [0.67, 0.88]). Relative advantages in parental education and maternal smoking were observed in both generations to a similar degree. However, a much smaller reduction in infant mortality was observed in the great-grandchildren (HR = 0.90, [0.70, 1.17]) and benefits across other outcomes were also less consistent, despite persisting socioeconomic and behavioural advantages. Lastly, maternal, and paternal lines of transmission were equipotent in the transmission of infant survival advantages. Conclusions Descendants of longevity-enriched sibships exhibit a broad health advantage manifesting as early the perinatal period. However, this effect is strongly diluted over successive generations. Our findings suggest that exceptional health and survival may have early developmental components and implicate heritable genetic and or epigenetic factors in their specific transmission. Key Messages ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement Research reported in this publication was supported by the National Institute on Aging of the National Institutes of Health (NIA/NIH) under award number U19AG063893. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: This study has been ethically approved by The Regional Scientific Ethical Committees for Southern Denmark (S-VF-20030227), The Danish Data Protection Agency (J.nr. 2008-41-1753), and University of Southern Denmark, Research & Innovation Organisation (J.nr. 10.635). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data for this research was obtained on a per-project basis in liaison with a government agency in Denmark (Statistics Denmark) and there are strict restrictions on its use and sharing. The data cannot be deposited in a public database and exports of summary data is only allowed as material for direct use in a scientific publication.