Titan mice as a model to test interventions that attenuate frailty and increase longevity.

Wild-type murine models for aging research have lifespans of several years, which results in long experimental duration and late output. Here we explore the short-lived non-inbred Titan mouse (DU6) as a mouse model to test longevity interventions. We show that Titan mice exhibit increased frailty and senescence-associated beta-galactosidase activity at an early age. Dietary intervention attenuates the frailty progression of Titan mice. Additionally, cyclic administration of the senolytic drug Navitoclax at an early age increases the lifespan and reduces senescence-associated beta-galactosidase activity. Our data suggests that Titan mice can serve as a cost-effective and timely model for longevity interventions in mammals.

Altered insulin, leptin and ghrelin hormone levels and atypical estrous cycle lengths in two highly fertile mouse lines.

Mouse models of decreased fertility mainly support scientific knowledge in the field of reproductive biology. In this study, we changed the perspective, using Dummerstorf high-fertility mouse lines FL1 and FL2 selected for increased reproductive performances that doubled the amount of ovulated oocytes per cycle and the number of offspring per litter compared to an unselected control line (founder population, FZTDU, ctrl). After recent observations, both fertility lines seem to show a lower pregnancy rate compared to ctrl together with an atypical reproductive cycle. We analysed the estrous cycle of those mice, but also plasma levels of insulin, glucagon, leptin and ghrelin that, when irregular, may have an impact on the reproductive cycle length by modifying the GnRH release. We included females of another independent line (DU6P), selected from the same founder population but independently of fertility traits, as an additional model of decreased pregnancy rate. We aim to evaluate if do they use a similar mechanism associated in the regulation of the estrous cycle or implicated in altered pregnancy mechanism compared to control, because they show a similar situation as FL2 line does, even without an increase in fertility parameters. We speculate that FLs' estrous cycle undergoes changes during the selection period and aim to demonstrate that some hormonal dysfunctions link with altered reproductive cycle, dampened pregnancy rates and reduced first delivery rates mostly in FL2, but also with higher-fertility phenotype rather than lower in both FLs.

Two mouse lines selected for large litter size display different lifetime fecundities.

We recently described two outbred mouse lines that were selected for large litter size at first delivery. However, lifetime fecundity appears to be economically more important for the husbandry of many polytocous species for which mouse lines might serve as bona fide animal models (e.g. for pigs). In the present study, we compared the lifetime fecundities of two highly fertile mouse lines (FL1 and FL2: >20 offspring/litter at first delivery) with those of an unselected control line (ctrl) and two lines that were selected for high body weight (DU6) and high protein mass (DU6P) without selection pressure on fertility. We tested the hypothesis that selection for large litter size at first parturition would also increase lifetime fecundity in mice, and we observed very large differences between lines. Whereas FL1 and ctrl delivered up to nine and ten litters, none of the DU6 and DU6P females gave birth to more than five litters. In line with this observation, FL1 delivered the most pups per lifetime (85.7/female). FL2 females produced the largest average litter sizes (20.4 pups/litter) in the first four litters; however, they displayed a reduced number of litters. With the exception of ctrl, litter sizes declined from litter to litter. Repeated delivery of litters with high offspring numbers did not affect the general health of FL females. The presented data demonstrate that two biodiverse, highly fertile mouse lines selected for large litter size at first delivery show different lifetime reproductive fitness levels. Thus, these mouse lines might serve as valuable mouse models for investigating lifetime productivity and longevity in farm animals.

Turning Observed Founder Alleles into Expected Relationships in an Intercross Population.

Pedigree-derived relationships for individuals from an intercross of several lines cannot easily account for the segregation variance that is mainly caused by loci with alternative alleles fixed in different lines. However, when all founders are genotyped for a large number of markers, such relationships can be derived for descendants as expected genomic relationships conditional on the observed founder allele frequencies. A tabular method was derived in detail for autosomes and the X-chromosome. As a case study, we analyzed litter size and body weights at three different ages in an advanced mouse intercross (29 generations, total pedigree size 19,266) between a line selected for high litter size (FL1) and a highly inbred control line (DUKsi). Approximately 60% of the total genetic variance was due to segregation variance. Estimated heritability values were 0.20 (0.03), 0.34 (0.04), 0.23 (0.03), 0.41 (0.03) and 0.47 (0.02) for litter size, litter weight and body weight at ages of 21, 42 and 63 days, respectively (standard errors in brackets). These values were between 12% and 65% higher than observed in analyses that treated founders as unrelated. Fields of applications include experimental populations (selection experiments or advanced intercross lines) with a limited number of founders, which can be genotyped at a reasonable cost. In principle any number of founder lines can be treated. Additional genotypes from individuals in later generations can be combined into a joint relationship matrix by capitalizing on previously published approaches.