Abdelrahman AlOkda

McGill University

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Jeremy M. Van Raamsdonk

Van Andel Institute

Bokang Ko

McGill University

Annika Traa

McGill University Health Centre

Zenith D. Rudich

McGill University

Aura A. Tamez González

McGill University

Sonja K. Soo

McGill University Health Centre

Hazel J. Shields

McGill University Health Centre

Alibek Moldakozhayev

Brigham and Women's Hospital

Suleima Jacob‐Tomas

McGill University Health Centre

Gustavo Duque

McGill University Health Centre

Cooperative Institutions

McGill University Health Centre

McGill University

Zewail City of Science and Technology

Harvard University

Jewish General Hospital

Brigham and Women's Hospital

University of British Columbia

University of Melbourne

Australian Institute for Musculoskeletal Science

Western Health

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Evolutionarily Conserved Role of Thioredoxin Systems in Determining Longevity

Antioxidants (2023)

Abdelrahman AlOkda Jeremy M. Van Raamsdonk

Thioredoxin and thioredoxin reductase are evolutionarily conserved antioxidant enzymes that protect organisms from oxidative stress. These proteins also play roles in redox signaling and can act as a redox-independent cellular chaperone. In most organisms, there is a cytoplasmic and mitochondrial thioredoxin system. A number of studies have examined the role of thioredoxin and thioredoxin reductase in determining longevity. Disruption of either thioredoxin or thioredoxin reductase is sufficient to shorten lifespan in model organisms including yeast, worms, flies and mice, thereby indicating conservation across species. Similarly, increasing the expression of thioredoxin or thioredoxin reductase can extend longevity in multiple model organisms. In humans, there is an association between a specific genetic variant of thioredoxin reductase and lifespan. Overall, the cytoplasmic and mitochondrial thioredoxin systems are both important for longevity.

Ferredoxin-thioredoxin reductase

10.3390/antiox12040944

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Citations (15)

Biological resilience and aging: Activation of stress response pathways contributes to lifespan extension

Ageing Research Reviews (2023)

Sonja K. Soo Zenith D. Rudich Bokang Ko Alibek Moldakozhayev Abdelrahman AlOkda

While aging was traditionally viewed as a stochastic process of damage accumulation, it is now clear that aging is strongly influenced by genetics. The identification and characterization of long-lived genetic mutants in model organisms has provided insights into the genetic pathways and molecular mechanisms involved in extending longevity. Long-lived genetic mutants exhibit activation of multiple stress response pathways leading to enhanced resistance to exogenous stressors. As a result, lifespan exhibits a significant, positive correlation with resistance to stress. Disruption of stress response pathways inhibits lifespan extension in multiple long-lived mutants representing different pathways of lifespan extension and can also reduce the lifespan of wild-type animals. Combined, this suggests that activation of stress response pathways is a key mechanism by which long-lived mutants achieve their extended longevity and that many of these pathways are also required for normal lifespan. These results highlight an important role for stress response pathways in determining the lifespan of an organism.

Model Organism

Stressor

Cellular stress response

10.1016/j.arr.2023.101941

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Overexpression of mitochondrial fission or mitochondrial fusion genes enhances resilience and extends longevity

Aging Cell (2024)

Annika Traa Allison Keil Abdelrahman AlOkda Suleima Jacob‐Tomas Aura A. Tamez González

Abstract The dynamicity of the mitochondrial network is crucial for meeting the ever‐changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected, and well‐organized in young, healthy C. elegans , but become fragmented and disorganized with advancing age and in models of age‐associated neurodegenerative disease. In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp‐1 or the mitochondrial fusion genes fzo‐1 and eat‐3 , individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance, and lifespan. Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which in the case of the mitochondrial fusion overexpression strains appears to be at least partially due to the upregulation of multiple pathways of cellular resilience in these strains. Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity.

DNAJA3

MFN2

FIS1

10.1111/acel.14262

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Endosomal trafficking protein TBC‐2 modulates stress resistance and lifespan through DAF‐16‐dependent and independent mechanisms

Aging Cell (2023)

