Developmental origins of exceptional health and survival: A four-generation family cohort study
Authors: Keys Matthew Thomas , Pedersen Dorthe Almind , Larsen Pernille Stemann , Kulminski Alexander , Feitosa Mary F. , Wojczynski Mary , Province Michael , Christensen Kaare 
Published: May 2024

AbstractDescendants 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.BackgroundPrevious 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.MethodsWe 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.ResultsLower 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.ConclusionsDescendants 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 MessagesPrevious 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.In our study of third and fourth-generation descendants of longevity-enriched sibships, we observed a broad infant health and survival advantage reflected by protection against a diverse range of adverse birth outcomes.These advantages were strongly attenuated between the third and fourth generations, independent of otherwise stable socioeconomic and behavioural parental advantages, as well as maternal and paternal lines of transmission.Our findings suggest that familial aggregation of exceptional health and survival may have early life developmental components and triangulate to implicate heritable genetic and or epigenetic factors in their transmission.