Longevity Relatives Count score defines heritable longevity carriers and suggest case improvement in genetic studies

Longevity loci represent key mechanisms of a life-long decreased mortality, decreased morbidity, and compression of morbidity towards the end of life. However, identifying such loci has shown to be challenging. One of the most plausible reasons is the uncertainty in defining long-lived cases with a heritable longevity trait amongst long living phenocopies. We observed that longevity is only heritable for persons belonging to the top 10% survivors of their birth cohort, or more extreme, with equally long-lived family members. Here we refine that definition to identify individuals with the heritable longevity trait by using a unique dataset connecting living study participants to their deceased ancestors covering 57,337 persons from 1,326 five-generational families, living between 1788 and 2019. In the first study phase, transmission of longevity to descendants in case and control families was measured by Standard Mortality Ratios. In the second phase we combined all families and compared longevity transmission in groups based on a novel score, summarizing the familial history of longevity (Longevity Relatives Count score, LRC). Using this score, we observed that longevity is transmitted for at least 2 subsequent generations only when at least 20%, and optimally 30%, of all relatives are long-lived. A stronger survival advantage was observed for F3 descendants with ≥30% long-lived ancestors than those with at least one long-lived parent. For future studies, we suggest to include cases with ≥ 30% relatives who belong at least to the top 10% survivors of their birth cohort and are themselves among the 10% longest lived.