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3. Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used

Author

Harrison, David E., Strong, Randy, Reifsnyder, Peter, Rosenthal, Nadia, Korstanje, Ron, Fernandez, Elizabeth, Flurkey, Kevin, Ginsburg, Brett C., Murrell, Meredith D., Javors, Martin A., Lopez-Cruzan, Marisa, Nelson, James F., Willcox, Bradley J., Allsopp, Richard, Watumull, David M., Watumull, David G., Cortopassi, Gino, Kirkland, James L., Tchkonia, Tamar, Choi, Young Geun, Yousefzadeh, Matthew J., Robbins, Paul D., Mitchell, James R., Acar, Murat, Sarnoski, Ethan A., Bene, Michael R., Salmon, Adam, Kumar, Navasuja, and Miller, Richard A.

Published
2024
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4. Ending a diagnostic odyssey: Moving from exome to genome to identify cockayne syndrome.

Author

Friedman, Jennifer, Bird, Lynne M, Haas, Richard, Robbins, Shira L, Nahas, Shareef A, Dimmock, David P, Yousefzadeh, Matthew J, Witt, Mariah A, Niedernhofer, Laura J, and Chowdhury, Shimul

Subjects
ERCC6, DNA repair, cockayne syndrome, whole-genome sequencing, ERCC6, Medicinal and Biomolecular Chemistry, Genetics, Clinical Sciences
Abstract

BackgroundCockayne syndrome (CS) is a rare autosomal recessive disorder characterized by growth failure and multisystemic degeneration. Excision repair cross-complementation group 6 (ERCC6 OMIM: *609413) is the gene most frequently mutated in CS.MethodsA child with pre and postnatal growth failure and progressive neurologic deterioration with multisystem involvement, and with nondiagnostic whole-exome sequencing, was screened for causal variants with whole-genome sequencing (WGS).ResultsWGS identified biallelic ERCC6 variants, including a previously unreported intronic variant. Pathogenicity of these variants was established by demonstrating reduced levels of ERCC6 mRNA and protein expression, normal unscheduled DNA synthesis, and impaired recovery of RNA synthesis in patient fibroblasts following UV-irradiation.ConclusionThe study confirms the pathogenicity of a previously undescribed upstream intronic variant, highlighting the power of genome sequencing to identify noncoding variants. In addition, this report provides evidence for the utility of a combination approach of genome sequencing plus functional studies to provide diagnosis in a child for whom a lengthy diagnostic odyssey, including exome sequencing, was previously unrevealing.

Published
2021

5. Neurodegeneration as the presenting symptom in 2 adults with xeroderma pigmentosum complementation group F.

Author

Shanbhag, Niraj M, Geschwind, Michael D, DiGiovanna, John J, Groden, Catherine, Godfrey, Rena, Yousefzadeh, Matthew J, Wade, Erin A, Niedernhofer, Laura J, Malicdan, May Christine V, Kraemer, Kenneth H, Gahl, William A, and Toro, Camilo

Subjects
Genetics, Neurosciences
Abstract

ObjectiveTo describe the features of 2 unrelated adults with xeroderma pigmentosum complementation group F (XP-F) ascertained in a neurology care setting.MethodsWe report the clinical, imaging, molecular, and nucleotide excision repair (NER) capacity of 2 middle-aged women with progressive neurodegeneration ultimately diagnosed with XP-F.ResultsBoth patients presented with adult-onset progressive neurologic deterioration involving chorea, ataxia, hearing loss, cognitive deficits, profound brain atrophy, and a history of skin photosensitivity, skin freckling, and/or skin neoplasms. We identified compound heterozygous pathogenic mutations in ERCC4 and confirmed deficient NER capacity in skin fibroblasts from both patients.ConclusionsThese cases illustrate the role of NER dysfunction in neurodegeneration and how adult-onset neurodegeneration could be the major symptom bringing XP-F patients to clinical attention. XP-F should be considered by neurologists in the differential diagnosis of patients with adult-onset progressive neurodegeneration accompanied by global brain atrophy and a history of heightened sun sensitivity, excessive freckling, and skin malignancies.

Published
2018

6. Metabolism in the Midwest: research from the Midwest Aging Consortium at the 49th Annual Meeting of the American Aging Association

Author

Murphy, Michaela E., Narasimhan, Akilavalli, Adrian, Alexis, Kumar, Ankur, Green, Cara L., Soto-Palma, Carolina, Henpita, Chathurika, Camell, Christina, Morrow, Christopher S., Yeh, Chung-Yang, Richardson, Claire E., Hill, Cristal M., Moore, Darcie L., Lamming, Dudley W., McGregor, Eric R., Simmons, Heather A., Pak, Heidi H., Bai, Hua, Denu, John M., Clark, Josef, Simcox, Judith, Chittimalli, Kishore, Dahlquist, Korbyn, Lee, Kyoo-a, Calubag, Mariah, Bouska, Mark, Yousefzadeh, Matthew J., Sonsalla, Michelle, Babygirija, Reji, Yuan, Rong, Tsuji, Tadataka, Rhoads, Timothy, Menon, Vinal, Jarajapu, Yagna PR., and Zhu, Yun

Published
2022
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7. An aged immune system drives senescence and ageing of solid organs

Author

Yousefzadeh, Matthew J., Flores, Rafael R., Zhu, Yi, Schmiechen, Zoe C., Brooks, Robert W., Trussoni, Christy E., Cui, Yuxiang, Angelini, Luise, Lee, Kyoo-A, McGowan, Sara J., Burrack, Adam L., Wang, Dong, Dong, Qing, Lu, Aiping, Sano, Tokio, O’Kelly, Ryan D., McGuckian, Collin A., Kato, Jonathan I., Bank, Michael P., Wade, Erin A., Pillai, Smitha P. S., Klug, Jenna, Ladiges, Warren C., Burd, Christin E., Lewis, Sara E., LaRusso, Nicholas F., Vo, Nam V., Wang, Yinsheng, Kelley, Eric E., Huard, Johnny, Stromnes, Ingunn M., Robbins, Paul D., and Niedernhofer, Laura J.

