Abstract
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 foxo overexpression, we utilized two different Drosophila transgenic lines expressing high and relatively low foxo levels and overexpressed foxo, either ubiquitously or in a tissue-specific manner. We found that ubiquitous foxo 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 foxo. Interestingly, there is a defined dosage of foxo 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 foxo OE stimulates in an Nrf2/cncC dependent-manner, counteracting proteostatic pathways, e.g., the ubiquitin-proteasome pathway, which is central in ameliorating the aberrant foxo 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.
Highlights
Aging is a complex phenomenon caused by the time-dependent loss of cellular homeodynamics and, physiological organismal functions
To better understand the functional implication of foxo in longevity and proteostasis, we sought to investigate the effects of inducible ubiquitous (TubGal4) foxo OE in Drosophila flies
We found no significant alternations in cellular cathepsins activity status in either foxo overexpressing lines (Figure 6c), we noted in both lines upregulation of antioxidant and autophagy-related (hDAC6, ref(2)P, Atg8a) genes (Figure 6d); we found a significant induction of proteasomal genes (Prosα7, Prosβ1, Prosβ5, Rpn6, Rpn10) (Figure 6e) and of most protein subunits [20S-(a), Prosβ5 and Rpn6] (Figure 6f and Figure S6a), as well as of both of chymotrypsin- (CT-L) and caspase- (C-L) like 26S proteasome activities after ubiquitous foxo OE (Figure 6g)
Summary
Aging is a complex phenomenon caused by the time-dependent loss of cellular homeodynamics and, physiological organismal functions. Since the initial discovery that mutations in IIS-related genes extend lifespan [4], several research groups have shown that either pharmacological or genetic IIS downregulation extends lifespan in a wide variety of model organisms [5]. Another vital process for organismal homeostasis is maintenance of proteostasis, which has been proven to be central in decelerating the onset of age-related phenotypes; proteostasis is ensured by proteome quality control mechanisms [6] that refer to a highly integrated multilevel system, known as the proteostasis network (PN) [7]. The disruption of the major PN signaling cascades or the deregulation of the PN regulators leads to PN impairment and to increased risk for premature aging [10]
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