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

Stephen E Wilkie,James R Mitchell,Christopher Hine,Nicholas M Morton,Lorna Mulvey,Roderick N Carter,Diana E Marcu,Colin Selman,William A Sands

doi:10.1007/s11357-020-00168-2

Abstract

Modulation of the ageing process by dietary restriction (DR) across multiple taxa is well established. While the exact mechanism through which DR acts remains elusive, the gasotransmitter hydrogen sulphide (H2S) may play an important role. We employed a comparative-type approach using females from three ILSXISS recombinant inbred mouse strains previously reported to show differential lifespan responses following 40% DR. Following long-term (10 months) 40% DR, strain TejJ89—reported to show lifespan extension under DR—exhibited elevated hepatic H2S production relative to its strain-specific ad libitum (AL) control. Strain TejJ48 (no reported lifespan effect following 40% DR) exhibited significantly reduced hepatic H2S production, while H2S production was unaffected by DR in strain TejJ114 (shortened lifespan reported following 40% DR). These differences in H2S production were reflected in highly divergent gene and protein expression profiles of the major H2S production and disposal enzymes across strains. Increased hepatic H2S production in TejJ89 mice was associated with elevation of the mitochondrial H2S-producing enzyme 3-mercaptopyruvate sulfurtransferase (MPST). Our findings further support the potential role of H2S in DR-induced longevity and indicate the presence of genotypic-specificity in the production and disposal of hepatic H2S in response to 40% DR in mice.

Highlights

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)
DRinduced protection from ischemia-reperfusion injury was abrogated in mice treated with an inhibitor of cystathionase-γ-lyase (CSE), the major hepatic H2Sproducing enzyme (Hine et al 2015), and longevity in mice following methionine restriction was associated with increased H2S production and a reduction in various senescence markers within the kidney (Wang et al 2019)
Post hoc analysis indicated that H2S production was significantly elevated by 40% DR in strain TejJ89 (p = 0.005), but significantly reduced by 40% DR in strain TejJ48 (p = 0.031) relative to their strain-appropriate ad libitum (AL) controls (Fig. 1a, b)

Summary

Introduction

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). How DR facilitates its beneficial effects on lifespan and healthspan has proved challenging to elucidate, many mechanisms have been proposed (Fontana and Partridge 2015; Hine and Mitchell 2015; Kennedy et al 2007; Mair and Dillin 2008; Masoro 2005). One such putative mechanism is the gasotransmitter hydrogen sulphide (H2S). It has been proposed that elevation of endogenous H2S may play a prominent role in the lifespan and healthspan effects of DR (Hine and Mitchell 2015)

Methods

Results

Conclusion