Published
2021
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9. The 3 I's of immunity and aging: immunosenescence, inflammaging, and immune resilience.

Author

Wrona, Marianna V., Ghosh, Rituparna, Coll, Kaitlyn, Chun, Connor, and Yousefzadeh, Matthew J.

Subjects
PSYCHOLOGICAL resilience, SOCIAL determinants of health, BEHAVIOR modification, KILLER cells, BODY mass index, GUT microbiome, CELLULAR aging, SEX distribution, IMMUNE system, FUNCTIONAL status, AGING, HEALTH behavior, MTOR inhibitors, INFLAMMATION, DISEASE susceptibility, NATURAL immunity, DENDRITIC cells, COGNITION
Abstract

As we age, our immune system's ability to effectively respond to pathogens declines, a phenomenon known as immunosenescence. This age-related deterioration affects both innate and adaptive immunity, compromising immune function and leading to chronic inflammation that accelerates aging. Immunosenescence is characterized by alterations in immune cell populations and impaired functionality, resulting in increased susceptibility to infections, diminished vaccine efficacy, and higher prevalence of age-related diseases. Chronic low-grade inflammation further exacerbates these issues, contributing to a decline in overall health and resilience. This review delves into the characteristics of immunosenescence and examines the various intrinsic and extrinsic factors contributing to immune aging and how the hallmarks of aging and cell fates can play a crucial role in this process. Additionally, it discusses the impact of sex, age, social determinants, and gut microbiota health on immune aging, illustrating the complex interplay of these factors in altering immune function. Furthermore, the concept of immune resilience is explored, focusing on the metrics for assessing immune health and identifying strategies to enhance immune function. These strategies include lifestyle interventions such as diet, regular physical activity, stress management, and the use of gerotherapeutics and other approaches. Understanding and mitigating the effects of immunosenescence are crucial for developing interventions that support robust immune responses in aged individuals. [ABSTRACT FROM AUTHOR]

Published
2024
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13. Cellular senescence: a key therapeutic target in aging and diseases

Author

Zhang, Lei, Pitcher, Louise E., Yousefzadeh, Matthew J., Niedernhofer, Laura J., Robbins, Paul D., and Zhu, Yi

Subjects
Research, Health aspects, Longevity -- Research, Pharmacological research, Cell aging -- Health aspects, Cells -- Aging, Pharmacology, Experimental
Abstract

Introduction Aging is a complex process driven, at least in part, by hallmarks of aging, including cellular senescence, genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, [...], Cellular senescence is a hallmark of aging defined by stable exit from the cell cycle in response to cellular damage and stress. Senescent cells (SnCs) can develop a characteristic pathogenic senescence-associated secretory phenotype (SASP) that drives secondary senescence and disrupts tissue homeostasis, resulting in loss of tissue repair and regeneration. The use of transgenic mouse models in which SnCs can be genetically ablated has established a key role for SnCs in driving aging and age-related disease. Importantly, senotherapeutics have been developed to pharmacologically eliminate SnCs, termed senolytics, or suppress the SASP and other markers of senescence, termed senomorphics. Based on extensive preclinical studies as well as small clinical trials demonstrating the benefits of senotherapeutics, multiple clinical trials are under way. This Review discusses the role of SnCs in aging and age-related diseases, strategies to target SnCs, approaches to discover and develop senotherapeutics, and preclinical and clinical advances of senolytics.

Published
2022
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14. ERCC1-deficient cells and mice are hypersensitive to lipid peroxidation

Author

Czerwińska, Jolanta, Nowak, Małgorzata, Wojtczak, Patrycja, Dziuban-Lech, Dorota, Cieśla, Jarosław M., Kołata, Daria, Gajewska, Beata, Barańczyk-Kuźma, Anna, Robinson, Andria R., Shane, Hillary L., Gregg, Siobhán Q., Rigatti, Lora H., Yousefzadeh, Matthew J., Gurkar, Aditi U., McGowan, Sara J., Kosicki, Konrad, Bednarek, Małgorzata, Zarakowska, Ewelina, Gackowski, Daniel, Oliński, Ryszard, Speina, Elżbieta, Niedernhofer, Laura J., and Tudek, Barbara

Published
2018
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15. Spontaneous DNA damage to the nuclear genome promotes senescence, redox imbalance and aging

Author

Robinson, Andria R., Yousefzadeh, Matthew J., Rozgaja, Tania A., Wang, Jin, Li, Xuesen, Tilstra, Jeremy S., Feldman, Chelsea H., Gregg, Siobhán Q., Johnson, Caroline H., Skoda, