Ras-pathway has a dual role in yeast galactose metabolism

In the yeast Saccharomyces cerevisiae the genes involved in galactose metabolism (GAL1,7,10) are transcriptionally activated more than a 1000-fold in the presence of galactose as the sole carbon source in the culture media. In the present work, we monitored the activity of the GAL10 gene promoter in different Ras-cAMP genetic backgrounds. We demonstrate that overexpression of C-terminus of the nucleotide exchange factor Cdc25p stimulates GAL10 transcription in yeast strains carrying the contemporary deletion of both RAS genes. Moreover, the deletion of the chromosomal CDC25 gene provokes impaired growth on galactose based media in yeast strain lacking both RAS genes and adenylate cyclase (whose viability is assured by the presence of the Bcy1-11 allele). Surprisingly, reconstitution of the Ras-pathway inhibits GAL10-promoter activation. Activation of GAL10 gene promoter is indeed possible in the presence of Ras protein but only in strains with chromosomal deletion of adenylate cyclase. These results indicate a dual role of Ras-pathway on galactose metabolism and suggest that Cdc25p has a Ras-independent role in cellular metabolism

mtDNA analysis of the human remains buried in the sarcophagus of Federico II

The sarcophagus containing the remains of Federico II, located in the Cathedral of Palermo (Sicily, Italy), was opened on 1998 to perform a multidisciplinary survey [1]. Next to the remains of Federico II and in close contact with them were laying two other skeletons belonging, according to historical records, to Pietro II di Aragona and to an anonymous person (“The Third Individual”), probably a woman. The bones appeared severely deteriorated. Chemical analysis performed on bone samples excluded that the bodies underwent some kind of embalming process. The analysis of mtDNA from bone samples taken from the three skeletons was successful in only one of the two labs involved. The HVR1-mtDNA sequence (region: from nt 16,035 to nt 16,395), obtained from the bone samples of Federico II and “The Third Individual” appear identical but bear double peaks at the same nucleotide positions, suggesting mixing (i.e. contamination) of different mtDNA types. The HVR1 sequence obtained from the bone sample of Pietro II di Aragona does not present double peaks and differ from the Cambridge Reference Sequence (CRS) at six nucleotide positions. Cloning experiment of the Federico II amplicon demonstrated that the mixed mtDNA types are only two: one identical to CRS, the other identical to the sequence of Pietro II di Aragona. A reconstruction of these data are proposed in the Discussion. Due to the problematic context in which this study was carried out (mixed and deteriorated biological material, failure to replicate results in two different labs), our results and reconstruction can only be offered on a tentative basis. It is hoped that the data presented in this study will reveal useful, for future comparison, if further molecular genetics research will be carried out on the royal dynasties that ruled Sicily in the early centuries of the past millennium

Tor-Sch9 deficiency activates catabolism of the ketone body-like acetic acid to promote trehalose accumulation and longevity.

n mammals, extended periods of fasting leads to the accumulation of blood ketone bodies including acetoacetate. Here we show that similar to the conversion of leucine to acetoacetate in fasting mammals, starvation conditions induced ketone body-like acetic acid generation from leucine in S. cerevisiae. Whereas wild-type and ras2Δ cells accumulated acetic acid, long-lived tor1Δ and sch9Δ mutants rapidly depleted it through a mitochondrial acetate CoA transferase-dependent mechanism, which was essential for lifespan extension. The sch9Δ-dependent utilization of acetic acid also required coenzyme Q biosynthetic genes and promoted the accumulation of intracellular trehalose. These results indicate that Tor-Sch9 deficiency extends longevity by switching cells to an alternative metabolic mode, in which acetic acid can be utilized for the storage of stress resistance carbon sources. These effects are reminiscent of those described for ketone bodies in fasting mammals and raise the possibility that the lifespan extension caused by Tor-S6K inhibition may also involve analogous metabolic changes in higher eukaryotes

Dietary restriction: could it be considered as speed bump on tumor progression road?

Dietary restrictions, including fasting (or long-term starvation), calorie restriction (CR), and short-term starvation (STS), are considered a strong rationale that may protect against various diseases, including age-related diseases and cancer. Among dietary approaches, STS, in which food is not consumed during designed fasting periods but is typically not restricted during designated feeding periods, seems to be more suitable, because other dietary regimens involving prolonged fasting periods could worsen the health conditions of cancer patients, being they already naturally prone to weight loss. Until now, the limited amount of available data does not point to a single gene, pathway, or molecular mechanism underlying the benefits to the different dietary approaches. It is well known that the healthy effect is mediated in part by the reduction of nutrient-related pathways. The calorie restriction and starvation (long- and short-term) also suppress the inflammatory response reducing the expression, for example, of IL-10 and TNF-α, mitigating pro-inflammatory gene expression and increasing anti-inflammatory gene expression. The dietary restriction may regulate both genes involved in cellular proliferation and factors associated to apoptosis in normal and cancer cells. Finally, dietary restriction is an important tool that may influence the response to chemotherapy in preclinical models. However, further data are needed to correlate dietary approaches with chemotherapeutic treatments in human models. The aim of this review is to discuss the effects of various dietary approaches on the cancer progression and therapy response, mainly in preclinical models, describing some signaling pathways involved in these processes

Prolonged Fasting Reduces IGF-1/PKA to Promote Hematopoietic-Stem-Cell-Based Regeneration and Reverse Immunosuppression

