Female XX sex chromosomes increase survival and extend lifespan in aging mice

Female longevity is observed in humans and much of the animal kingdom, but its causes remain elusive. Using a genetic manipulation that generates XX and XY mice, each with either ovaries or testes, we show that the female XX sex chromosome complement increases survival during aging in male and female mice. In combination with ovaries, it also extends lifespan.

Understanding causes of sex‐based differences in aging could lead to new pathways to counter age‐induced decline in both sexes.

Women live longer than men around the world, regardless of culture or socioeconomic status (UnitedNations, 2015; Zarulli et al., 2018). Female longevity is also observed in the animal kingdom (Barrett & Richardson, 2011; Bronikowski et al., 2011; Clutton‐Brock & Isvaran, 2007) due to causes that may be extrinsic, intrinsic, or both. Extrinsic causes of sex difference in invertebrates can signal antagonistic survival strategies: female pheromones reduce male lifespan in Drosophila (Gendron et al., 2014), and male secretions shorten hermaphrodite lifespan in C. elegans (Maures et al., 2014).

Intrinsic effects—operating within the organism—underlie longer life in organisms following removal of reproductive cells or organs in C. elegans hermaphrodites (Berman & Kenyon, 2006), male and female dogs (Hoffman, Creevy, & Promislow, 2013), and possibly men as suggested by a study of eunuchs (Min, Lee, & Park, 2012). Nonetheless, causes of intrinsic sex difference in lifespan remain largely unknown. The pervasive nature of female longevity in humans, even in early death during severe epidemics and famine (Zarulli et al., 2018), suggests a role for innate biology in the survival gap between the sexes. Here, we sought to identify intrinsic causes of female longevity in mammalian lifespan.

Sex chromosomes or gonads cause intrinsic sex differences in mammals, but whether they directly contribute to increased female lifespan is unknown in mammalian aging. To dissect these etiologies, we used four core genotypes (FCG) mice (Arnold, 2004). In mice and humans, the Sry gene normally resides on the Y chromosome and codes for a protein (testicular determining Y factor) that induces development of testes and perinatal masculinization. In FCG mice, Sry resides instead on an autosome, enabling inheritance of Sry—and thus male, testicular phenotype—with or without the Y chromosome.

The genetic manipulation of SRY generates XX and XY mice, each with either ovaries (O) or testes (T): XX(O), XX(T), XY(O), XY(T). Gonadal hormone levels in FCG mice with the same gonads are comparable, regardless of their sex chromosomes (Gatewood et al., 2006; McCullough et al., 2016). In FCG model mice, a sex difference with a main effect that statistically differs by genotype (XX vs. XY) is sex chromosome‐mediated; one that differs by phenotype (ovaries vs. testes) is gonadal sex‐mediated. Examples of age‐relevant FCG mouse studies show that XX improves blood pressure regulation (Pessoa et al., 2015) and attenuates experimental brain injuries (Du et al., 2014; McCullough et al., 2016).

Full article: Aging Cell

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