Biology subjects

Alfatah, M.

Publications and source records attributed to Alfatah, M..

6 recordsLinked to original sources

bioRxiv2023

Systematic transcriptomics analysis of calorie restriction and rapamycin unveils their synergistic interaction in prolonging cellular lifespan

Aging is a multifaceted biological process marked by the decline in both mitotic and postmitotic cellular function, often central to the development of age-related diseases. In the pursuit of slowing or even reversing the aging process, a prominent strategy of significant interest is calorie restriction (CR), also known as dietary restriction, and the potential influence of a drug called rapamycin (RM). Both CR and RM have demonstrated the capacity to extend healthspan and lifespan across a diverse array of species, including yeast, worms, flies, and mice. Nevertheless, their individual and combined effects on mitotic and postmitotic cells, as well as their comparative analysis, remain areas that demand a thorough investigation. In this study, we employ RNA-sequencing methodologies to comprehensively analyze the impact of CR, RM, and their combination (CR+RM) on gene expression in yeast cells. Our analysis uncovers distinctive, overlapping, and even contrasting patterns of gene regulation, illuminating the unique and shared effects of CR and RM. Most notably, our findings reveal a synergistic effect of CR+RM in extending the lifespan of postmitotic cells, a result validated in both yeast and human cells. This research offers valuable insights into the processes of aging and presents potential strategies for enhancing healthspan and delaying the onset of age-related diseases. These findings have the potential to revolutionize our approach to implementing these interventions under specific conditions and within the context of age-related diseases.

genomics↗

bioRxiv2023

Curcumin extends the lifespan of aging postmitotic cells with mitochondrial dysfunction

Aging is an inevitable biological process intricately linked to age-related diseases, including cardiovascular diseases, neurodegeneration, sarcopenia, and age-related macular degeneration. These ailments are often exacerbated by mitochondrial dysfunction, which plays a pivotal role in postmitotic cells. Curcumin, a natural compound, is explored for its anti-aging potential. This study explores the influence of curcumin on the postmitotic cellular lifespan (PoMiCL) of yeast during chronological aging, examining its potential implications for age-related diseases. Our findings reveal that curcumin significantly extends the lifespan of postmitotic wildtype yeast cells, with maximal effects observed at lower concentrations, displaying a hormetic response. Importantly, curcumin mitigates accelerated aging in cells afflicted by mitochondrial dysfunction. Intriguingly, the hormetic effect is absent under these conditions. Mechanistically, curcumin enhances ATP levels but induces oxidative stress and inhibits TORC1. These findings shed light on curcumins potential as an anti-aging modulator and its relevance to age-related diseases, offering insights into novel therapeutic approaches for healthy aging while highlighting the context-dependent nature of its effects.

genetics↗

bioRxiv2023

Hemin decreases cellular aging and enhances healthspan and lifespan through the AMPK pathway

The quest to understand and manipulate the mechanisms of cellular aging has far-reaching implications for improving human health and longevity. Our comprehensive effort has led to the discovery of the intriguing anti-aging potential of hemin, an FDA-approved drug primarily used for the treatment of acute intermittent porphyria. Leveraging both yeast and human cell models, we investigate the multifaceted effects of hemin on extending cellular lifespan. Intriguingly, the involvement of the AMPK pathway emerges as a pivotal mechanism underlying hemins anti-aging effects. The exploration of hemins impact on cellular functionality further uncovers its influence on mitochondrial processes. Notably, both mitochondrial-dependent and -independent mechanisms are implicated in hemins ability to extend cellular lifespan, with autophagy playing a significant role in the latter. Additionally, a striking synergy between hemin and the TORC1 inhibitor rapamycin is unveiled, underlining the complexity of cellular signaling networks involved in lifespan extension. Translating these findings to human cells, hemin demonstrates an analogous ability to induce mitochondrial biogenesis, reduce proinflammatory cytokine expression, and enhance antioxidant response. The conservation of hemins anti-aging effects across species holds promise for therapeutic applications in addressing age-related diseases and promoting healthier aging.

genetics↗

bioRxiv2023

Uncharacterized yeast gene YBR238C, an effector of TORC1 signaling in a mitochondrial feedback loop, accelerates cellular aging via HAP4- and RMD9-dependent mechanisms

