Biology subjects

Antebi, A.

Publications and source records attributed to Antebi, A..

At least 19 recordsLinked to original sources

bioRxiv2026

mTOR regulates longevity through a bile-acid like hormonal mechanism and DHS- 26/DHRS1

The mTOR pathway is a central regulator of cellular metabolism and growth whose downregulation extends life span across taxa. In C. elegans, mTOR acts cell non-autonomously to influence organismal longevity, yet underlying mechanisms remain elusive. Here, we show that deletion of the TORC1 regulator, raga-1/RRAGA, enhances production of the bile acid-like hormone, dafachronic acid (DA), and extends life span dependent on DA-hormone biosynthetic genes and DA-cognate nuclear hormone receptor DAF-12, a homolog of mammalian farnesoid X receptor (FXR). Through functional genomic screens, we identify the evolutionarily conserved short chain dehydrogenase DHS-26/DHRS1 as a previously uncharacterized downstream regulatory target and effector of the mTOR-steroid axis essential for organismal longevity. Worm DHS-26 is expressed prominently in the canal associated neurons, cells which are essential to growth and development, suggesting a neuroendocrine mechanism. Murine DHRS1 also exhibits regulation by mTOR signaling and nuclear receptor FXR suggesting that the mTOR-DHS-26/DHRS1 axis is evolutionarily conserved. These findings suggest that mTOR signaling systemically impacts metazoan longevity through the regulation of bile acid-like hormone availability and nuclear receptor signal transduction.

genetics↗

bioRxiv2026

Modulation of the RNAse P/MRP complex and mitochondrial ribosome enhances cytosolic ribosome coordination and sustains longevity

Aging is accompanied by a progressive decline in protein synthesis and ribosome abundance, yet paradoxically, genetic or pharmacological attenuation of translation extends lifespan across species. Whether the age-associated decline in translation is adaptive or reflects a pathological failure of ribosome homeostasis remains unclear. Here, we show that shortened lifespan is driven by dysregulated ribosome biogenesis (RiBi) and impaired ribosome assembly. Using Caenorhabditis elegans ncl-1 loss-of-function mutants as a model of accelerated aging, we find that nucleolar enlargement coincides with decoupling of precursor and mature rRNA, ribosomal protein (RP) transcripts, and protein abundance, loss of RP stoichiometry, defective ribosomal subunit joining, and compromised proteostasis. Strikingly, lifespan can be restored downstream of the nucleolus by targeting either the RNAse P/MRP complex or the mitochondrial ribosome. These interventions rebalance mature rRNA and RP abundance, improve ribosomal assembly, and reduce protein aggregation despite persistent nucleolar enlargement and elevated pre-rRNA levels. Our findings identify accelerated age-associated ribosome dysfunction as a qualitative failure of ribosomal biogenesis, and demonstrate that restoring ribosomal homeostasis is sufficient to improve proteostasis and extend lifespan.

cell biology↗

bioRxiv2025

Rare longevity-associated variants, including a reduced-function mutation in cGAS, identified in multigenerational long-lived families

Life expectancy has steadily increased in the last two centuries, while healthspan has been lagging behind. Survival into extreme ages strongly clusters within families which often exhibit a delayed onset of (multi)morbidity, yet the underlying protective genetic mechanisms are still largely undefined. We performed affected sib-pair linkage analysis in 212 sibships enriched for ancestral longevity and identified four genomic regions (LODmax [≥]3.0) at 1q21.1, 6p24.3, 6q14.3, and 19p13.3. Within these regions, we prioritized 12 rare protein-altering variants in seven candidate genes (NUP210L, SLC27A3, CD1A, CGAS, IBTK, RARS2, and SH2D3A) located in longevity-associated loci. Notably, a missense variant in CGAS (rs200818241), was present in two sibships. Using human- and mouse-based cell models, we showed that rs200818241 reduced protein stability and attenuated activation of the canonical cGAS-STING pathway in a cell-type specific manner. This dampened signalling mitigated inflammation and delayed cellular senescence, mechanisms that may contribute to the survival advantage of CGAS variant carriers. Our findings indicate novel rare variants and candidate genes linked to familial longevity and highlight the cGAS-STING pathway as a potential contributor to the protective mechanisms underlying human longevity.

