Mitochondrial DNA copy number and function decrease with age in the short‐lived fish Nothobranchius furzeri

Abstract

SummaryAmong vertebrates that can be kept in captivity, the annual fish Nothobranchius furzeri possesses the shortest known lifespan. It also shows typical signs of aging and is therefore an ideal model to assess the role of different physiological and environmental parameters on aging and lifespan determination. Here, we used Nothobranchius furzeri to study whether aging is associated with mitochondrial DNA (mtDNA) alterations and changes in mitochondrial function. We sequenced the complete mitochondrial genome of N. furzeri and found an extended control region. Large-scale mtDNA deletions have been frequently described to accumulate in other organisms with age, but there was no evidence for the presence of detectable age-related mtDNA deletions in N. furzeri. However, mtDNA copy number significantly decreased with age in skeletal muscle, brain, liver, skin and dorsal fin. Consistent with this finding, expression of Pgc-1a that encodes a transcriptional coactivator of mitochondrial biogenesis and expression of Tfam and mtSsbp both encoding mtDNA binding factors was downregulated with age. The investigation of possible changes in mitochondrial function revealed that the content of respiratory chain complexes III and IV was reduced in skeletal muscle with age. In addition, ADP-stimulated and succinate-dependent respiration was decreased in mitochondria of old fish. These findings suggest that despite the short lifespan, aging in N. furzeri is associated with a decline in mtDNA copy number, the downregulation of mtDNA-associated genes and an impairment of mitochondrial function.

The African turquoise killifish: A research organism to study vertebrate aging and diapause

“…Aging in the turquoise killifish has been extensively characterized at both the phenotypical and molecular level in both the GRZ strain and other strains such as MZM0403 and 0410 (Baumgart et al., 2012, 2014; Di Cicco, Tozzini, Rossi & Cellerino, 2011; Hartmann et al., 2009, 2011; Priami et al., 2015; Terzibasi Tozzini et al., 2014; Terzibasi et al., 2008; Tozzini, Baumgart, Battistoni & Cellerino, 2012). Indeed, despite their short lifespan compared to other vertebrates, various strains of the turquoise killifish recapitulate numerous stereotypical aging traits that have been reported in other vertebrates (Figure 5), including decline in reproduction, fertility, cognition, mobility, regeneration, and tissue homeostasis, along with increased incidence of senescence, neural and muscular degeneration, and cancerous lesions (Di Cicco et al., 2011; Terzibasi, Valenzano & Cellerino, 2007; Terzibasi et al., 2008; Valenzano, Terzibasi, Cattaneo, Domenici & Cellerino, 2006; Wendler, Hartmann, Hoppe & Englert, 2015).…”

“…Importantly, the turquoise killifish does not die of just one disease, but appears to have multiple causes of death in old age, indicating that its lifespan is truly compressed rather than limited by a specific disease. Old turquoise killifish also exhibit molecular markers of aging, such as a decrease in mitochondrial DNA copy number and telomere length with age (Hartmann et al., 2009, 2011). Finally, environmental stimuli known to impact lifespan in other species (e.g., dietary restriction) also extend the lifespan of the turquoise killifish (Terzibasi et al., 2009).…”

Comparison of captive lifespan, age-associated liver neoplasias and age-dependent gene expression between two annual fish species: Nothobranchius furzeri and Nothobranchius korthause

“…Nothobranchius furzeri is the shortest-lived vertebrate that can be cultured in captivity with a life span of 3-7 months depending on the genetic background of the different strains (Terzibasi et al 2008;Valdesalici and Cellerino 2003) and has emerged in the last decade as new animal model for ageing studies because it expresses a series of typical ageing phenotypes (Genade et al 2005;Hartmann et al 2009Hartmann et al , 2011Tozzini et al 2012;Valenzano et al 2006) and also shows high incidence of age dependent neoplasias (Di Cicco et al 2011). Several other species of Nothobranchius were studied in the context of ageing, such as N. guentheri (Cooper et al 1983;Genade and Lang 2013;Liu et al 2012) N. korthause (Lucas-Sanchez et al 2011 and N. rachovii (Herrera and Jagadeeswaran 2004;Hsu and Chiu 2009;Hsu et al 2008;Lucas-Sanchez et al 2014).…”

A microinjection protocol for the generation of transgenic killifish (Species: Nothobranchius furzeri)

“…Another characteristic of N. furzeri is that the short lifespan has been associated with rapid aging as shown by an early onset of aging biomarkers, a decline in learning and behavioral capabilities, age-related telomere shortening and an age-related impairment of mitochondrial function (Terzibasi et al, 2008;Hartmann et al, 2009Hartmann et al, , 2011. Further genetic studies in N. furzeri will benefit from completion of the genome and transcriptome project, which are under way Valenzano et al, 2009).…”