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1.
Aging Cell ; 17(2)2018 04.
Article in English | MEDLINE | ID: mdl-29314608

ABSTRACT

Aging is commonly defined as the loss of global homeostasis, which results from progressive alteration of all organs function. This model is currently challenged by recent data showing that interventions that extend lifespan do not always increase the overall fitness of the organism. These data suggest the existence of tissue-specific factors that regulate the pace of aging in a cell-autonomous manner. Here, we investigated aging of Caenorhabditis elegans striated muscles at the subcellular and the physiological level. Our data show that muscle aging is characterized by a dramatic decrease in the expression of genes encoding proteins required for muscle contraction, followed by a change in mitochondria morphology, and an increase in autophagosome number. Myofilaments, however, remain unaffected during aging. We demonstrated that the conserved transcription factor UNC-120/SRF regulates muscle aging biomarkers. Interestingly, the role of UNC-120/SRF in the control of muscle aging can be dissociated from its broader effect on lifespan. In daf-2/insulin/IGF1 receptor mutants, which exhibit a delayed appearance of muscle aging biomarkers and are long-lived, disruption of unc-120 accelerates muscle aging but does not suppress the lifespan phenotype of daf-2 mutant. Conversely, unc-120 overexpression delays muscle aging but does not increase lifespan. Overall, we demonstrate that UNC-120/SRF controls the pace of muscle aging in a cell-autonomous manner downstream of the insulin/IGF1 receptor.


Subject(s)
Caenorhabditis elegans Proteins/metabolism , Caenorhabditis elegans/genetics , Longevity/genetics , MADS Domain Proteins/genetics , Muscles/metabolism , Aging , Animals , Caenorhabditis elegans Proteins/genetics , Transcription Factors
2.
J Proteome Res ; 13(6): 2910-9, 2014 Jun 06.
Article in English | MEDLINE | ID: mdl-24819046

ABSTRACT

Dietary restriction (DR) is one of the most universal means of extending lifespan. Yet, whether and how DR specifically affects the metabolic changes associated with aging is essentially unknown. Here, we present a comprehensive and unbiased picture of the metabolic variations that take place with age at the whole organism level in Caenorhabditis elegans by using (1)H high-resolution magic-angle spinning (HR-MAS) nuclear magnetic resonance (NMR) analysis of intact worms. We investigate metabolic variations potentially important for lifespan regulation by comparing the metabolic fingerprint of two previously described genetic models of DR, the long-lived eat-2(ad465) and slcf-1(tm2258) worms, as single mutants or in combination with a genetic suppressor of their lifespan phenotype. Our analysis shows that significant changes in metabolite profiles precede the major physiological decline that accompanies aging and that DR protects from some of those metabolic changes. More specifically, low phosphocholine (PCho) correlates with high life expectancy. A mutation in the tumor suppressor gene PTEN/DAF-18, which suppresses the beneficial effects of DR in both C. elegans and mammals, increases both PCho level and choline kinase expression. Furthermore, we show that choline kinase function in the intestine can regulate lifespan. This study highlights the relevance of NMR metabolomic approaches for identifying potential biomarkers of aging.


Subject(s)
Aging , Caenorhabditis elegans/metabolism , Metabolome , Animals , Caenorhabditis elegans Proteins/genetics , Caenorhabditis elegans Proteins/metabolism , Caloric Restriction , Choline Kinase/genetics , Choline Kinase/metabolism , Gene Expression , Intestines/enzymology , Magnetic Resonance Spectroscopy , Metabolomics , Mutation , Phosphorylcholine/metabolism
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