cep-1/p53-dependent dysplastic pathology of the aging C. elegans gonad

McGee, Mathew D.; Day, Nicholas U.; Graham, Jill B.; Melov, Simon

doi:10.18632/aging.100448

Cited by 35 publications

(50 citation statements)

References 42 publications

(106 reference statements)

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“…During aging the C. elegans gonad undergoes hypertrophy marked by increased cell DNA content and increased cell number. This phenotype is more severe in cep-1 (p53-related gene) mutants, suggesting an aging-associated loss of normal germ-line PCD activity (Andux and Ellis, 2008; McGee et al, 2012). Taken together the studies with the model systems support the conclusion that aging can cause increased susceptibility to apoptosis in some cell types, and decreased apoptosis in other cell types.…”

Section: Pcd-like Events In Tissues Of Old Animalsmentioning

confidence: 99%

Programmed cell death in aging

Tower

2015

Ageing Research Reviews

331

208

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Programmed cell death (PCD) pathways, including apoptosis and regulated necrosis, are required for normal cell turnover and tissue homeostasis. Mis-regulation of PCD is increasingly implicated in aging and aging-related disease. During aging the cell turnover rate declines for several highly-mitotic tissues. Aging-associated disruptions in systemic and inter-cell signaling combined with cell-autonomous damage and mitochondrial malfunction result in increased PCD in some cell types, and decreased PCD in other cell types. Increased PCD during aging is implicated in immune system decline, skeletal muscle wasting (sarcopenia), loss of cells in the heart, and neurodegenerative disease. In contrast, cancer cells and senescent cells are resistant to PCD, enabling them to increase in abundance during aging. PCD pathways limit life span in fungi, but whether PCD pathways normally limit adult metazoan life span is not yet clear. PCD is regulated by a balance of negative and positive factors, including the mitochondria, which are particularly subject to aging-associated malfunction.

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Section: Pcd-like Events In Tissues Of Old Animalsmentioning

confidence: 99%

Programmed cell death in aging

Tower

2015

Ageing Research Reviews

331

208

View full text Add to dashboard Cite

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“…Apoptotic-like events are also associated with aging in Drosophila muscle and fat cells [65]. In contrast, a down-regulation of apoptosis is associated with both cell senescence and cancer in mammals [66–68] and with tissue over-growth in the aging C. elegans gonad [69]. …”

Section: Mis-regulated Apoptosis During Agingmentioning

confidence: 99%

Mitochondrial maintenance failure in aging and role of sexual dimorphism

Tower¹

2015

Archives of Biochemistry and Biophysics

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Gene expression changes during aging are partly conserved across species, and suggest that oxidative stress, inflammation and proteotoxicity result from mitochondrial malfunction and abnormal mitochondrial-nuclear signaling. Mitochondrial maintenance failure may result from trade-offs between mitochondrial turnover versus growth and reproduction, sexual antagonistic pleiotropy and genetic conflicts resulting from uni-parental mitochondrial transmission, as well as mitochondrial and nuclear mutations and loss of epigenetic regulation. Aging phenotypes and interventions are often sex-specific, indicating that both male and female sexual differentiation promote mitochondrial failure and aging. Studies in mammals and invertebrates implicate autophagy, apoptosis, AKT, PARP, p53 and FOXO in mediating sex-specific differences in stress resistance and aging. The data support a model where the genes Sxl in Drosophila, sdc-2 in C. elegans, and Xist in mammals regulate mitochondrial maintenance across generations and in aging. Several interventions that increase life span cause a mitochondrial unfolded protein response (UPRmt), and UPRmt is also observed during normal aging, indicating hormesis. The UPRmt may increase life span by stimulating mitochondrial turnover through autophagy, and/or by inhibiting the production of hormones and toxic metabolites. The data suggest that metazoan life span interventions may act through a common hormesis mechanism involving liver UPRmt, mitochondrial maintenance and sexual differentiation.

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“… A. Schematic summary of major age changes in the anatomy of the hermaphrodite gonad, derived from previous sources [16, 18–20, 62, 63] and this study. Top, young, reproductive adult.…”

Section: Introductionmentioning

confidence: 99%

Run-on of germline apoptosis promotes gonad senescence inC. elegans

et al. 2016

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Aging (senescence) includes causal mechanisms (etiologies) of late-life disease, which remain poorly understood. According to the recently proposed hyperfunction theory, based on the older theory of antagonistic pleiotropy, senescent pathologies can arise from futile, post-reproductive run-on of processes that in early life promote fitness. Here we apply this idea to investigate the etiology of senescent pathologies in the reproductive system of Caenorhabditis elegans hermaphrodites, particularly distal gonad degeneration and disintegration. Hermaphrodite germ cells frequently undergo “physiological” (non-damage-induced) apoptosis (PA) to provision growing oocytes. Run-on of such PA is a potential cause of age-related gonad degeneration. We document the continuation of germline apoptosis in later life, and report that genetically blocking or increasing PA retards or accelerates degeneration, respectively. In wild-type males, which lack germ line apoptosis, gonad disintegration does not occur. However, mutational induction of PA in males does not lead to gonad disintegration. These results suggest that as germ-cell proliferation rate declines markedly in aging hermaphrodites (but not males), run-on of PA becomes a pathogenic mechanism that promotes gonad degeneration. This illustrates how hyperfunction, or non-adaptive run-on in later life of a process that promotes fitness in early life, can promote atrophic senescent pathology in C. elegans.

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cep-1/p53-dependent dysplastic pathology of the aging C. elegans gonad

Cited by 35 publications

References 42 publications

Programmed cell death in aging

Programmed cell death in aging

Mitochondrial maintenance failure in aging and role of sexual dimorphism

Run-on of germline apoptosis promotes gonad senescence inC. elegans

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