Association of LINE-1 RNA expressions in cell lines with longevity and reproductive lifespan

Long Interspersed Nucleotide Element-1 (LINE-1, or L1) sequences occupy approximately 17% of the human genome. L1 RNA expression, required for embryogenesis, is low in middle childhood, but increases in adults, eroding heterochromatin and leading to ectopic gene misexpressions, sterile chronic inflammation, and physiological deterioration. To our knowledge, no studies have yet tested whether adults with high L1 RNA levels for their age are shorter-lived, and whether the women with higher L1 RNA levels have shorter reproductive lifespans, as would be expected if higher L1 RNA expressions accelerate both systemic and reproductive aging.

The RNA levels of 127 subfamilies of L1 elements in lymphoblastoid cell lines (LCLs) from 43 grandmothers and 43 grandfathers of the three-generation Utah CEPH (Centre d'Étude du Polymorphisme Humain) families were obtained from the Genetic European Variation in Disease (GEUVADIS) project. Survival and reproductive lifespan data for these subjects were obtained from the University of Utah. The sum of the RNA levels across all 127 L1 element subfamilies (a.k.a. total L1 RNA level), and the variance of RNA levels across the 127 subfamilies, were calculated for each research subject and tested for associations with longevity in both sexes and with age at last birth (ALB) for the women.

Women in the top half of summed L1 RNA expressions, or in the top half of variance in RNA expression across the L1 subfamilies, had significantly higher mortality rates than women in the bottom half for those measures (for top half vs. bottom half total L1 RNA levels, Hazard Ratio (HR) 4.00, 95% CI 1.50-10.67, P = 0.0057; for top half vs. bottom half variance across the L1 subfamilies, HR 3.84, 95% CI 1.49-10.72, P = 0.0068). No significant associations of L1 RNA levels, or their variance, with mortality were observed in the full set of 43 men; however, restricting the analysis to the men who were 68 years or older at blood draw and survived at least four years after the blood draw (n = 31) revealed significantly higher mortality rates, within this subset of men, for those in the top half of total L1 RNA levels vs. men in the bottom half (HR 2.79, 95% CI 1.11-7.05, P = 0.03). Among the 37 women whose ALB was ≥ 30 years, the approximate age when fertility begins to decline, higher total L1 RNA levels were associated, though not significantly, with a younger ALB. However, selecting for relatively healthy individuals by restricting the analyses to women who were younger than 75.5 years at blood draw and survived at least five years after the blood draw (n = 27) revealed a strong association of higher intra-individual variance in L1 RNA expression across the 127 L1 subfamilies with a younger ALB (Pearson r = -0.44, p = 0.02).

These results from a small cohort of research subjects lend support to the hypothesis that the regulation of L1 RNA expressions in adults significantly influences the rates of both systemic and reproductive aging. Expanded studies of similar design are needed to further test this hypothesis.