genetics↗

bioRxiv2025

Vitamin B12 alleviates Verheij syndrome-like defects via phospholipid remodeling in a C. elegans PUF60 spliceosomopathy model

Verheij syndrome (VRJS) is a rare genetic disorder caused by mutations in the poly(U)-binding splicing factor 60 (PUF60), a core component of the spliceosomal complex. VRJS triggers multiple congenital anomalies, but the underlying pathomechanisms remain poorly understood. Mutation of the Caenorhabditis elegans PUF60 ortholog, rnp-6, recapitulates several hallmarks of VRJS, including growth delay and smaller body size. Here, we demonstrate that developmental defects in rnp-6 mutants are rescued by dietary K12-type Escherichia coli strains. Through complementary genetic screens and multi-omics analyses, we identify vitamin B12 (VB12) as a potent suppressor of these defects, acting via the methionine/S-adenosylmethionine/phosphatidylcholine metabolic axis. Mechanistically, rnp-6 mutation causes aberrant splicing with methionine and phospholipid metabolism-related genes, which cumulatively impair cellular methylation potential, dysregulate phosphatidylcholine metabolism, and induce integrated stress response. We identify intron retention of the nhr-114/HNF4 transcription factor as a primary driver of growth defects, and restoring its splicing robustly suppresses these phenotypes. VB12 supplementation bypasses the aberrant splicing, restores metabolic balance, and activates mTORC1 to rescue developmental phenotypes. Finally, we show that PUF60 deficiency induces aberrant splicing of methionine and phospholipid metabolism-related genes in a human cell line, and is associated with altered plasma methionine and phospholipid levels in VRJS patients. Our findings establish C. elegans as a tractable model for VRJS and uncover SAM/SAH/phospholipid dysregulation as a key mechanism underlying the spliceosomopathy, suggesting VB12 as a potential strategy to mitigate VRJS-related anomalies.

genetics↗

bioRxiv2025

Resilience and restoration from fasting-refeeding mediated by a nutrient-regulated linker histone

Intermittent fasting and fasting-refeeding regimens can slow biological aging across taxa1. Shifts between fed and fasted states activate ancient nutrient-sensing pathways which alter cellular and epigenetic states to promote longevity2-4. Yet how biological age trajectories progress during fasting-refeeding, and how nutrient-sensing pathways reprogram epigenetic state remain largely unknown. Here we observe increases in predicted biological age of Caenorhabditis elegans during prolonged fasting in adult reproductive diapause, followed by extraordinary reduction of biological age during refeeding. We identify hil-1/H1-0 as an evolutionarily conserved nutrient-regulated linker histone which mediates adaptations to fasting and refeeding downstream of FOXO and TFEB transcription factors. In C. elegans and human cell culture, hil-1/H1-0 upregulation during low-nutrient states promotes long-term survival and subsequent refeeding-induced recovery. Restoration of C. elegans after prolonged fasting is improved by enhancing the natural downregulation of hil-1 specifically during refeeding. Our study identifies HIL-1/H1.0 as part of an ancestral epigenetic switch during fasting-refeeding that reprograms metabolic and cellular states underlying resilience and restoration.

genetics↗

bioRxiv2024

Amyloid Beta Precursor Protein contributes to brain aging and learning decline in short-lived turquoise killifish (Nothobranchius furzeri)

