Age and Diet Affect Gene Expression Profiles in Canine Liver Tissue

Kil, Dong Yong; Boler, Brittany M. Vester; Apanavicius, Carolyn J.; Schook, Lawrence B.; Swanson, Kelly S.

doi:10.1371/journal.pone.0013319

Cited by 17 publications

(13 citation statements)

References 59 publications

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“…PCK1 has been demonstrated to be a multifunctional gene and was closely related to gluconeogenesis, obesity, and diabetes [11,12]. Recent studies have shown that PCK1 expression is significantly reduced in aging nematodes after the peak reproductive period, and PCK1 expression is downregulated in skeletal muscle and liver in aging mammals [13][14][15][16]. Nonetheless, the effect and detailed molecular mechanism of PCK1 on aging process are still far to be elucidated.…”

Section: Introductionmentioning

confidence: 99%

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

Yuan

Lin

Cui

et al. 2020

BioMed Research International

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The cytosolic isozyme of phosphoenolpyruvate carboxykinase (PCK1) was the first rate-limiting enzyme in the gluconeogenesis pathway, which exerted a critical role in maintaining the blood glucose levels. PCK1 has been established to be involved in various physiological and pathological processes, including glucose metabolism, lipid metabolism, diabetes, and tumorigenesis. Nonetheless, the association of PCK1 with aging process and the detailed underlying mechanisms of PCK1 on aging are still far to be elucidated. Hence, we herein constructed the PCK1-deficient (pck1Δ) and PCK1 overexpression (PCK1 OE) Saccharomyces cerevisiae. The results unveiled that PCK1 deficiency significantly shortened the replicative lifespan (RLS) in the S. cerevisiae, while overexpression of PCK1 prolonged the RLS. Additionally, we noted that the ROS level was significantly enhanced in PCK1-deficient strain and decreased in PCK1 OE strain. Then, a high throughput analysis by deep sequencing was performed in the pck1Δ and wild-type strains, in an attempt to shed light on the effect of PCK1 on the lifespan of aging process. The data showed that the most downregulated mRNAs were enriched in the regulatory pathways of glucose metabolism. Fascinatingly, among the differentially expressed mRNAs, PFK1 was one of the most upregulated genes, which was involved in the glycolysis process and ROS generation. Thus, we further constructed the pfk1Δpck1Δ strain by deletion of PFK1 in the PCK1-deficient strain. The results unraveled that pfk1Δpck1Δ strain significantly suppressed the ROS level and restored the RLS of pck1Δ strain. Taken together, our data suggested that PCK1 deficiency enhanced the ROS level and shortened the RLS of S. cerevisiae via PFK1.

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Section: Introductionmentioning

confidence: 99%

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

Yuan

Lin

Cui

et al. 2020

BioMed Research International

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“…Here, we propose that PEPCK-C is a major energy metabolism adaptor that promotes health and longevity. Because PEPCK-C mRNA is decreased and PK mRNA is increased in aged muscle and liver of mammals (14,15), we hypothesize that a decline in PEPCK-C with age and a reciprocal increase in PK disrupt energy homeostasis, reduce cellular function and integrity, and promote aging. Because PEPCK-C catalyzes only one chemical reaction, which converts oxaloacetate to phosphoenolpyruvate (PEP), its modification has a direct and traceable impact on energy metabolism.…”

