Biology subjects

Cheng, T. Y. N.

Publications and source records attributed to Cheng, T. Y. N..

5 recordsLinked to original sources

bioRxiv2026

TORC1 integrates metabolic state transitions during aging

Target of rapamycin complex 1 (TORC1) coordinates nutrient availability with anabolic metabolism, yet how TORC1-linked metabolic states influence cellular aging remains unclear. Using genetic, transcriptomic, metabolomic, and pharmacological analyses in prototrophic Saccharomyces cerevisiae, we identify context-dependent metabolic state transitions that uncouple cellular proliferation from long-term survival during aging. Loss of the SEACIT complex, conserved with mammalian GATOR1, establishes a low-flux metabolic state characterized by coordinated remodeling of nitrogen, nucleotide, and central carbon metabolism during stationary phase. Pharmacological restraint of nucleotide, glycolytic, or sterol metabolism converges on similar adaptive metabolic programs, whereas perturbations that impair mitochondrial respiratory capacity destabilize these states and reduce survival. Integrative analyses in human cancer and primary cells further reveal that diverse metabolic perturbations converge on mTORC1 suppression but generate distinct mitochondrial and stress responses depending on nutrient availability. Together, these findings demonstrate that TORC1 integrates metabolic state transitions in which nutrient availability and mitochondrial function determine cellular survival during aging.

systems biology↗

bioRxiv2026

Copper modulates iron-dependent survival through distinct TORC1 and AMPK signaling pathways

Copper and iron are redox-active micronutrients with tightly coupled homeostasis, yet how copper modulates iron-dependent stress responses remains unclear. Using Saccharomyces cerevisiae under nutrient-limited conditions, we uncoupled proliferative growth from long-term survival to dissect metal-dependent adaptation. Copper selectively preserved survival without affecting growth, whereas iron showed similar effects. Iron chelation impaired growth and suppressed electron transport chain gene expression; copper partially rescued these defects but required iron for its pro-survival activity. Despite this interdependence, copper and iron engaged distinct signaling programs. Iron-dependent survival required a Target of Rapamycin complex 1 (TORC1)-permissive state and was attenuated by rapamycin, whereas copper remained active under TORC1 inhibition. In contrast, copper promoted survival through AMP-activated protein kinase (AMPK) and antioxidant pathways, while iron exhibited context-dependent AMPK reliance. Together, these findings identify copper and iron as state-dependent regulators of cellular survival.

cell biology↗

bioRxiv2026

Mitochondrial competence determines responses to metabolic interventions during aging

Cellular responses to metabolic interventions vary across physiological contexts, but the basis for this variability remains unclear. Here, we show that mitochondrial competence determines whether cells can engage adaptive metabolic states that support survival during aging. Using 4-methylbenzoic acid (4-MBA), identified as a lifespan-extending compound, as a perturbation probe, we find that modulation of Target of Rapamycin Complex 1 (TORC1) signaling induces a shift from anabolic growth to maintenance-associated metabolism; however, signaling output alone does not predict outcomes. Instead, survival closely correlates with mitochondrial function, with its disruption abolishing adaptive responses. Genetic and biochemical analyses define a mitochondrial regulatory circuit that constrains signaling dynamics and governs state transitions. This regulatory logic is conserved across mammalian systems and operates under oxidative stress, replicative aging, and Hutchinson-Gilford progeria syndrome (HGPS), extending to proliferative cancer cells. These findings establish mitochondrial competence as a key determinant of cellular responsiveness and provide a framework for understanding context-dependent effects of metabolic interventions during aging.

cell biology↗

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

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↗