Περίληψη:
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.
Συγγραφείς:
Manola, Maria S.
Gumeni, Sentiljana
Trougakos, Ioannis P.