Annika Traa Sonja K. Soo Abdelrahman AlOkda Bokang Ko Christian E. Rocheleau

Abstract The FOXO transcription factor, DAF‐16, plays an integral role in insulin/IGF‐1 signaling (IIS) and stress response. In conditions of stress or decreased IIS, DAF‐16 moves to the nucleus where it activates genes that promote survival. To gain insight into the role of endosomal trafficking in resistance to stress, we disrupted tbc‐2 , which encodes a GTPase activating protein that inhibits RAB‐5 and RAB‐7. We found that tbc‐2 mutants have decreased nuclear localization of DAF‐16 in response to heat stress, anoxia, and bacterial pathogen stress, but increased nuclear localization of DAF‐16 in response to chronic oxidative stress and osmotic stress. tbc‐2 mutants also exhibit decreased upregulation of DAF‐16 target genes in response to stress. To determine whether the rate of nuclear localization of DAF‐16 affected stress resistance in these animals, we examined survival after exposure to multiple exogenous stressors. Disruption of tbc‐2 decreased resistance to heat stress, anoxia, and bacterial pathogen stress in both wild‐type worms and stress‐resistant daf‐2 insulin/IGF‐1 receptor mutants. Similarly, deletion of tbc‐2 decreases lifespan in both wild‐type worms and daf‐2 mutants. When DAF‐16 is absent, the loss of tbc‐2 is still able to decrease lifespan but has little or no impact on resistance to most stresses. Combined, this suggests that disruption of tbc‐2 affects lifespan through both DAF‐16‐dependent and DAF‐16‐independent pathways, while the effect of tbc‐2 deletion on resistance to stress is primarily DAF‐16‐dependent. Overall, this work demonstrates the importance of endosomal trafficking for the proper nuclear localization of DAF‐16 during stress and that perturbation of normal endosomal trafficking is sufficient to decrease both stress resistance and lifespan.

Rab

Osmotic shock

10.1111/acel.13762

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Endosomal trafficking protein TBC-2 is required for the longevity of long-lived mitochondrial mutants

Frontiers in Aging (2023)

Annika Traa Hazel J. Shields Abdelrahman AlOkda Zenith D. Rudich Bokang Ko

Mutations that result in a mild impairment of mitochondrial function can extend longevity. Previous studies have shown that the increase in lifespan is dependent on stress responsive transcription factors, including DAF-16/FOXO, which exhibits increased nuclear localization in long-lived mitochondrial mutants. We recently found that the localization of DAF-16 within the cell is dependent on the endosomal trafficking protein TBC-2. Based on the important role of DAF-16 in both longevity and resistance to stress, we examined the effect of disrupting tbc-2 on lifespan and stress resistance in the long-lived mitochondrial mutants nuo-6 and isp-1 in Caenorhabditis elegans. Loss of tbc-2 markedly reduced the long lifespans of both mitochondrial mutants. Disruption of tbc-2 also decreased resistance to chronic oxidative stress in nuo-6 and isp-1 mutants but had little or no detrimental effect on resistance to other stressors. In contrast, tbc-2 inhibition had no effect on oxidative stress resistance or lifespan in isp-1 worms when DAF-16 is absent, suggesting that the effect of tbc-2 on mitochondrial mutant lifespan may be mediated by mislocalization of DAF-16. However, this result is complicated by the fact that deletion of daf-16 markedly decreases both phenotypes in isp-1 worms, which could result in a floor effect. In exploring the contribution of DAF-16 further, we found that disruption of tbc-2 did not affect the nuclear localization of DAF-16 in isp-1 worms or prevent the upregulation of DAF-16 target genes in the long-lived mitochondrial mutants. This suggests the possibility that the effect of tbc-2 on lifespan and stress resistance in the long-lived mitochondrial mutants is at least partially independent of its effects on DAF-16 localization. Overall, this work demonstrates the importance of endosomal trafficking for the extended longevity and enhanced stress resistance resulting from mild impairment of mitochondrial function.

10.3389/fragi.2023.1145198

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Mild activation of the mitochondrial unfolded protein response increases lifespan without increasing resistance to stress

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Alexa Di Pede Bokang Ko Abdelrahman AlOkda Aura A. Tamez González Jeremy M. Van Raamsdonk

Abstract The mitochondrial unfolded protein response (mitoUPR) is a stress response pathway that responds to mitochondrial insults by altering gene expression to recover mitochondrial homeostasis. The mitoUPR is mediated by the stress-activated transcription factor ATFS-1. Constitutive activation of ATFS-1 increases resistance to exogenous stressors but paradoxically decreases lifespan. In this work, we determined the optimal levels of expression of activated ATFS-1 with respect to lifespan and resistance to stress by treating constitutively-active atfs-1(et17) worms with different concentrations of RNA interference (RNAi) bacteria targeting atfs-1. We observed the maximum lifespan of atfs-1(et17) worms at full-strength atfs-1 RNAi, which was significantly longer than wild-type lifespan. Under the conditions of maximum lifespan, atfs-1(et17) worms did not show enhanced resistance to stress, suggesting a trade-off between stress resistance and longevity. The maximum resistance to stress in atfs-1(et17) worms occurred on empty vector (0% atfs-1 knockdown). Under these conditions, atfs-1(et17) worms are short-lived. This indicates that constitutive activation of ATFS-1 can increase lifespan or enhance resistance to stress but not both, at the same time. Finally, we determined the timing requirements for ATFS-1 to affect lifespan. We found that knocking down atfs-1 expression only during development is sufficient to extend atfs-1(et17) lifespan, while adult-only knockdown has no effect. Overall, these results demonstrate that constitutively active ATFS-1 can extend lifespan when expressed at low levels and that this lifespan extension is not dependent on the ability of ATFS-1 to enhance resistance to stress.

