FOXO/4E-BP Signaling in Drosophila Muscles Regulates Organism-wide Proteostasis during Aging
Open accessAbstract
The progressive loss of muscle strength during aging is a common degenerative event of unclear pathogenesis. Although muscle functional decline precedes age-related changes in other tissues, its contribution to systemic aging is unknown. Here, we show that muscle aging is characterized in Drosophila by the progressive accumulation of protein aggregates that associate with impaired muscle function. The transcription factor FOXO and its target 4E-BP remove damaged proteins at least in part via the autophagy/lysosome system, whereas foxo mutants have dysfunctional proteostasis. Both FOXO and 4E-BP delay muscle functional decay and extend life span. Moreover, FOXO/4E-BP signaling in muscles decreases feeding behavior and the release of insulin from producing cells, which in turn delays the age-related accumulation of protein aggregates in other tissues. These findings reveal an organism-wide regulation of proteostasis in response to muscle aging and a key role of FOXO/4E-BP signaling in the coordination of organismal and tissue aging.
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Ubiquitinated proteins accumulate in aged Drosophila muscles.
“Recent studies in Drosophila showed that ubiquitinated proteins accumulated in aged muscles[12, 13]”
From Overexpression of pink1 or parkin in indirect flight muscles promotes mitochondrial proteostasis and extends lifespan in Drosophila melanogaster (2019) · cites this paper as [12]
Skeletal muscle autophagy declines with aging in Drosophila and can be rescued by FOXO overexpression or constitutive activation of EIF4EBP1.
“On the one hand, skeletal muscle autophagy declines with aging in Drosophila and can be rescued by FOXO overexpression or constitutive activation of EIF4EBP1 [490].”
From Autophagy and ALS: mechanistic insights and therapeutic implications (2022) · cites this paper as [490]
FoxO transcriptionally activates several protein-folding chaperone genes, some of which may regulate aging.
“FoxO transcriptionally activates several protein-folding chaperone genes82–84 some of which may regulate aging84–87.”
From Stem cell aging: mechanisms, regulators and therapeutic opportunities (2014) · cites this paper as [84]
In Drosophila, dysfunction of the gut and skeletal muscle appear to be primary drivers of aging and mortality.
“In Drosophila, dysfunction of the gut and skeletal muscle appear to be primary drivers of aging and mortality.39,40,41,42”
From Asynchronous, contagious and digital aging (2021) · cites this paper as [41]
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Autophagy and ALS: mechanistic insights and therapeutic implications
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Skeletal muscle autophagy and its role in sarcopenia and organismal aging
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Self-citationProtein synthesis and quality control in aging
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Signaling networks determining life span
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Systemic Nutrient and Stress Signaling via Myokines and Myometabolites
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“In Drosophila, the progressive accumulation of protein aggregates is a characteristic of aging in skeletal muscle (Demontis and Perrimon, 2010).”
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- Authors
- Demontis, F., & Perrimon, N.
- Affiliations
- Harvard University (US)
- Howard Hughes Medical Institute (US)
- Corresponding author
- Demontis, Fabio
- Perrimon, Norbert
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2010-11
- Volume
- 143
- Issue
- 5
- Pages
- 813-825
- ISSN
- 0092-8674 (ISSN-L)
- PMC
- PMC3066043
- OpenAlex
- W1972597570
- Cited by
- 656
- References
- 64
- Citations by year
- 2026: 26 · 2025: 41 · 2024: 40 · 2023: 34 · 2022: 54 · 2021: 73 · 2020: 42 · 2019: 38 · 2018: 37 · 2017: 48 · 2016: 49 · 2015: 39 · 2014: 44 · 2013: 42 · 2012: 22
- FWCI
- 9.93
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (vor, 1025 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- Funders
- Ellison Medical Foundation
- National Institutes of Health
- National Cancer Institute (P01CA120964)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK088718)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR057352)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › FOXO transcription factor regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
- Keywords
- FOXO, 4E-BP, muscle aging, proteostasis, protein aggregates, autophagy-lysosome system, Drosophila, lifespan extension, insulin signaling, feeding behavior, systemic aging
- MeSH terms
- Aging, Animals, Autophagy, Drosophila melanogaster, Humans, Lysosomes, Muscle Proteins, Muscles, Peptide Initiation Factors, Signal Transduction, Models, Animal, Drosophila Proteins, Intracellular Signaling Peptides and Proteins, Forkhead Transcription Factors
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