Brain aging is a key risk factor for many neurodegenerative diseases, yet its molecular and cellular mechanisms remain elusive. Amyloid-beta precursor protein (APP) is among the most studied proteins linked to brain pathology; however, its role in non-pathological brain aging remains poorly characterized. Here, we investigate the natural impact of APP on normal brain aging using the short-lived turquoise killifish (Nothobranchius furzeri), which exhibits rapid and spontaneous age-related decline. We found that a pyroglutamated APP derivative (APPpE11) accumulates intra-neuronally in an age-dependent manner, co-localizing with a marker of cell death. We found that intraneuronal APPpE11 is also present in brains from healthy elderly humans, suggesting deep evolutionary conservation. To determine APPs role in spontaneous brain aging, we knock-out "amyloid precursor protein a" (appa) in killifish via CRISPR/Cas9. The lack of appa mitigated brain aging from a proteome-wide perspective, reduced age-related cell death and inflammation, and improved neuronal activity and learning capacity in aged individuals. Our findings show an ancestral and previously unrecognized role of amyloid-beta precursor protein in non-pathological brain aging, making it an ideal target for anti-aging interventions.

neuroscience↗

bioRxiv2024

Loss of killifish cGAS/STING function attenuates cellular senescence and age-related signatures but does not extend organismal life span

The cGAS/STING pathway is a central innate immune signaling pathway whose chronic activation has been implicated in numerous age-related pathologies, yet its impact on life span itself is unknown. Here we engineered knockouts of this pathway in the killifish Nothobranchius furzeri, and assessed physiology and aging. In vitro, loss of killifish cGAS or STING mitigated DNA damage-induced senescence in cultured fibroblasts. In vivo, cGAS knockout unexpectedly led to low-grade inflammation. It also attenuated changes in gene expression in response to DNA damage in young animals, and age-related changes in the old, suggesting dampening of senescence and aging. Necroscopy indicated that tissue pathology appeared milder overall in both mutants, though some tissues showed enhanced sterile macrophage infiltration. Despite an attenuated aging signature, however, longevity was not significantly different from wild type. Our findings reveal a potential tradeoff, where inhibiting the cGAS/STING pathway alleviates age-related signatures, but increases sterile inflammation, offsetting beneficial effects on lifespan.

developmental biology↗

bioRxiv2024

Epg5 links proteotoxic stress due to defective autophagic clearance and epileptogenesis in Drosophila and Vici Syndrome patients

Epilepsy is a common neurological condition that arises from dysfunctional neuronal circuit control due to either acquired or innate disorders. Autophagy is an essential neuronal housekeeping mechanism, which causes severe proteotoxic stress when impaired. Autophagy impairment has been associated to epileptogenesis through a variety of molecular mechanisms. Vici Syndrome (VS) is the paradigmatic congenital autophagy disorder in humans due to recessive variants in the ectopic P-granules autophagy tethering factor 5 (EPG5) gene that is crucial for autophagosome-lysosome fusion and ultimately for effective autophagic clearance. VS is characterized by a wide range of neurodevelopmental, neurodegenerative, and neurological features, including epilepsy. Here, we used Drosophila melanogaster to study the importance of epg5 in development, ageing, and seizures. Our data indicate that proteotoxic stress due to impaired autophagic clearance and seizure-like behaviors correlate and are commonly regulated, suggesting that seizures occur as a direct consequence of proteotoxic stress and age-dependent neurodegenerative progression in epg5 Drosophila mutants, in the absence of evident neurodevelopmental abnormalities. We provide complementary evidence from EPG5-mutated patients demonstrating an epilepsy phenotype consistent with Drosophila predictions and propose autophagy stimulating diets as a feasible approach to control EPG5-related pharmacoresistant seizures.

neuroscience↗

bioRxiv2023

A primordial TFEB-TGFβ signaling axis systemically regulates diapause and stem cell longevity

