FOXO/4E-BP Signaling in Drosophila Muscles Regulates Organism-wide Proteostasis During Aging

By Fabio Demontis, Norbert Perrimon. Cell, 2010

655 citations recorded by the source corpus.

SUMMARY 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, while foxo mutants have dysfunctional proteostasis. Both FOXO and 4E-BP delay muscle functional decay and extend lifespan. 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.

Subfields: Aging, Epidemiology, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/b4288efa1591b9cc332a427b374225196c7def36

How researchers see this paper

The researchers whose trusted networks rank it highest, strongest advocate first. Every researcher gets a different order.

In Aging

1. M. Hayer-Hartl
2. Jesús Gil
3. F. Hartl
4. Guido Kroemer
5. Guillermo Mariño
6. Rute Martins
7. W. Link
8. G. Lithgow

In Epidemiology

1. Guido Kroemer
2. Guillermo Mariño
3. D. Rubinsztein
4. Jesús Gil
5. Domhnall McHugh
6. S. Imai
7. M. Sandri
8. Beth Levine

In Molecular Biology

1. F. Hartl
2. Guillermo Mariño
3. M. Hayer-Hartl
4. D. Rubinsztein
5. P. Bonaldo
6. Jesús Gil
7. Guido Kroemer
8. P. Jat

Citations in the corpus

• Senescence and aging: Causes, consequences, and therapeutic avenues (2018, background): “Interestingly FOXO transcription factors regulate aging, with FOXO activity in Drosophila melanogaster leading to delayed aging in response to disrupted protein homeostasis and oxidative stress (Demontis and Perrimon, 2010).”
• Mechanisms of Cellular Senescence: Cell Cycle Arrest and Senescence Associated Secretory Phenotype (2021, background): “thereby delaying muscle function decay and extending life span (Demontis and Perrimon, 2010).”
• Long live FOXO: unraveling the role of FOXO proteins in aging and longevity (2015, background): “FOXOs affect the expression of genes involved in autophagy and mitophagy (muscle-specific autophagy) in muscle cells from flies (dFOXO) to mammals (FOXO3), allowing adaptation of the tissues to starvation (Zhao et al., 2007; Sengupta et al., 2009; Demontis & Perrimon, 2010).”
• Autophagy and aging. (2011, background): “…abolishes the age-associated decline in autophagy and increases longevity while it reduces food intake and insulin release from neurosecretory cells (Demontis and Perrimon , 2010), suggesting that maintenance of a normal autophagy level in one organ may positively affect whole-body metabolism.”
• Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. (2013, background): “Recent studies 416 Cell Metabolism 18, 416–430, September 3, 2013 ª2013 Elsevie in worms and flies have also suggested that systemic interplay between multiple tissues regulates aging and longevity (Demontis and Perrimon, 2010; Durieux et al., 2011).”
• Cellular and molecular mechanisms of muscle atrophy (2013, background): “Selective activation of autophagy in skeletal muscle via FoxO prevents accumulation of protein aggregates and, consequently, muscle weakness, thus providing the first genetic evidence correlating FoxO, autophagy and healthy muscles to lifespan extension (Demontis and Perrimon, 2010).”
• Molecular chaperones in protein folding and proteostasis (2011, background): “Proteostasis collapse in ageing and disease The accumulation of misfolded and/or oxidized proteins in cells during ageing is a challenge to the proteostasis system and eventually results in the deposition of aggregates, as shown in model organisms such as Caenorhabditis elegans and Drosophila”
• Molecular definitions of autophagy and related processes (2017, neutral): “In D. melanogaster the control of proteostasis by aggrephagy impinges on forkhead box, subgroup O (FOXO)-dependent transcription (Demontis & Perrimon, 2010).”