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We report upon the realization of a novel fast nondeterministic random number generator whose randomness relies on the intrinsic randomness of the quantum physical processes of photonic emission in semiconductors and subsequent detection by the photoelectric effect. Timing information of detected photons is used to generate binary random digits-bits. The bit extraction method based on the restartable clock method theoretically eliminates both bias and autocorrelation while reaching efficiency of almost 0.5 bits per random event. A prototype has been built and statistically tested. [ABSTRACT FROM AUTHOR]

Calorie restriction has many beneficial effects on healthspan and lifespan in a variety of species. However, how late in life application of caloric restriction can extend fly life is not clear. Here we show that late-life calorie restriction increases lifespan in female Drosophila melanogaster aged on a high-calorie diet. This shift results in rapid decrease in mortality rate and extends fly lifespan. In contrast, shifting female flies from a low- to a high-calorie diet leads to a rapid increase in mortality and shorter lifespan. These changes are mediated by immediate metabolic and physiological adaptations. One of such adaptation is rapid adjustment in egg production, with flies directing excess energy towards egg production when shifted to a high diet, or away from reproduction in females shifted to low-caloric diet. However, lifelong female fecundity reveals no associated fitness cost due to CR when flies are shifted to a high-calorie diet. In view of high conservation of the beneficial effects of CR on physiology and lifespan in a wide variety of organisms, including humans, our findings could provide valuable insight into CR applications that could provide health benefits later in life., (© 2024. The Author(s).)

To address the challenge of finding new combination therapies against castration-sensitive prostate cancer, we introduce Vini, a computational tool that predicts the efficacy of drug combinations at the intracellular level by integrating data from the KEGG, DrugBank, Pubchem, Protein Data Bank, Uniprot, NCI-60 and COSMIC databases. Vini is a computational tool that predicts the efficacy of drugs and their combinations at the intracellular level. It addresses the problem comprehensively by considering all known target genes, proteins and small molecules and their mutual interactions involved in the onset and development of cancer. The results obtained point to new, previously unexplored combination therapies that could theoretically be promising candidates for the treatment of castration-sensitive prostate cancer and could prevent the inevitable progression of the cancer to the incurable castration-resistant stage. Furthermore, after analyzing the obtained triple combinations of drugs and their targets, the most common targets became clear: ALK, BCL-2, mTOR, DNA and androgen axis. These results may help to define future therapies against castration-sensitive prostate cancer. The use of the Vini computer model to explore therapeutic combinations represents an innovative approach in the search for effective treatments for castration-sensitive prostate cancer, which, if clinically validated, could potentially lead to new breakthrough therapies., (© 2024. The Author(s).)

Aging is linked to a time-associated decline in both cellular function and repair capacity leading to malfunction on an organismal level, increased frailty, higher incidence of diseases, and death. As the population grows older, there is a need to reveal mechanisms associated with aging that could spearhead treatments to postpone the onset of age-associated decline, extend both healthspan and lifespan. One possibility is targeting the sirtuin SIRT1, the founding member of the sirtuin family, a highly conserved family of histone deacetylases that have been linked to metabolism, stress response, protein synthesis, genomic instability, neurodegeneration, DNA damage repair, and inflammation. Importantly, sirtuins have also been implicated to promote health and lifespan extension, while their dysregulation has been linked to cancer, neurological processes, and heart disorders. SIRT1 is one of seven members of sirtuin family; each requiring nicotinamide adenine dinucleotide (NAD + ) as co-substrate for their catalytic activity. Overexpression of yeast, worm, fly, and mice SIRT1 homologs extend lifespan in each animal, respectively. Moreover, lifespan extension due to calorie restriction are associated with increased sirtuin activity. These findings led to the search for a calorie restriction mimetic, which revealed the compound resveratrol; (3, 5, 4'-trihydroxy-trans-stilbene) belonging to the stilbenoids group of polyphenols. Following this finding, resveratrol and other sirtuin-activating compounds have been extensively studied for their ability to affect health and lifespan in a variety of species, including humans via clinical studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Rogina and Tissenbaum.)