Fasting/refeeding enhances animal health and lifespan across taxa. C. elegans can endure months of fasting in adult reproductive diapause (ARD) and upon refeeding, regenerate and reproduce. hlh-30/TFEB is an ARD master regulator whose mutants live mere days in ARD and dont recover with refeeding. Here we find that downregulation of TGF{beta} signaling bypasses hlh-30 collapse, and restores recovery, germline stem cell proliferation and reproductive competence. Upon fasting, HLH-30/TFEB(+) downregulates TGF{beta} in sensory neurons, to inhibit Notch and promote reproductive quiescence in the germline. Upon refeeding, these pathways are upregulated to activate stem cells and promote reproduction. hlh-30 loss induces a senescent-like DNA damage, immune and growth metabolic signature reversed by inhibiting TGF{beta} signaling. TFEBs role is conserved in mammalian diapause models, including mouse embryonic and human cancer diapause. Thus, TFEB-TGF{beta} axis relays systemic signals matching nutrient supply with growth signaling, to regulate stem cell longevity, senescence and regeneration across species.

cell biology↗

bioRxiv2023

Unveiling the Intercompartmental Signaling Axis: Mitochondrial to ER Stress Response (MERSR) and its Impact on Proteostasis

Maintaining protein homeostasis is essential for cellular health. Our previous research uncovered a cross-compartmental Mitochondrial to Cytosolic Stress Response, activated by the perturbation of mitochondrial proteostasis, which ultimately results in the improvement of proteostasis in the cytosol. Here, we found that this signaling axis also influences the unfolded protein response of the endoplasmic reticulum (UPRER), suggesting the presence of a Mitochondria to ER Stress Response (MERSR). During MERSR, the IRE1 branch of UPRER is inhibited, introducing a previously unknown regulatory component of MCSR. Moreover, proteostasis is enhanced through the upregulation of the PERK-eIF2 signaling pathway, increasing phosphorylation of eIF2 and improving the ERs ability to handle proteostasis. MERSR activation in both polyglutamine and amyloid-beta peptide-expressing C. elegans disease models also led to improvement in both aggregate burden and overall disease outcome. These findings shed light on the coordination between the mitochondria and the ER in maintaining cellular proteostasis and provide further evidence for the importance of intercompartmental signaling.

cell biology↗

bioRxiv2023

Hexokinase regulates Mondo-mediated longevity via the PPP and organellar dynamics

The transcriptional complex Mondo/Max-like, MML-1/MXL-2, acts as a convergent transcriptional regulatory output of multiple longevity pathways in Caenorhabditis elegans. These transcription factors coordinate nutrient sensing with carbohydrate and lipid metabolism across the evolutionary spectrum. While most studies have focused on the downstream outputs, little is known about the upstream inputs that regulate these transcription factors in a live organism. Here, we found that knockdown of various glucose metabolic enzymes decreases MML-1 localization in the nucleus and identified two hexokinase isozymes, hxk-1 and hxk-2, as the most vigorous regulators of MML-1 function. Upon hexokinase knockdown, MML-1 redistributes to mitochondria and lipid droplets (LD), and concomitantly, transcriptional targets are downregulated and germline longevity is abolished. Further, we found that hxk-1 regulates MML-1 through mitochondrial {beta}-oxidation, while hxk-2 regulates MML-1 by modulating the pentose phosphate pathway (PPP) and its coordinated association with lipid droplets. Similarly, inhibition of the PPP rescues mammalian MondoA nuclear translocation and transcriptional function upon starvation. These studies reveal how metabolic signals and organellar communication regulate a key convergent metabolic transcription factor to promote longevity.

cell biology↗

bioRxiv2023

Mitochondrial translocation of TFEB regulates complex I and inflammation

TFEB is a master regulator of autophagy, lysosome biogenesis and mitochondrial metabolism that works, and immunity, primarily through transcription controlled by cytosol-to-nuclear translocation. Emerging data indicate additional regulatory interactions at the surface of organelles such as lysosomes. Here we show that TFEB has a non-transcriptional role in mitochondria, regulating the electron transport chain complex I to down-modulate inflammation. Proteomic analysis revealed extensive TFEB co-precipitation with several mitochondrial proteins, whose interactions are disrupted upon infection with S. Typhimurium. Localization of TFEB in the mitochondrial matrix was confirmed by high resolution confocal microscopy and biochemistry with translocation dependent on a conserved N-terminal TOMM20-binding motif enhanced by mTOR inhibition. Within the mitochondria, TFEB and protease LONP1 antagonistically co-regulate complex I, reactive oxygen species and the inflammatory response. Consequently, during infection, lack of TFEB specifically in the mitochondria exacerbates the expression of pro-inflammatory cytokines, contributing to innate immune pathogenesis.