Uncovering the regulators of cellular aging will unravel the complexity of aging biology and identify potential therapeutic interventions to delay the onset and progress of chronic, aging-related diseases. In this work, we systematically compared gene sets involved in regulating the lifespan of Saccharomyces cerevisiae (a powerful model organism to study the cellular aging of humans) and those with expression changes under rapamycin treatment. Among the functionally uncharacterized genes in the overlap set, YBR238C stood out as the only one downregulated by rapamycin and with an increased chronological and replicative lifespan upon deletion. We show that YBR238C and its paralogue RMD9 oppositely affect mitochondria and aging. YBR238C deletion increases the cellular lifespan by enhancing mitochondrial function. Its overexpression accelerates cellular aging via mitochondrial dysfunction. We find that the phenotypic effect of YBR238C is largely explained by HAP4- and RMD9-dependent mechanisms. Further, we find that genetic or chemical-based induction of mitochondrial dysfunction increases TORC1 (Target of Rapamycin Complex 1) activity that, subsequently, accelerates cellular aging. Notably, TORC1 inhibition by rapamycin (or deletion of YBR238C) improves the shortened lifespan under these mitochondrial dysfunction conditions in yeast and human cells. The growth of mutant cells (a proxy of TORC1 activity) with enhanced mitochondrial function is sensitive to rapamycin whereas the growth of defective mitochondrial mutants is largely resistant to rapamycin compared to wild type. Our findings demonstrate a feedback loop between TORC1 and mitochondria (the TORC1-MItochondria-TORC1 (TOMITO) signaling process) that regulates cellular aging processes. Hereby, YBR238C is an effector of TORC1 modulating mitochondrial function.

genetics↗

bioRxiv2022

Metabolism of glucose activates TORC1 through multiple mechanisms in Saccharomyces cerevisiae

Target of Rapamycin Complex 1 (TORC1) is a conserved eukaryotic protein complex that links the presence of nutrients with cell growth. In Saccharomyces cerevisiae, TORC1 activity is positively regulated by the presence of amino acids and glucose in the medium. However, mechanisms underlying nutrient-induced TORC1 activation remain poorly understood. By utilizing a TORC1 activation assay, we demonstrate that differential metabolism of glucose activates TORC1 through three distinct pathways in yeast. The first canonical Rag GTPase-dependent pathway requires conversion of glucose to fructose 1,6-bisphosphate which activates TORC1 via the Rag GTPase heterodimer Gtr1GTP/Gtr2GDP. The second non-canonical Rag GTPase-dependent pathway requires conversion of glucose to glucose 6-phosphate which activates TORC1 via Gtr1GTP/Gtr2GTP. The third Rag GTPase-independent pathway requires complete glycolysis and vacuolar ATPase reassembly for TORC1 activation. Glucose-induced TORC1 activation can be uncoupled from glucose-induced AMPK inactivation. We have established a roadmap to deconstruct the link between glucose metabolism and TORC1 activation.

genetics↗

bioRxiv2019

TORC1 regulates the transcriptional response to glucose and developmental cycle via the Tap42-Sit4-Rrd1/2 pathway in Saccharomyces cerevisiae

Target of Rapamycin Complex 1 (TORC1) is a highly conserved eukaryotic protein complex that couples the presence of growth factors and nutrients in the environment with cellular proliferation. TORC1 is primarily implicated in linking amino acid levels with cellular growth in yeast and mammals. Although glucose deprivation has been shown to cause TORC1 inactivation in yeast, the precise role of TORC1 in glucose signaling and the underlying mechanisms remain unclear. In this paper, we demonstrate that the presence of glucose in the growth medium is both necessary and sufficient for TORC1 activation. TORC1 activity increases upon addition of glucose to yeast cells growing in a non-fermentable carbon source. Conversely, shifting yeast cells from glucose to a non-fermentable carbon source reduces TORC1 activity. Analysis of transcriptomic data revealed that glucose and TORC1 co-regulate about 27% (1668/6004) of yeast genes. We demonstrate that TORC1 orchestrates the expression of glucose-response genes mainly via the Tap42-Sit4-Rrd1/Rrd2 pathway. To confirm TORC1s role in glucose-signaling, we tested its role in spore germination, a glucose-dependent developmental state transition in yeast. TORC1 regulates the glucose-responsive genes during spore germination and inhibition of TORC1 blocks spore germination. We propose that a regulatory loop that involves activation of TORC1 by glucose and regulation of glucose-responsive genes by TORC1, mediates nutritional control of growth and development in yeast.

genetics↗