The prevalence of obesity is increasing in older adults and contributes to age-related decline. Caloric restriction (CR) alleviates obesity phenotypes and delays the onset of age-related changes. However, how late in life organisms benefit from switching from a high-(H) to a low-calorie (L) diet is unclear. We transferred male flies from a H to a L (HL) diet or vice versa (LH) at different times during life. Both shifts immediately change fly rate of aging even when applied late in life. HL shift rapidly reduces fly mortality rate to briefly lower rate than in flies on a constant L diet, and extends lifespan. Transcriptomic analysis uncovers that flies aged on H diet have acquired increased stress response, which may have temporal advantage over flies aged on L diet and leads to rapid decrease in mortality rate after HL switch. Conversely, a LH shift increases mortality rate, which is temporarily higher than in flies aged on a H diet, and shortens lifespan. Unexpectedly, more abundant transcriptomic changes accompanied LH shift, including increase in ribosome biogenesis, stress response and growth. These changes reflect protection from sudden release of ROS, energy storage, and use of energy to growth, which all likely contribute to higher mortality rate. As the beneficial effects of CR on physiology and lifespan are conserved across many organisms, our study provides framework to study underlying mechanisms of CR interventions that counteract the detrimental effects of H diets and reduce rate of aging even when initiated later in life., Competing Interests: Competing interests statement:The authors declare no competing interest.

I'm Not Dead Yet (Indy) is a fly homologue of the mammalian SLC13A5 (mSLC13A5) plasma membrane citrate transporter, a key metabolic regulator and energy sensor involved in health, longevity, and disease. Reduction of Indy gene activity in flies, and its homologs in worms, modulates metabolism and extends longevity. The metabolic changes are similar to what is obtained with caloric restriction (dietary restriction). Similar effects on metabolism have been observed in mice and rats. As a citrate transporter, INDY regulates cytoplasmic citrate levels. Indy flies heterozygous for a P-element insertion have increased spontaneous physical activity, increased fecundity, reduced insulin signaling, increased mitochondrial biogenesis, preserved intestinal stem cell homeostasis, lower lipid levels, and increased stress resistance. Mammalian Indy knockout ( mIndy -KO) mice have higher sensitivity to insulin signaling, lower blood pressure and heart rate, preserved memory and are protected from the negative effects of a high-fat diet and some of the negative effects of aging. Reducing mIndy expression in human hepatocarcinoma cells has recently been shown to inhibit cell proliferation. Reduced Indy expression in the fly intestine affects intestinal stem cell proliferation, and has recently been shown to also inhibit germ cell proliferation in males with delayed sperm maturation and decreased spermatocyte numbers. These results highlight a new connection between energy metabolism and cell proliferation. The overrall picture in a variety of species points to a conserved role of INDY for metabolism and health. This is illustrated by an association of high mIndy gene expression with non-alcoholic fatty liver disease in obese humans. mIndy ( mSLC13A5 ) coding region mutations (e.g., loss-of-function) are also associated with adverse effects in humans, such as autosomal recessive early infantile epileptic encephalopathy and Kohlschütter-Tönz syndrome. The recent findings illustrate the importance of mIndy gene for human health and disease. Furthermore, recent work on small-molecule regulators of INDY highlights the promise of INDY-based treatments for ameliorating disease and promoting healthy aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Mishra, Kannan, Meadows, Macro, Li, Frankel and Rogina.)

I'm Not Dead Yet ( Indy ) is a fly gene that encodes a homologue of mammalian SLC13A5 plasma membrane citrate transporter. Reducing expression of Indy gene in flies, and its homologues in worms, extends longevity. Indy reduction in flies, worms, mice and rats affects metabolism by regulating the levels of cytoplasmic citrate, inducing a state similar to calorie restriction. Changes include lower lipid levels, increased insulin sensitivity, increased mitochondrial biogenesis, and prevention of weight gain, among others. The INDY protein is predominantly expressed in fly metabolic tissues: the midgut, fat body and oenocytes. Changes in fly midgut metabolism associated with reduced Indy gene activity lead to preserved mitochondrial function and reduced production of reactive oxygen species. All these changes lead to preserved intestinal stem cell homeostasis, which has a key role in maintaining intestinal epithelium function and enhancing fly healthspan and lifespan. Indy gene expression levels change in response to caloric content of the diet, inflammation and aging, suggesting that INDY regulates metabolic adaptation to nutrition or energetic requirements by controlling citrate levels.