Immune system defects are at the center of aging and a range of diseases. Here, we show that prolonged fasting reduces circulating IGF-1 levels and PKA activity in various cell populations, leading to signal transduction changes in long-term hematopoietic stem cells (LT-HSCs) and niche cells that promote stress resistance, self-renewal, and lineage-balanced regeneration. Multiple cycles of fasting abated the immunosuppression and mortality caused by chemotherapy and reversed age-dependent myeloid-bias in mice, in agreement with preliminary data on the protection of lymphocytes from chemotoxicity in fasting patients. The proregenerative effects of fasting on stem cells were recapitulated by deficiencies in either IGF-1 or PKA and blunted by exogenous IGF-1. These findings link the reduced levels of IGF-1 caused by fasting to PKA signaling and establish their crucial role in regulating hematopoietic stem cell protection, self-renewal, and regeneration

Analysis of the gastrin-releasing peptide receptor gene in Italian patients with autism spectrum disorders

The gastrin-releasing peptide receptor (GRPR) was implicated for the first time in the pathogenesis of Autism spectrum disorders (ASD) by Ishikawa-Brush et al. [Ishikawa-Brush et al. (1997): Hum Mol Genet 6: 1241-1250]. Since this original observation, only one association study [Marui et al. (2004): Brain Dev 26: 5-7] has further investigated, though unsuccessfully, the involvement of the GRPR gene in ASD. With the aim of contributing further information to this topic we have sequenced the entire coding region and the intron/exon junctions of the GRPR gene in 149 Italian autistic patients. The results of this study led to the identification of four novel point mutations, two of which, that is, C6S and L181F, involve amino acid changes identified in two patients with ASD and Rett syndrome, respectively. Both the leucine at position 181 and the cysteine at position 6 are strongly conserved in vertebrates. C6S and L181F mutant proteins were expressed in COS-7 and BALB/3T3 cells, but they did not affect either GRP's binding affinity or its potency for stimulating phospholipase C-mediated production of inositol 1,4,5-trisphosphate. In summary, our results do not provide support for a major role of the GRPR gene in ASD in the population of patients we have studied. However, there is a potential role of C6S and L181F mutations on GRPR function, and possibly in the pathogenesis of the autistic disorders in the two patient

Association between IGF-1 levels ranges and all-cause mortality: A meta-analysis

The association between IGF-1 levels and mortality in humans is complex with low levels being associated with both low and high mortality. The present meta-analysis investigates this complex relationship between IGF-1 and all-cause mortality in prospective cohort studies. A systematic literature search was conducted in PubMed/MEDLINE, Scopus, and Cochrane Library up to September 2019. Published studies were eligible for the meta-analysis if they had a prospective cohort design, a hazard ratio (HR) and 95% confidence interval (CI) for two or more categories of IGF-1 and were conducted among adults. A random-effects model with a restricted maximum likelihood heterogeneity variance estimator was used to find combined HRs for all-cause mortality. Nineteen studies involving 30,876 participants were included. Meta-analysis of the 19 eligible studies showed that with respect to the low IGF-1 category, higher IGF-1 was not associated with increased risk of all-cause mortality (HR = 0.84, 95% CI = 0.68–1.05). Dose–response analysis revealed a U-shaped relation between IGF-1 and mortality HR. Pooled results comparing low vs. middle IGF-1 showed a significant increase of all-cause mortality (HR = 1.33, 95% CI = 1.14–1.57), as well as comparing high vs. middle IGF-1 categories (HR = 1.23, 95% CI = 1.06–1.44). Finally, we provide data on the association between IGF-1 levels and the intake of proteins, carbohydrates, certain vitamins/minerals, and specific foods. Both high and low levels of IGF-1 increase mortality risk, with a specific 120–160 ng/ml range being associated with the lowest mortality. These findings can explain the apparent controversy related to the association between IGF-1 levels and mortality.Funding was provided by the USC Edna Jones chair fund and NIH P01 AG055369?01 to V.D.L.Scopu

Longevity: epigenetic and biomolecular aspects

Many aging theories and their related molecular mechanisms have been proposed. Simple model organisms such as yeasts, worms, fruit flies and others have massively contributed to their clarification, and many genes and pathways have been associated with longevity regulation. Among them, insulin/IGF-1 plays a key and evolutionary conserved role. Interestingly, dietary interventions can modulate this pathway. Calorie restriction (CR), intermittent fasting, and protein and amino acid restriction prolong the lifespan of mammals by IGF-1 regulation. However, some recent findings support the hypothesis that the long-term effects of diet also involve epigenetic mechanisms. In this review, we describe the best characterized aging pathways and highlight the role of epigenetics in diet-mediated longevity

Acetic acid and acidification accelerate chronological and replicative aging in yeast

yeast is widely regarded as one of the most valuable model systems to study aging and particularly the genetics of aging. Researchers have established two different methods to study yeast aging known as the replicative lifespan (RLS) and the chronological lifes- pan (CLS). These have led to the identifica- tion of many mammalian genes that affect aging suggesting that they will continue to shed light on the fundamental biology of aging

A radical signal activates the epigenetic regulation of longevity

Hormesis is an adaptive stress response implicated in longevity regulation. Schroeder et al. (2013) have now connected stress, epigenetic changes, and aging in yeast by showing that mitochondria-derived reactive oxygen species modulate the chromatin binding capacity of the histone demethylase Rph1p at subtelomeres, resulting in lifespan extension