Insulin/IGF-I-signaling pathway: an evolutionarily conserved mechanism of longevity from yeast to humans
ABSTRACT Although the underlying mechanisms of longevity are not fully understood, it is known that mutation in genes that share similarities with those in humans involved in the insulin/insulin-like growth factor I (IGF-I) signal response pathway can significantly extend life span in diverse species, including yeast, worms, fruit flies, and rodents. Intriguingly, the long-lived mutants, ranging from yeast to mice, share some important phenotypic characteristics, including reduced insulin signaling, enhanced sensitivity to insulin, and reduced IGF-I plasma levels. Such genetic homologies and phenotypic similarities between insulin/IGF-I pathway mutants raise the possibility that the fundamental mechanism of aging may be evolutionarily conserved from yeast to mammals. Very recent findings also provide novel and intriguing evidence for the involvement of insulin and IGF-I in the control of aging and longevity in humans. In this study, we focus on how the insulin/IGF-I pathway controls yeast, nematode, fruit fly, and rodent life spans and how it is related to the aging process in humans to outline the prospect of a unifying mechanism in the genetics of longevity.
SourceAvailable from: Augusto Schneider[Show abstract] [Hide abstract]
ABSTRACT: Background The insulin receptor substrate 1 (IRS1), phosphoinositide 3-kinase (Pi3k), protein kinase B (Akt1), Forkhead Box O3a (FOXO3a) pathway is directly involved in aging and ovarian activation of follicle growth. Therefore, the aim of this work was to measure the expression of genes related to the ovarian pathway for activation of primordial follicles and FOXO3a protein phosphorylation between young and old female Ames dwarf (df/df) and normal (N) mice.Methods For this study ovaries from N (n¿=¿10) and df/df (n¿=¿10) female mice were collected at 5¿6 months of age and at 21¿22 months of age. For immunohistochemistry ovaries from 12 month-old and df/df mice were used.ResultsThe expression of Irs1, Pi3k, Akt1, mammalian target of rapamycin (Mtor), suppressor of cytokine signaling ¿2 (Socs2), Socs3 was lower (P¿<¿0.05) in older than younger N mice and not different (P¿>¿0.05) between young and old df/df mice. The expression of Foxo3a was also lower (P¿<¿0.05) in old than younger N and df/df mice and was higher (P¿<¿0.05) in old df/df than N mice. Expression of Amh was lower (P¿<¿0.05) in old than young N and df/df mice and was higher (P¿=¿0.0009) in df/df than N mice. Imunnostaining for p-FOXO3 was lower in df/df than N mice (P¿<¿0.001), although FOXO3 immunostaining was not different (P¿>¿0.05) between df/df and N mice.Conclusions In sum, the present study indicates that lower expression of Irs1, Socs2, Socs3, Akt1, Pi3k, Mtor and Foxo3a mRNA in the ovaries of older mice of both genotypes is associated to a reduced ovarian activity revealed by lower expression of Amh mRNA. At the same time, ovaries of old df/df mice maintained higher expression of Foxo3a mRNA, which was associated to higher ovarian activity. We have shown that df/df females have a lower level of p-FOXO3 in oocytes from primordial/primary follicles, an important activator of follicular growth. Therefore, this study strongly indicates that Prop1df mutation causes delayed ovarian aging.Journal of Ovarian Research 12/2014; 7(1):284. DOI:10.1186/s13048-014-0120-4 · 2.03 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Electrical current at physiological strength has been applied as a therapeutic approach for various diseases. Several of our works showed that mild electrical stimulation (MES) at 0.1-ms pulse width has positive impact on organisms. But despite the growing evidence of the beneficial effects of MES, its effects on individual animals and the molecular underpinnings are poorly understood and rarely studied. Here, we examined the effects of MES on individual animal and its mechanisms by mainly using Caenorhabditis elegans, a powerful genetic model organism. Interestingly, MES increased stress resistance and suppressed excess fat accumulation in wild-type N2 worms but not in AMPK/AAK-2 and LKB1/PAR-4 mutant worms. MES promoted the nuclear localization of transcription factors DAF-16 and SKN-1 and consequently increased the expression of anti-stress genes, whereas MES inhibited the nuclear localization of SBP-1 and suppressed the expression of lipogenic genes. Moreover, we found that MES induced the activation of LKB1/PAR4-AMPK/AAK2 pathway in C. elegans and in several mammalian cell lines. The mitochondrial membrane potential and cellular ATP level were slightly and transiently decreased by MES leading to the activation of LKB1-AMPK signaling pathway. Together, we firstly and genetically demonstrated that MES exerts beneficial effects such as stress resistance and suppression of excess fat accumulation, via activation of LKB1-AMPK signaling pathway.PLoS ONE 12/2014; 9(12):e114690. DOI:10.1371/journal.pone.0114690 · 3.53 Impact Factor
[Show abstract] [Hide abstract]
ABSTRACT: Aging influences stem cells, but the processes involved remain unclear. Insulin signaling, which controls cellular nutrient sensing and organismal aging, regulates the G2 phase of Drosophila female germ line stem cell (GSC) division cycle in response to diet; furthermore, this signaling pathway is attenuated with age. The role of insulin signaling in GSCs as organisms age, however, is also unclear. Here, we report that aging results in the accumulation of tumorous GSCs, accompanied by a decline in GSC number and proliferation rate. Intriguingly, GSC loss with age is hastened by either accelerating (through eliminating expression of Myt1, a cell cycle inhibitory regulator) or delaying (through mutation of insulin receptor (dinR) GSC division, implying that disrupted cell cycle progression and insulin signaling contribute to age-dependent GSC loss. As flies age, DNA damage accumulates in GSCs, and the S phase of the GSC cell cycle is prolonged. In addition, GSC tumors (which escape the normal stem cell regulatory microenvironment, known as the niche) still respond to aging in a similar manner to normal GSCs, suggesting that niche signals are not required for GSCs to sense or respond to aging. Finally, we show that GSCs from mated and unmated females behave similarly, indicating that female GSC-male communication does not affect GSCs with age. Our results indicate the differential effects of aging and diet mediated by insulin signaling on the stem cell division cycle, highlight the complexity of the regulation of stem cell aging, and describe a link between ovarian cancer and aging. © 2014 The Authors. Aging Cell published by the Anatomical Society and John Wiley & Sons Ltd.Aging cell 12/2014; DOI:10.1111/acel.12288 · 7.55 Impact Factor