CHIP Deficiency Decreases Longevity, with Accelerated Aging Phenotypes Accompanied by Altered Protein Quality Control

Min, Jin Na; Whaley, Ryan; Sharpless, Norman E.; Lockyer, Pamela; Portbury, Andrea L.; Patterson, Cam

doi:10.1128/mcb.00296-08

Cited by 227 publications

(210 citation statements)

References 49 publications

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“…(d) Activation of the nuclear protein deacetylase Sirt1 (an antioxidant protein involved in aging) has recently been shown to decrease adipocyte development from preadipocytes, therefore promoting differentiation of mesenchymal stem cells into osteoblasts via inhibition of PPARγ (Backesjo et al 2009). (e) Loss of the carboxyl terminus of Hsp70-interacting protein (CHIP or STUB1), a ubiquitin ligase co-chaperone, is associated with reduced longevity and accelerated aging, including atrophy of skeletal muscle, low BMD, and severe kyphosis in mice (Min et al 2008). (f) Recently, in a meta-analysis of GWAS for BMD, gene ARHGAP1 (at the 11p12) was found to be genome-wide significantly associated with BMD loci.…”

Section: Pleiotropymentioning

confidence: 99%

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Karasik

2010

AGE

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Genetic study can provide insight into the biologic mechanisms underlying inter-individual differences in susceptibility to (or resistance to) organisms' aging. Recent advances in molecular genetics and genetic epidemiology provide the necessary tools to perform a study of the genetic sources of biological aging. However, to be successful, the genetic study of a complex condition requires a heritable phenotype to be developed and validated. Genome-wide association studies offer an unbiased approach to identify new candidate genes for human diseases. It is hypothesized that convergent results from multiple aging-related traits will point out the genes responsible for the general aging of the organism. This perspective focuses on the musculoskeletal aging as an example of an approach to identify a downstream common pathway that summarizes aging processes. Since the musculoskeletal traits are linked to the state of many vital functions, disability, and ultimately survival rates, we postulate that there is significance in studying musculoskeletal aging. Construction of an integrated phenotype of aging can be achieved based on shared genetics among multiple musculoskeletal biomarkers. Valid biomarkers from other systems of the organism should be similarly explored. The new composite aging score needs to be validated by determining whether it predicts all-cause mortality, incidences of major chronic diseases, and disability late in life. Comprehensive databases on biomarkers of musculoskeletal aging in multiple large cohort studies, along with information on various health outcomes, are needed to validate the proposed measure of biological aging.

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Section: Pleiotropymentioning

confidence: 99%

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Karasik

2010

AGE

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“…Conversely, impaired protein quality control results in features of premature aging and shortened LS in mice (Min et al ., 2008). …”

Section: Introductionmentioning

confidence: 99%

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

et al. 2015

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SummaryCombating the social and economic consequences of a growing elderly population will require the identification of interventions that slow the development of age‐related diseases. Preserved cellular homeostasis and delayed aging have been previously linked to reduced cell proliferation and protein synthesis rates. To determine whether changes in these processes may contribute to or predict delayed aging in mammals, we measured cell proliferation rates and the synthesis and replacement rates (RRs) of over a hundred hepatic proteins in vivo in three different mouse models of extended maximum lifespan (maxLS): Snell Dwarf, calorie‐restricted (CR), and rapamycin (Rapa)‐treated mice. Cell proliferation rates were not consistently reduced across the models. In contrast, reduced hepatic protein RRs (longer half‐lives) were observed in all three models compared to controls. Intriguingly, the degree of mean hepatic protein RR reduction was significantly correlated with the degree of maxLS extension across the models and across different Rapa doses. Absolute rates of hepatic protein synthesis were reduced in Snell Dwarf and CR, but not Rapa‐treated mice. Hepatic chaperone levels were unchanged or reduced and glutathione S‐transferase synthesis was preserved or increased in all three models, suggesting a reduced demand for protein renewal, possibly due to reduced levels of unfolded or damaged proteins. These data demonstrate that maxLS extension in mammals is associated with improved hepatic proteome homeostasis, as reflected by a reduced demand for protein renewal, and that reduced hepatic protein RRs hold promise as an early biomarker and potential target for interventions that delay aging in mammals.

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“…CHIP-deficient mice display a decreased life span and accelerated aging characterized by an accumulation of misfolded proteins at the cellular level (Min et al, 2008). The co-chaperone is apparently a determining factor for life span in mammals.…”

Section: Figurementioning

confidence: 99%

Chaperone-assisted degradation: multiple paths to destruction

Kettern

Dreiseidler

Tawo³

et al. 2010

Biological Chemistry

154

155

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Molecular chaperones are well known as facilitators of protein folding and assembly. However, in recent years multiple chaperone-assisted degradation pathways have also emerged, including CAP ( haperone-ssisted roteasomal degradac a p tion), CASA ( haperone-ssisted elective utophagy), and c a s a CMA ( haperone-ediated utophagy). Within these pathc m a ways chaperones facilitate the sorting of non-native proteins to the proteasome and the lysosomal compartment for disposal. Impairment of these pathways contributes to the development of cancer, myopathies, and neurodegenerative diseases. Chaperone-assisted degradation thus represents an essential aspect of cellular proteostasis, and its pharmacological modulation holds the promise to ameliorate some of the most devastating diseases of our time. Here, we discuss recent insights into molecular mechanisms underlying chaperone-assisted degradation in mammalian cells and highlight its biomedical relevance.

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CHIP Deficiency Decreases Longevity, with Accelerated Aging Phenotypes Accompanied by Altered Protein Quality Control

Cited by 227 publications

References 49 publications

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

How pleiotropic genetics of the musculoskeletal system can inform genomics and phenomics of aging

Reduced in vivo hepatic proteome replacement rates but not cell proliferation rates predict maximum lifespan extension in mice

Chaperone-assisted degradation: multiple paths to destruction

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