cell biology↗

bioRxiv2022

Refeeding-associated AMPKγ1 complex activity is a hallmark of health and longevity.

Late-life-initiated dietary interventions negligibly extend longevity or reduce frailty, yet the reason remains unknown. We investigated the age-related changes associated with the fasting response in adipose tissue of the short-lived killifish N. furzeri. Transcriptomic analysis revealed the presence of a fasting-like transcriptional program (FLTP) in old animals that is irrespective of their nutritional status and characterized by widespread suppression of anabolic processes. FLTP is associated with reduced expression of the AMPK {gamma}1 regulatory subunit. Accordingly, refeeding positively regulates {gamma}1 expression in young but not in old animals. Fish having sustained AMPK{gamma}1 activation had no sign of FLTP in old age and exhibited metabolic health and longevity. In humans, we found that {gamma}1 expression declines with age and is associated with multimorbidity and multidimensional frailty risk. Our study highlights the importance of the refeeding arm in promoting health and longevity and identifies the AMPK{gamma}1 complex as a potential target to prevent age-related diseases in humans.

physiology↗

bioRxiv2022

The Nuclear RNAi Pathway Regulates DAF-16/FOXO to Control C. elegans Longevity and Dauer Entry

Caenorhabditis elegans with impaired insulin/IGF-1 receptor signalling (IIS) or with germline ablation live longer and this phenomenon is entirely dependent on the transcription factor DAF-16 - the C. elegans homolog of the class O of the forkhead box transcription factors (FoxO). In a candidate RNAi screen designed to search for new modifiers of DAF-16 function among genes involved in histone modification and/or small RNA-mediated silencing pathways, we found nrde-1, wago-1, and adr-1 as positive regulators of DAF-16. We confirmed by several methods and in different models that DAF-16 translocation to the nucleus and, subsequently, its function is tightly controlled by these genes and narrowed down to components of the NRDE complex and the nuclear RNAi pathway as key DAF-16 modulators. Importantly, we found that the NRDE pathway controls DAF-16-mediated longevity and dauer entry. Our epistasis data indicate that nrde-1 interacts with akt-1 to control lifespan. We also demonstrated that NRDE-1 acts downstream of AGE-1/PI3K and partially requires mTORC2 and AKT-1 to control DAF-16 translocation. These results unveil a mechanism of regulation of dauer formation and longevity in C. elegans via nuclear RNAi-mediated modulation of DAF-16 function in a manner that involves the mTORC2-AKT axis.

genetics↗

bioRxiv2022

Decreased spliceosome fidelity inhibits mTOR signalling and promotes longevity via an intron retention event

Changes in splicing fidelity are associated with loss of homeostasis and ageing1-3, yet only a handful of splicing factors have been shown to be causally required to promote longevity 1-3, and the underlying mechanisms and downstream targets in these paradigms remain elusive. Surprisingly, we found a hypomorphic mutation within RNP-6/PUF60, a spliceosome component promoting weak 3 splice site recognition, which causes aberrant splicing, elevated stress responses, and enhances longevity in Caenorhabditis elegans. Through genetic suppressor screens, we identify a gain-of-function mutation within rbm-39, an RNP-6 interacting splicing factor, which increases nuclear speckle formation, alleviates splicing defects and curtails longevity caused by rnp-6 mutation. By leveraging the splicing changes induced by RNP-6/RBM-39 activities, we uncover a single intron retention event in egl-8/phospholipase C B4 as a key splicing target prolonging life. Genetic and biochemical evidence show that neuronal RNP-6/EGL-8 downregulate mTORC1 signaling to control organismal life span. In mammalian cells, PUF60 downregulation also potently and specifically inhibits mTORC1 signaling. Altogether, our results reveal that splicing fidelity modulates mTOR signaling and suggest a potential therapeutic strategy to delay ageing.