mentioning

confidence: 99%

Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans

Yuan¹,

Hakimi²,

Kao³

et al. 2016

Journal of Biological Chemistry

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Aging involves progressive loss of cellular function and integrity, presumably caused by accumulated stochastic damage to cells. Alterations in energy metabolism contribute to aging, but how energy metabolism changes with age, how these changes affect aging, and whether they can be modified to modulate aging remain unclear. In locomotory muscle of post-fertile Caenorhabditis elegans, we identified a progressive decrease in cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C), a longevity-associated metabolic enzyme, and a reciprocal increase in glycolytic pyruvate kinase (PK) that were necessary and sufficient to limit lifespan. Decline in PEPCK-C with age also led to loss of cellular function and integrity including muscle activity, and cellular senescence. Genetic and pharmacologic interventions of PEPCK-C, muscle activity, and AMPK signaling demonstrate that declines in PEPCK-C and muscle function with age interacted to limit reproductive life and lifespan via disrupted energy homeostasis. Quantifications of metabolic flux show that reciprocal changes in PEPCK-C and PK with age shunted energy metabolism toward glycolysis, reducing mitochondrial bioenergetics. Last, calorie restriction countered changes in PEPCK-C and PK with age to elicit antiaging effects via TOR inhibition. Thus, a programmed metabolic event involving PEPCK-C and PK is a determinant of aging that can be modified to modulate aging.Aging is characterized by the progressive decline in cellular function and integrity that leads to disease vulnerability and eventually death of organisms (1). The leading proposed cause of decline in cellular function and integrity with age is the accumulation of stochastic damage of molecules and organelles by reactive molecules, such as reactive oxygen species (ROS). Whether ROS are detrimental to organisms and whether ROS limit lifespan, however, are in debate (2).Energy metabolism supplies ATP for cellular function and maintenance. Alterations in energy metabolism are linked to the aging process and aging-associated diseases (3). In model organisms, environmental and genetic factors that change energy metabolism, such as calorie restriction (CR) (4), inhibition of target of rapamycin (TOR) (5), and 5Ј AMP kinase (AMPK) (6) are determinants of longevity. A large body of aging research has been focusing on the signaling of CR, TOR inhibition, and AMPK in regulating longevity. The exact alterations in energy metabolism that occur with age, how these changes impact aging, and whether they can be modified to modulate aging are understudied and remain poorly understood, largely due to the intrinsic complexity of energy metabolism, and the indirect impact of these longevity paradigms on energy metabolism. This impedes the understanding of aging mechanisms and the development of mechanism-based strategies to modulate aging.A key regulation of energy metabolism at the cellular level is the reciprocal changes of PK and PEPCK-C (7). Whether this regulation of cellular energy metabolism contributes to organismal aging is...

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“…In the CAST x B6 cross it has a strong cis-eQTL peak with LOD score of 15.9 which essentially coincides with the HDL QTL peak on chromosome 2 (Supplementary Figure 11). To the best of our knowledge this gene has not been associated with HDL, although it has been observed that its expression increases with higher cholesterol levels in aging canine livers (72). Interestingly, the human WDC2 gene is located on chromosome 20 at base The next causal candidate gene is histone deacetylase 3 ( Hdac3 ) .…”

Section: Resultsmentioning

confidence: 99%

A systems genetic analysis of high density lipoprotein metabolism and network preservation across mouse models

Langfelder¹,

Castellani

Zhou

et al. 2012

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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We report a systems genetics analysis of high density lipoproteins (HDL) levels in an F2 intercross between inbred strains CAST/EiJ and C57BL/6J. We previously showed that there are dramatic differences in HDL metabolism in a cross between these strains, and we now report co-expression network analysis of HDL that integrates global expression data from liver and adipose with relevant metabolic traits. Using data from a total of 293 F2 intercross mice, we constructed weighted gene co-expression networks and identified modules (subnetworks) associated with HDL and clinical traits. These were examined for genes implicated in HDL levels based on large human genome-wide associations studies (GWAS) and examined with respect to conservation between tissue and sexes in a total of 9 data sets. We identify genes that are consistently ranked high by association with HDL across the 9 data sets. We focus in particular on two genes, Wfdc2 and Hdac3, that are located in close proximity to HDL QTL peaks where causal testing indicates that they may affect HDL. Our results provide a rich resource for studies of complex metabolic interactions involving HDL.

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Age and Diet Affect Gene Expression Profiles in Canine Liver Tissue

Cited by 17 publications

References 59 publications

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

PCK1Deficiency Shortens the Replicative Lifespan ofSaccharomyces cerevisiaethrough Upregulation ofPFK1

Reciprocal Changes in Phosphoenolpyruvate Carboxykinase and Pyruvate Kinase with Age Are a Determinant of Aging in Caenorhabditis elegans

A systems genetic analysis of high density lipoprotein metabolism and network preservation across mouse models

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