Aging has provided fruitful challenges for evolutionary theory, and evolutionary theory has deepened our understanding of aging. A great deal of genetic and molecular data now exists concerning mortality regulation and there is a growing body of knowledge concerning the life histories of diverse species. Assimilating all relevant data into a framework for the evolution of aging promises to significantly advance the field. We propose extensions of some key concepts to provide greater precision when applying these concepts to age-structured contexts. Secondary or byproduct effects of mutations are proposed as an important factor affecting survival patterns, including effects that may operate in small populations subject to genetic drift, widening the possibilities for mutation accumulation and pleiotropy. Molecular and genetic studies have indicated a diverse array of mechanisms that can modify aging and mortality rates, while transcriptome data indicate a high level of tissue and species specificity for genes affected by aging. The diversity of mechanisms and gene effects that can contribute to the pattern of aging in different organisms may mirror the complex evolutionary processes behind aging., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Frankel and Rogina.)

The Indy ( I'm Not Dead Yet ) gene encodes the fly homolog of the mammalian SLC13A5 citrate transporter. Reduced expression of the Indy gene in flies and worms extends their longevity. INDY is expressed in the plasma membrane of metabolically active tissues. Decreased expression of Indy in worms, flies, mice, and rats alters metabolism in a manner similar to calorie restriction. Reducing INDY activity prevents weight gain in flies, worms, and mice, and counteracts the negative effects of age or a high fat diet on metabolism and insulin sensitivity. The metabolic effects of reducing INDY activity are the result of reduced cytoplasmic citrate. Citrate is a key metabolite and has a central role in energy status of the cell by effecting lipid and carbohydrate metabolism and energy production. Thereby newly described drugs that reduce INDY transporting activity increase insulin sensitivity and reduce hepatic lipid levels via its effect on hepatic citrate uptake. A recent report presented the first direct link between increased hepatic levels of human INDY, insulin resistance, and non-alcoholic fatty liver disease in obese humans. Similarly increased hepatic mIndy levels were observed in non-human primates fed on a high fat diet for 2 years. This effect is mediated via the stimulatory effect of the interleukin-6/Stat3 pathway on mINDY hepatic expression. These findings make INDY a potential and very promising target for the treatment of metabolic disorders in humans.

BACKGROUND: Rpd3 is a conserved histone deacetylase that removes acetyl groups from lysine residues within histones and other proteins. Reduction or inhibition of Rpd3 extends longevity in yeast, worms, and flies. Previous studies in flies suggest an overlap with the mechanism of lifespan extension by dietary restriction. However, the mechanism of rpd3 's effects on longevity remains unclear. OBJECTIVES: In this study we investigated how rpd3 reduction affects fly spontaneous physical activity, fecundity, and stress resistance. METHODS: We examined the effects of rpd3 reduction on fly spontaneous physical activity by using population monitors, we determined female fecundity by counting daily egg laying, and we determined fly survivorship in response to starvation and paraquat. RESULTS: In flies, rpd3 reduction increases peak spontaneous physical activity of rpd3 def male flies at a young age but does not affect total 24 hour activity. Male and female rpd3 def mutants are more resistant to starvation on low and high calorie diets. In addition, increased resistance to paraquat was observed in females of one allele. A decrease in rpd3 levels does not affect female fecundity. CONCLUSIONS: A decrease in rpd3 levels mirrors some but not all changes associated with calorie restriction, illustrated by an increased peak of spontaneous activity in rpd3 def /+ heterozygous male flies but no effect on total spontaneous activity and fecundity.

The epigenetic regulation of DNA structure and function is essential for changes in gene expression involved in development, growth, and maintenance of cellular function. Epigenetic changes include histone modifications such as methylation, acetylation, ubiquitination, and phosphorylation. Histone deacetylase (HDAC) proteins have a major role in epigenetic regulation of chromatin structure. HDACs are enzymes that catalyze the removal of acetyl groups from lysine residues within histones, as well as a range of other proteins including transcriptional factors. HDACs are highly conserved proteins divided into two families and based on sequence similarity in four classes. Here we will discuss the roles of Rpd3 in physiology and longevity with emphasis on its role in flies. Rpd3, the Drosophila HDAC1 homolog, is a class I lysine deacetylase and a member of a large family of HDAC proteins. Rpd3 has multiple functions including control of proliferation, development, metabolism, and aging. Pharmacological and dietary HDAC inhibitors have been used as therapeutics in psychiatry, cancer, and neurology., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Histone deacetylase (HDAC) 1 regulates chromatin compaction and gene expression by removing acetyl groups from lysine residues within histones. HDAC1 affects a variety of processes including proliferation, development, metabolism, and cancer. Reduction or inhibition of Rpd3, yeast and fly HDAC1 orthologue, extends longevity. However, the mechanism of rpd3 's effects on longevity remains unclear. Here we report an overlap between rpd3 and the Insulin/Insulin-like growth factor signaling (IIS) longevity pathways. We demonstrated that rpd3 reduction downregulates expression of members of the IIS pathway, which is associated with altered metabolism, increased energy storage, and higher resistance to starvation and oxidative stress. Genetic studies support the role of IIS in rpd3 longevity pathway, as illustrated with reduced stress resistance and longevity of flies double mutant for rpd3 and dfoxo, a downstream target of IIS pathway, compared to rpd3 single mutant flies. Our data suggest that increased dfoxo is a mediator of rpd3 's effects on fly longevity and intermediary metabolism, and confer a new link between rpd3 and IIS longevity pathways., Competing Interests: The authors have no conflict of interests to declare.

