Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans

Herndon, Laura A.; Schmeissner, Peter J.; Dudaronek, Justyna M.; Brown, Paula A.; Listner, Kristin M.; Sakano, Yuko; Paupard, M.-C.; Hall, David H.; Driscoll, Monica

doi:10.1038/nature01135

Cited by 1,100 publications

(1,273 citation statements)

References 45 publications

Supporting

Mentioning

1,194

Contrasting

Unclassified

Order By: Relevance

“…Mitochondrial decline and dysfunction are common features of aging and of many age‐dependent diseases in mammals and in model organisms including nematodes (Braeckman et al, 2002; Gruber et al, 2011; Herndon et al, 2002; López‐Otín, Blasco, Partridge, Serrano, & Kroemer, 2013; Yasuda et al, 2006). In humans, one of the mechanisms that is believed to be involved in mitochondrial aging is loss of mtDNA integrity and accumulation of mutant mtDNA (Stewart & Chinnery, 2015).…”

Section: Discussionmentioning

confidence: 99%

“…Oxygen consumption and ATP levels (indicators of metabolism) significantly decline with age in nematodes (Braeckman, Houthoofd, & Vanfleteren, 2002; Gruber et al, 2011; Yasuda et al, 2006). Behaviors based on muscular and nervous system function, including pharyngeal pumping, spontaneous movement, and motility type, also decline rapidly with age in C. elegans (Collins, Huang, Hughes, & Kornfeld, 2008; Fisher, 2004; Gruber et al, 2011; Herndon et al, 2002). A significant decline in muscle function and structural integrity is a prominent feature of aging in C. elegans (Collins et al, 2008; Fisher, 2004; Gruber et al, 2011; Herndon et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…Behaviors based on muscular and nervous system function, including pharyngeal pumping, spontaneous movement, and motility type, also decline rapidly with age in C. elegans (Collins, Huang, Hughes, & Kornfeld, 2008; Fisher, 2004; Gruber et al, 2011; Herndon et al, 2002). A significant decline in muscle function and structural integrity is a prominent feature of aging in C. elegans (Collins et al, 2008; Fisher, 2004; Gruber et al, 2011; Herndon et al, 2002). This age‐dependent deterioration of the C. elegans musculature resembles sarcopenia, involving muscle cell shrinkage, fraying, and loss of structure of muscle fibers with loosening of packing geometry of sarcomere fibers (Herndon et al, 2002).…”

Section: Introductionmentioning

confidence: 99%

“…A significant decline in muscle function and structural integrity is a prominent feature of aging in C. elegans (Collins et al, 2008; Fisher, 2004; Gruber et al, 2011; Herndon et al, 2002). This age‐dependent deterioration of the C. elegans musculature resembles sarcopenia, involving muscle cell shrinkage, fraying, and loss of structure of muscle fibers with loosening of packing geometry of sarcomere fibers (Herndon et al, 2002). Aging in C. elegans is also associated with increased oxidative damage and loss of structural integrity of muscle mitochondria (Yasuda et al, 2006).…”

Section: Introductionmentioning

confidence: 99%

“…In humans, mtDNA deletions are detected late in life, typically at >50 years of age, by which age, atrophied muscle fibers are found to be enriched with clonally expanded mtDNA deletions (Bua et al, 2006). By contrast, nematodes can exhibit signs of sarcopenia as early as 7 days after hatching (Fisher, 2004; Herndon et al, 2002). We have previously shown that mtDNA maintenance, in particular mtDNA turnover, is a crucial determinant of the dynamics of mutant mtDNA accumulation (Poovathingal, Gruber, Halliwell, & Gunawan, 2009; Poovathingal, Gruber, Lakshmanan, Halliwell, & Gunawan, 2012; Tam, Gruber, Halliwell, & Gunawan, 2013, 2015).…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

Lakshmanan

Yee

et al. 2018

Aging Cell

View full text Add to dashboard Cite

Disruption of mitochondrial metabolism and loss of mitochondrial DNA (mtDNA) integrity are widely considered as evolutionarily conserved (public) mechanisms of aging (López‐Otín et al., Cell, 153, 2013 and 1194). Human aging is associated with loss in skeletal muscle mass and function (Sarcopenia), contributing significantly to morbidity and mortality. Muscle aging is associated with loss of mtDNA integrity. In humans, clonally expanded mtDNA deletions colocalize with sites of fiber breakage and atrophy in skeletal muscle. mtDNA deletions may therefore play an important, possibly causal role in sarcopenia. The nematode Caenorhabditis elegans also exhibits age‐dependent decline in mitochondrial function and a form of sarcopenia. However, it is unclear if mtDNA deletions play a role in C. elegans aging. Here, we report identification of 266 novel mtDNA deletions in aging nematodes. Analysis of the mtDNA mutation spectrum and quantification of mutation burden indicates that (a) mtDNA deletions in nematode are extremely rare, (b) there is no significant age‐dependent increase in mtDNA deletions, and (c) there is little evidence for clonal expansion driving mtDNA deletion dynamics. Thus, mtDNA deletions are unlikely to drive the age‐dependent functional decline commonly observed in C. elegans. Computational modeling of mtDNA dynamics in C. elegans indicates that the lifespan of short‐lived animals such as C. elegans is likely too short to allow for significant clonal expansion of mtDNA deletions. Together, these findings suggest that clonal expansion of mtDNA deletions is likely a private mechanism of aging predominantly relevant in long‐lived animals such as humans and rhesus monkey and possibly in rodents.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Clonal expansion of mitochondrial DNA deletions is a private mechanism of aging in long‐lived animals

Lakshmanan

Yee

et al. 2018

Aging Cell

View full text Add to dashboard Cite

show abstract

Effects of Anticonvulsant Drugs on Life Span

Kornfeld¹,

Evason²

2006

Arch Neurol

View full text Add to dashboard Cite

A ging is characterized by widespread degenerative changes in tissue morphology and function and an increase in the incidence of human diseases such as cancer, stroke, and Alzheimer disease. Findings from recent genetic studies suggest that molecular mechanisms that influence life span are evolutionarily conserved, and interventions that extend the life span of model organisms such as worms and flies are likely to have similar effects on vertebrates such as humans. However, little progress has been made in identifying drugs that delay aging. We identified 3 pharmacologic compounds, ethosuximide, trimethadione, and 3,3-diethyl-2pyrrolidinone, that extend lifespan and delay age-related degenerative changes in the nematode worm Caenorhabditis elegans. All 3 compounds are anticonvulsants that modulate neural activity in vertebrates, and ethosuximide and trimethadione are used to treat absence seizures in humans. We discuss existing evidence that these drugs might also delay vertebrate aging and suggest experiments that could test this hypothesis. Genetic and cell ablation studies conducted with model organisms have demonstrated connections between the nervous system and aging. Our studies provide additional support for the hypothesis that neural activity plays a role in lifespan determination, since ethosuximide and trimethadione regulated neuromuscular activity in nematodes. Our findings suggest that the lifespan extending activity of these compounds is related to the anticonvulsant activity, implicating neural activity in the regulation of aging. We also discuss models that explain how the nervous system influences lifespan.

show abstract