Differential Dose- and Tissue-Dependent Effects of foxo on Aging, Metabolic and Proteostatic Pathways

• Published in: Cells (Basel, Switzerland) Vol. 10; no. 12; p. 3577
• Main Authors: Manola, Maria S, Gumeni, Sentiljana, Trougakos, Ioannis P
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 18.12.2021; MDPI
• Subjects: Aging; Aging - metabolism; Animals; Animals, Genetically Modified; Cardiomyocytes; Drosophila; Drosophila melanogaster - metabolism; Drosophila Proteins - metabolism; Energy Metabolism; Energy resources; Forkhead protein; Forkhead Transcription Factors - metabolism; FOXO; Gene expression; Heat-Shock Response; Homeostasis; Insects; Insulin; Insulin-like growth factors; Kinases; Longevity; Metabolic Networks and Pathways; Metabolism; Middle age; Muscles; Muscles - metabolism; Myocytes, Cardiac - metabolism; Nrf2/cncC; Nutrients; Organ Specificity; Oxidative Stress; Phenotype; Phenotypes; proteasome; Proteasome Endopeptidase Complex - metabolism; Proteasomes; Proteins; Proteome - metabolism; Proteostasis; proteostasis network; Quality control; Toxicity; Transcription factors; Ubiquitin; New York; United States > US; Germany; Nrf2/cncC; FOXO; proteasome; proteostasis network; Drosophila
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells10123577

Aging is the gradual deterioration of physiological functions that culminates in death. Several studies across a wide range of model organisms have revealed the involvement of FOXO (forkhead box, class O) transcription factors in orchestrating metabolic homeostasis, as well as in regulating longevity. To study possible dose- or tissue-dependent effects of sustained overexpression, we utilized two different transgenic lines expressing high and relatively low levels and overexpressed , either ubiquitously or in a tissue-specific manner. We found that ubiquitous overexpression (OE) accelerated aging, induced the early onset of age-related phenotypes, increased sensitivity to thermal stress, and deregulated metabolic and proteostatic pathways; these phenotypes were more intense in transgenic flies expressing high levels of . Interestingly, there is a defined dosage of OE in muscles and cardiomyocytes that shifts energy resources into longevity pathways and thus ameliorates not only tissue but also organismal age-related defects. Further, we found that OE stimulates in an Nrf2/cncC dependent-manner, counteracting proteostatic pathways, e.g., the ubiquitin-proteasome pathway, which is central in ameliorating the aberrant OE-mediated toxicity. These findings highlight the differential dose- and tissue-dependent effects of foxo on aging, metabolic and proteostatic pathways, along with the foxo-Nrf2/cncC functional crosstalk.