Offspring's Leukocyte Telomere Length, Paternal Age, and Telomere Elongation in Sperm

Abstract

Leukocyte telomere length (LTL) is a complex genetic trait. It shortens with age and is associated with a host of aging-related disorders. Recent studies have observed that offspring of older fathers have longer LTLs. We explored the relation between paternal age and offspring's LTLs in 4 different cohorts. Moreover, we examined the potential cause of the paternal age on offspring's LTL by delineating telomere parameters in sperm donors. We measured LTL by Southern blots in Caucasian men and women (n=3365), aged 18–94 years, from the Offspring of the Framingham Heart Study (Framingham Offspring), the NHLBI Family Heart Study (NHLBI-Heart), the Longitudinal Study of Aging Danish Twins (Danish Twins), and the UK Adult Twin Registry (UK Twins). Using Southern blots, Q-FISH, and flow-FISH, we also measured telomere parameters in sperm from 46 young (<30 years) and older (>50 years) donors. Paternal age had an independent effect, expressed by a longer LTL in males of the Framingham Offspring and Danish Twins, males and females of the NHLBI-Heart, and females of UK Twins. For every additional year of paternal age, LTL in offspring increased at a magnitude ranging from half to more than twice of the annual attrition in LTL with age. Moreover, sperm telomere length analyses were compatible with the emergence in older men of a subset of sperm with elongated telomeres. Paternal age exerts a considerable effect on the offspring's LTL, a phenomenon which might relate to telomere elongation in sperm from older men. The implications of this effect deserve detailed study.

Meta-analysis of telomere length in 19 713 subjects reveals high heritability, stronger maternal inheritance and a paternal age effect

“…Recently, a paternal inheritance model has been gaining favor. 8,[24][25][26] The most recent study suggesting paternal inheritance from Nordfjall et al 26 contained a total of 217 parent-offspring pairs. In our study we included a total of 1244 father-offspring pairs and 1388 mother-offspring pairs and found both significant mother-offspring and father-offspring correlations for TL.…”

“…Finally, we found significant evidence for a positive association of paternal age with TL, supporting earlier reports. 24,27,28 At first glance, any positive association of TL with age seems counterintuitive. However, TL is known to be maintained, and even lengthened, in sperm, despite both mitotic and meiotic divisions during the proliferation and differentiation of the cells.…”

“…23 However, an increasing number of larger studies have reported stronger fatheroffspring than mother-offspring correlations for TL, suggesting that inheritance of this trait is mainly paternally determined. 8,[24][25][26] In addition to a paternal pattern of inheritance, a positive correlation between offspring TL and paternal age at birth has been observed. 24,27,28 Unlike somatic cells, sperm cell TL has been shown to increase with the age of the donor 24,29 because of the presence of active telomerase, suggesting that offspring of older fathers would inherit longer telomeres.…”

Effects of aging on the male reproductive system

“…Leukocyte telomere length is a biological marker of aging, and the telomere length of leukocytes of children of older fathers is higher than that of children of younger fathers. [86,[137][138][139]. However, the exact mechanism of longer offspring's leukocyte telomere length depending on paternal aging is not clear.…”

“…However, the exact mechanism of longer offspring's leukocyte telomere length depending on paternal aging is not clear. Previous studies have suggested two mechanisms to explain the longer telomere length in spermatozoa of older men [86,139] (Table 4). The former explanation is high expression of testicular telomerase leading to extension of Salas-Huetos et al [118] telomeres of spermatozoa chromosomal ends with advanced age [140].…”