Biology subjects

Naaz, A.

Publications and source records attributed to Naaz, A..

12 recordsLinked to original sources

bioRxiv2026

Fatty acid metabolic interactome atlas linked to cellular longevity

Fatty acid biosynthesis is a central metabolic process required for membrane formation, organelle maintenance, and cellular proliferation, yet its broader relationship with stress responses and cellular aging remains incompletely understood. Here, we combined human and yeast interactome analyses with transcriptomic profiling and chronological lifespan assays to investigate the systems-level organization of fatty acid metabolic pathways and their relationship to cellular longevity. Integrated interactome mapping of mammalian fatty acid metabolic regulators, including ACACA, FASN, SCD, ACSL, ELOVL, and SLC27 family proteins, together with conserved yeast orthologs including ACC1, FAS1/FAS2, ELO1-3, OLE1, FAA1-4, ACS1/ACS2, and FAT1 revealed strong enrichment of anabolic growth regulation, membrane organization, vesicle trafficking, proteostasis, and endoplasmic reticulum (ER)-associated stress pathways. In yeast, fatty acid metabolic networks segregated into distinct anabolic and membrane-associated functional modules. Pharmacological inhibition of fatty acid synthesis using cerulenin suppressed cellular proliferation while extending chronological lifespan and induced broad downregulation of translation-associated anabolic pathways together with activation of stress-associated and membrane lipid remodeling programs. ER-associated interactome analyses of DPAGT1 and ALG7 further identified strong enrichment of membrane trafficking and unfolded protein response (UPR)-associated pathways, while pharmacological ER stress induction using tunicamycin also promoted enhanced chronological longevity. Collectively, our findings support a conserved model in which perturbation of fatty acid metabolic pathways remodels anabolic growth and ER-associated stress responses to promote cellular longevity.

systems biology↗

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

Developing a multi-modal neuroimaging-based BrainAge model across childhood

BrainAge models hold promise as a clinical biomarker for developmental brain health, especially in childhood when there is the potential for early intervention. To distinguish between normative developmental variance and pathological divergence, BrainAge models should reflect the dynamic and diverse neurodevelopmental processes that occur in distinct developmental windows across childhood. We utilized multi-modal neuroimaging data from three pediatric cohorts covering ages 4 to 13 years (n = 1005, 2126 scans), split into Train and Test datasets. Twelve sex-stratified BrainAge models were built stratified by type and different combinations of neuroimaging features. Model types were "Full-Span" models covering the full age range, and "Phase-Specific" models split into early- and late-childhood. We first compared BrainAge estimates in the Test dataset amongst our candidate models, then benchmarked the best-performing model against published pre-trained models and DNA-based biological age measures. Our findings show that a BrainAge model that was phase-specific and consisted of both structural and functional features (cortical thickness, subcortical volumes, and functional network integration measures) showed good prediction of age and best distinguished between healthy and symptomatic subgroups. We present a proof-of-concept for developmental models supporting building BrainAge models of higher temporal resolution that align to different childhood developmental phases.

neuroscience↗

bioRxiv2026

Integrative Genomic Analyses Identify COL21A1 and ENPEP-FGF5 Regulatory Pathways for Blood Pressure Variation in East Asians

BackgroundHypertension is a highly heritable cardiovascular disorder and a major determinant of cardiometabolic disease, including diabetes. However, the regulatory genes and tissue-specific mechanisms underlying blood pressure variations remain incompletely understood. MethodsLeveraging a well-characterized prospective population-based cohort comprised of 27,308 participants from the Singapore Chinese Health Study (SCHS), we evaluated genome-wide genetic associations for five blood pressure traits: hypertension status, systolic blood pressure, diastolic blood pressure, mean arterial pressure (MAP) and pulse pressure (PP). Additionally, we conducted a transcriptome-wide association study (TWAS), integrating gene expression data from 49 tissues, followed by colocalization and fine-mapping to prioritize regulatory genes. Association of identified variants with incident diabetes was additionally evaluated in the longitudinal data. ResultsWe validated 10 blood pressure loci (P between 1.64 x 10-20 - 4.10 x 10-8) and identified an East-Asian specific splice donor variant at the COL21A1 gene associated with PP (rs149344559, P = 6.78 x 10-10). Integrative analyses prioritized FGF5 in kidney cortex and ENPEP in pituitary tissue as candidate regulatory genes. The blood pressure-lowering allele at ENPEP (T allele, rs1879056) was associated with reduced risk of incident diabetes. Mediation analysis demonstrated that approximately 21% of the genetic association with diabetes was mediated through MAP (Pindirect-effect = 2 x 10-16). ConclusionThis study refines genetic predispositions for blood pressure among East-Asians. We further delineate tissue-specific regulatory pathways underlying blood pressure variations and identify ENPEP-mediated dysfunctions linking blood pressure genetics to diabetes risk, underscoring integrated disease mechanisms.

genetics↗

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

Haems relevance genuine? Re-visiting the roles of TANGO2 homologues including HRG-9 and HRG-10 in C. elegans

Mutations in the TANGO2 gene are associated with a severe neurometabolic disorder in humans, often presenting with life-threatening metabolic crisis. However, the function of TANGO2 protein remains unknown. It has recently been proposed that TANGO2 transports heme within and between cells, from areas with high heme concentrations to those with lower concentrations. Here, we demonstrate that prior heme-related observations in Caenorhabditis elegans lacking TANGO2 homologs HRG-9 and HRG-10 may be better explained by a previously unreported metabolic phenotype, characterized by reduced feeding, decreased lifespan and brood sizes, and poor motility. We also show that several genes not implicated in heme transport are upregulated in the low heme state and conversely demonstrate that hrg-9 in particular is highly responsive to oxidative stress, independent of heme status. Collectively, these data implicate bioenergetic failure and oxidative stress as potential factors in the pathophysiology of TANGO2 deficiency, in alignment with observations from human patients. Our group performed several experiments in yeast and zebrafish deficient in TANGO2 homologs and was unable to replicate prior findings from these models. Overall, we believe there is insufficient evidence to support heme transport as the primary function for TANGO2. Impact statementCross-species examination of TANGO2 homologs demonstrates that phenotypes previously attributed to altered heme trafficking may instead reflect broader disturbances in mitochondrial function and cellular homeostasis.

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

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

Methionine uptake via SLC43A2 transporter is essential for regulatory T lymphocyte survival

It is increasingly clear that cell death, survival or growth decisions of T lymphocyte subsets depend on interplay between cytokine-dependent and metabolic processes. What the metabolic requirements of T regulatory cells (Tregs) for their survival are, and how these requirements are satisfied remain to be fully understood. In this study, we identified a necessary requirement of methionine uptake and utilization for Tregs survival upon interleukin 2 (IL-2) deprivation. Activated Tregs have high methionine uptake and consumption to S-adenosyl methionine (SAM) and S-adenosyl homocysteine (SAH). This methionine uptake is essential for Tregs survival, and is regulated by Notch1 activity. Notch1 controls the expression of the solute carrier protein SLC43A2 transporter during IL-2 deprivation. SLC43A2 is necessary for sufficient methionine uptake, and determines Tregs viability upon IL-2 withdrawal. Collectively, we identify a specifically regulated mechanism of methionine import in Tregs that is necessary for the survival of these cells. This highlights the need for methionine availability and metabolism in contextually regulating cell death in an immunosuppressive population of T lymphocytes.

immunology↗