genetics↗

bioRxiv2021

A systematic analysis of diet-induced nephroprotection reveals overlapping and conserved changes in cysteine catabolism

Caloric Restriction (CR) extends lifespan and augments cellular stress-resistance from yeast to primates, making CR an attractive strategy for organ protection in the clinic. Translation of CR to patients is complex, due to problems regarding adherence, feasibility and safety concerns in frail patients. Novel tailored dietary regimens, which modulate the dietary composition of macro- and micronutrients rather than reducing calorie intake promise similar protective effects and increased translatability. However, a direct head-to-head comparison to identify the most potent approach for organ protection as well as overlapping metabolic consequences has not been performed. We systematically analyzed six dietary preconditioning protocols - fasting mimicking diet (FMD), ketogenic diet (KD), dietary restriction of branched chained amino acids (BCAA), two dietary regimens restricting sulfur-containing amino acids (SR80/100) and CR - in a rodent model of renal ischemia-reperfusion injury (IRI) to quantify diet-induced resilience in kidneys. Of the administered diets, FMD, SR80/100 and CR efficiently protect from kidney damage after IRI. Interestingly, these approaches show overlapping changes in oxidative and hydrogen sulfide (H2S)-dependent cysteine catabolism as a potential common mechanism of organ protection. Importantly, these metabolic changes can be recapitulated in patients preconditioned by a diet limiting sulfur-containing amino acids indicating conserved diet-induced mechanisms of stress-resistance that may ultimately lead to clinical application.

biochemistry↗

bioRxiv2021

miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to affect muscle contractility upon proteotoxic challenge during ageing

Muscle function relies on the precise architecture of dynamic contractile elements, which must be fine-tuned to maintain motility throughout life. Muscle is also highly plastic, and remodelled in response to stress, growth, neural and metabolic inputs. The evolutionarily conserved muscle-enriched microRNA, miR-1, regulates distinct aspects of muscle biology during development, but whether it plays a role during ageing is unknown. Here we investigated the role of C. elegans miR-1 in muscle function in response to proteostatic stress during adulthood. mir-1 deletion results in improved mid-life muscle motility, pharyngeal pumping, and organismal longevity under conditions of polyglutamine repeat proteotoxic challenge. We identified multiple vacuolar ATPase subunits as subject to miR-1 control, and the regulatory subunit vha-13/ATP6VIA as a direct target downregulated via its 3UTR to mediate miR-1 physiology. miR-1 further regulates nuclear localization of lysosomal biogenesis factor HLH-30/TFEB and lysosomal acidification. In summary, our studies reveal that miR-1 coordinately regulates lysosomal v-ATPase and biogenesis to impact muscle function and health during ageing.

genetics↗

bioRxiv2020

Cell size is a determinant of stem cell potential during aging

Stem cells are remarkably small in size. Whether small size is important for stem cell function is unknown. We find that murine hematopoietic stem cells (HSCs) enlarge under conditions known to decrease stem cell function. This decreased fitness of large HSCs is due to reduced proliferative potential. Preventing HSC enlargement by inhibiting macromolecule biosynthesis or reducing large HSCs size by shortening G1 averts the loss of stem cell potential under conditions causing stem cell exhaustion. Finally, we show that a fraction of murine and human HSCs enlarge during aging. Preventing this age-dependent enlargement improves HSC function. We conclude that small cell size is important for stem cell function in vivo and propose that stem cell enlargement contributes to their functional decline during aging. One Sentence SummarySize increase drives stem cell aging.

cell biology↗