Single-gene mutations that extend longevity have revealed regulatory pathways related to aging and longevity. RPD3 is a conserved histone deacetylase (Class I HDAC). Previously we showed that Drosophila rpd3 mutations increase longevity. Here we tested the longevity effects of RPD3 on multiple nutrient levels. Dietary restriction (DR) has additive effects on RPD3-mediated longevity extension, but the effect may be modestly attenuated relative to controls. RPD3 and DR therefore appear to operate by distinct but interacting mechanisms. Since RPD3 regulates transcription, the mRNA levels for two proteins involved in nutrient signaling, 4E-BP and Tor, were examined in rpd3 mutant flies. 4E-BP mRNA was reduced under longevity-increasing conditions. Epistasis between RPD3 and 4E-BP with regard to longevity was then tested. Flies only heterozygous for a mutation in Thor, the 4E-BP gene, have modestly decreased life spans. Flies mutant for both rpd3 and Thor show a superposition of a large RPD3-mediated increase and a small Thor-mediated decrease in longevity at all food levels, consistent with each gene product having distinct effects on life span. However, DR-mediated extension was absent in males carrying both mutations and lessened in females. Our results support the view that multiple discrete but interacting mechanisms regulate longevity.

Indy (I'm Not Dead Yet) encodes the fly homolog of a mammalian SLC13A5 plasma membrane transporter. INDY is expressed in metabolically active tissues functioning as a transporter of Krebs cycle intermediates with the highest affinity for citrate. Decreased expression of the Indy gene extends longevity in Drosophila and C. elegans. Reduction of INDY or its respective homologs in C. elegans and mice induces metabolic and physiological changes similar to those observed in calorie restriction. It is thought that these physiological changes are due to altered levels of cytoplasmic citrate, which directly impacts Krebs cycle energy production as a result of shifts in substrate availability. Citrate cleavage is a key event during lipid and glucose metabolism; thus, reduction of citrate due to Indy reduction alters these processes. With regards to mammals, mice with reduced Indy (mIndy(-/-)) also exhibit changes in glucose metabolism, mitochondrial biogenesis and are protected from the negative effects of a high calorie diet. Together, these data support a role for Indy as a metabolic regulator, which suggests INDY as a therapeutic target for treatment of diet and age-related disorders such as Type II Diabetes and obesity.

It has been 20 years since the Orentreich Foundation for the Advancement of Science, under the leadership Dr. Norman Orentreich, first reported that low methionine (Met) ingestion by rats extends lifespan (Orentreich et al., 1993). Since then, several studies have replicated the effects of dietary methionine restricted (MR) in delaying age-related diseases (Richie et al., 1994; Miller et al., 2005; Ables et al., 2012; Sanchez-Roman and Barja, 2013). We report the abstracts from the First International Mini-Symposium on Methionine Restriction and Lifespan held in Tarrytown, NY, September 2013. The goals were (1) to gather researchers with an interest in MR and lifespan, (2) to exchange knowledge, (3) to generate ideas for future investigations, and (4) to strengthen relationships within this community. The presentations highlighted the importance of research on cysteine, growth hormone (GH), and ATF4 in the paradigm of aging. In addition, the effects of dietary restriction or MR in the kidneys, liver, bones, and the adipose tissue were discussed. The symposium also emphasized the value of other species, e.g., the naked mole rat, Brandt's bat, and Drosophila, in aging research. Overall, the symposium consolidated scientists with similar research interests and provided opportunities to conduct future collaborative studies (Figure 3).