Proteasome stress in skeletal muscle mounts a long-range protective response that delays retinal and brain aging

Rai, Mamta; Coleman, Zane; Curley, Michelle; Nityanandam, Anjana; Platt, Anna; Robles-Murguia, Maricela; Jiao, Jianqin; Finkelstein, David; Wang, Yongdong; Xu, Beisi; Fan, Yiping; Demontis, Fabio

doi:10.1016/j.cmet.2021.03.005

Cited by 54 publications

(59 citation statements)

References 119 publications

(143 reference statements)

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“…Proteostasis decline with aging and defects in protein quality control are the underlying cause of multiple age-related diseases ( Douglas and Dillin, 2010 ; Labbadia and Morimoto, 2015 ). We have recently found that proteostasis declines during skeletal muscle aging (sarcopenia) in mice ( Demontis et al., 2013 ; Hunt et al., 2021 ; Jiao and Demontis, 2017 ), and that protein quality control is compromised across tissues and organ systems in the fruit fly Drosophila during aging ( Demontis and Perrimon, 2010 ; Rai et al., 2021 ). Moreover, by using thermal stress as a proxy for age-induced challenge to proteostasis, we have investigated the role of genetic and chemical interventions on proteostasis of human brain organoids and HEK293 cells ( Rai et al., 2021 ).…”

Section: Before You Beginmentioning

confidence: 99%

“…We have recently found that proteostasis declines during skeletal muscle aging (sarcopenia) in mice ( Demontis et al., 2013 ; Hunt et al., 2021 ; Jiao and Demontis, 2017 ), and that protein quality control is compromised across tissues and organ systems in the fruit fly Drosophila during aging ( Demontis and Perrimon, 2010 ; Rai et al., 2021 ). Moreover, by using thermal stress as a proxy for age-induced challenge to proteostasis, we have investigated the role of genetic and chemical interventions on proteostasis of human brain organoids and HEK293 cells ( Rai et al., 2021 ). Below, we describe the protocols for the analysis of detergent-soluble and insoluble protein fractions in these models and provide details that can help adapt this protocol for the analysis of proteostasis in other experimental systems.…”

Section: Before You Beginmentioning

confidence: 99%

“…Tissues from Drosophila and mice of the desired genotypes and ages, and treatment of HKE293 cells and human brain organoids should be done according to the specific experimental requirements and following procedures as described in our and other recent studies ( Hunt et al., 2019a ; Hunt et al., 2021 ; Hunt et al., 2019b ; Hunt et al., 2015 ; Rai et al., 2021 ). Once obtained, these tissues can be examined following the procedures described below.…”

Section: Before You Beginmentioning

confidence: 99%

“…We describe key adaptations of this protocol and provide key information that will help modify this protocol for future studies in other tissues and disease models. For complete details on the use and execution of this protocol, please refer to Rai et al. (2021) and Hunt el al.…”

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confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Rai et al. (2021) and Hunt el al.…”

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confidence: 99%

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Analysis of proteostasis during aging with western blot of detergent-soluble and insoluble protein fractions

et al. 2021

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Summary Defects in protein quality control are the underlying cause of age-related diseases. The western blot analysis of detergent-soluble and insoluble protein fractions has proven useful in identifying interventions that regulate proteostasis. Here, we describe the protocol for such analyses in Drosophila tissues, mouse skeletal muscle, human organoids, and HEK293 cells. We describe key adaptations of this protocol and provide key information that will help modify this protocol for future studies in other tissues and disease models. For complete details on the use and execution of this protocol, please refer to Rai et al. (2021) and Hunt el al. (2021) .

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Section: Before You Beginmentioning

confidence: 99%

Section: Before You Beginmentioning

confidence: 99%

Section: Before You Beginmentioning

confidence: 99%

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confidence: 99%

“…For complete details on the use and execution of this protocol, please refer to Rai et al. (2021) and Hunt el al.…”

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Analysis of proteostasis during aging with western blot of detergent-soluble and insoluble protein fractions

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Exosome Release Delays Senescence by Disposing of Obsolete Biomolecules

et al. 2023

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Accumulation of obsolete biomolecules can accelerate cell senescence and organism aging. The two efficient intracellular systems, namely the ubiquitin‐proteasome system and the autophagy‐lysosome system, play important roles in dealing with cellular wastes. However, how multicellular organisms orchestrate the processing of obsolete molecules and delay aging remains unclear. Herein, it is shown that prevention of exosome release by GW4869 or Rab27a−/− accelerated senescence in various cells and mice, while stimulating exosome release by nutrient restriction delays aging. Interestingly, exosomes isolate from serum‐deprived cells or diet‐restricted human plasma, enriched with garbage biomolecules, including misfolded proteins, oxidized lipids, and proteins. These cellular wastes can be englobed by macrophages, eventually, for disintegration in vivo. Inhibition of nutrient‐sensing mTORC1 signaling increases exosome release and delays senescence, while constitutive activation of mTORC1 reduces exosome secretion and exacerbates senescence in vitro and in mice. Notably, inhibition of exosome release attenuates nutrient restriction‐ or rapamycin‐delayed senescence, supporting a key role for exosome secretion in this process. This study reveals a potential mechanism by which stimulated exosome release delays aging in multicellular organisms, by orchestrating the harmful biomolecules disposal via exosomes and macrophages.

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