10.1101/2024.09.13.612912

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Synchronization by bleaching does not affect longevity.

PubMed (2024)

Aura A. Tamez González Abdelrahman AlOkda Suleima Jacob‐Tomas Jeremy M. Van Raamsdonk

has been used extensively for research on the biology of aging due to its genetic tractability and short lifespan. In order to measure lifespan, populations of worms are synchronized so that all of the worms being measured begin the assay at the same age. This is typically accomplished by simply picking worms of a particular developmental stage to start the lifespan experiment or through bleaching, a process through which the body of the worm is dissolved in a solution of bleach (sodium hypochlorite) and sodium hydroxide to release its fertilized eggs. In this experiment, we examined the effect of bleaching on lifespan in wild-type worms and the long-lived mitochondrial mutant

Affect

10.17912/micropub.biology.001297

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Mitochondrial thioredoxin system is required for enhanced stress resistance and extended longevity in long-lived mitochondrial mutants

Redox Biology (2022)

Namasthée Harris-Gauthier Annika Traa Abdelrahman AlOkda Alibek Moldakozhayev Ulrich Anglas

Mild impairment of mitochondrial function has been shown to increase lifespan in genetic model organisms including worms, flies and mice. To better understand the mechanisms involved, we analyzed RNA sequencing data and found that genes involved in the mitochondrial thioredoxin system, trx-2 and trxr-2, are specifically upregulated in long-lived mitochondrial mutants but not other non-mitochondrial, long-lived mutants. Upregulation of trx-2 and trxr-2 is mediated by activation of the mitochondrial unfolded protein response (mitoUPR). While we decided to focus on the genes of the mitochondrial thioredoxin system for this paper, we identified multiple other antioxidant genes that are upregulated by the mitoUPR in the long-lived mitochondrial mutants including sod-3, prdx-3, gpx-6, gpx-7, gpx-8 and glrx-5. In exploring the role of the mitochondrial thioredoxin system in the long-lived mitochondrial mutants, nuo-6 and isp-1, we found that disruption of either trx-2 or trxr-2 significantly decreases their long lifespan, but has no effect on wild-type lifespan, indicating that the mitochondrial thioredoxin system is specifically required for their longevity. In contrast, disruption of the cytoplasmic thioredoxin gene trx-1 decreases lifespan in nuo-6, isp-1 and wild-type worms, indicating a non-specific detrimental effect on longevity. Disruption of trx-2 or trxr-2 also decreases the enhanced resistance to stress in nuo-6 and isp-1 worms, indicating a role for the mitochondrial thioredoxin system in protecting against exogenous stressors. Overall, this work demonstrates an important role for the mitochondrial thioredoxin system in both stress resistance and lifespan resulting from mild impairment of mitochondrial function.

Peroxiredoxin

Mitochondrial ROS

10.1016/j.redox.2022.102335

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Effect of DMSO on lifespan and physiology in C. elegans : Implications for use of DMSO as a solvent for compound delivery.

PubMed (2022)

Abdelrahman AlOkda Jeremy M. Van Raamsdonk

Dimethyl sulfoxide (DMSO) is a solvent that has been used for basic and medical research based on its ability to dissolve both polar and non-polar compounds. In order to use DMSO to deliver compounds that may impact longevity or neurodegeneration, it is important to first determine the effects of DMSO on aging and physiology. We examined the effect of different concentrations of DMSO on lifespan and development time in C. elegans. We found that DMSO concentrations up to 2% DMSO did not affect longevity in wild-type worms, while concentrations of up to 0.5% DMSO were compatible with normal development times. 0.5% DMSO also had minimal effect on fertility and movement. In summary, our results show that concentrations of DMSO up to 0.5% can be safely used to deliver compounds to C. elegans with little or no modifying effects on lifespan or physiologic rates.

10.17912/micropub.biology.000634

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The consequences of viral infection on host DNA damage response: a focus on SARS-CoVs

Journal of Genetic Engineering and Biotechnology (2022)

Asmaa S. Mekawy Zina Alaswad Aya A. Ibrahim Ahmed A. Mohamed Abdelrahman AlOkda

DNA damage and genome instability in host cells are introduced by many viruses during their life cycles. Severe acute respiratory syndrome coronaviruses (SARS-CoVs) manipulation of DNA damage response (DDR) is an important area of research that is still understudied. Elucidation of the direct and indirect interactions between SARS-CoVs and DDR not only provides important insights into how the viruses exploit DDR pathways in host cells but also contributes to our understanding of their pathogenicity. Here, we present the known interactions of both SARS-CoV and SARS-CoV-2 with DDR pathways of the host cells, to further understand the consequences of infection on genome integrity. Since this area of research is in its early stages, we try to connect the unlinked dots to speculate and propose different consequences on DDR mechanisms. This review provides new research scopes that can be further investigated in vitro and in vivo, opening new avenues for the development of anti-SARS-CoV-2 drugs.

10.1186/s43141-022-00388-3

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Citations (11)