Lifespan Modulation in Mice and the Confounding Effects of Genetic Background

Abstract

We are currently in the midst of a revolution in ageing research, with several dietary, genetic and pharmacological interventions now known to modulate ageing in model organisms. Excitingly, these interventions also appear to have beneficial effects on late-life health. For example, dietary restriction (DR) has been shown to slow the incidence of age-associated cardiovascular disease, metabolic disease, cancer and brain ageing in non-human primates and has been shown to improve a range of health indices in humans. While the idea that DR's ability to extend lifespan is often thought of as being universal, studies in a range of organisms, including yeast, mice and monkeys, suggest that this may not actually be the case. The precise reasons underlying these differential effects of DR on lifespan are currently unclear, but genetic background may be an important factor in how an individual responds to DR. Similarly, recent findings also suggest that the responsiveness of mice to specific genetic or pharmacological interventions that modulate ageing may again be influenced by genetic background. Consequently, while there is a clear driver to develop interventions to improve late-life health and vitality, understanding precisely how these act in response to particular genotypes is critical if we are to translate these findings to humans. We will consider of the role of genetic background in the efficacy of various lifespan interventions and discuss potential routes of utilising genetic heterogeneity to further understand how particular interventions modulate lifespan and healthspan.

Fox transcription factors: from development to disease

“…Like DAF-16 in C. elegans, FoxO transcription factors together with calorie restriction and insulin signaling have been reported to regulate lifespan in rodents (Mulvey et al, 2014;Shimokawa et al, 2015). For example, decreased insulin signaling correlates with human longevity (Kojima et al, 2004;Pawlikowska et al, 2009), as do several genetic variants in FOXO3 (Willcox et al, 2008;Pawlikowska et al, 2009;Flachsbart et al, 2009;Li et al, 2009).…”

The somatotropic axis and longevity in mice

“…In contrast, a 33% increase in lifespan was observed when this mutation was expressed on the short-living 129 background. In addition, the underlying impact of the strain on stress resistance may also be in play (81). In general, much of these data (53) GH, growth hormone; GHRHR, growth hormone-releasing hormone receptor; Tg, transgenic; IGF-IR, IGF-I receptor; ND, not determined; GHRKO, GH receptor knockout; FGF21, fibroblast growth factor 21; LID, liver IGF-I ablated; iLID, inducible liver-specific IGF-I knockout; FIRKO, fat insulin receptor knockout; ␣-MUPA, ␣-mouse urokinase-type plasminogen activator; Papp-A, pregnancy-associated plasma protein-A.…”

Strain-specificity in the hydrogen sulphide signalling network following dietary restriction in recombinant inbred mice

“…Empirical evidence has existed for over a century that dietary restriction (DR) increases lifespan and healthspan across multiple species (Fontana and Partridge 2015;Picca et al 2017;Weindruch and Walford 1988). In mice, significant strain-specific differences in lifespan exist (Turturro et al 1999;Yuan et al 2009) and genetic background may consequently play an important but under-appreciated role in how particular strains respond to DR (Hempenstall et al 2010;Ingram and de Cabo 2017;Mitchell et al 2016;Mulvey et al 2014;Selman and Swindell 2018;Swindell 2012). For example, two independent studies have reported that recombinant inbred ILSXISS mice show significant strain-specificity in longevity following 40% DR (Liao et al 2010;Rikke et al 2010), and phenotypic parameters linked to the ageing process, such as in mitochondrial function and adiposity, have been shown to differ between ILSXISS strains under 40% DR (Liao et al 2011;Mulvey et al 2016).…”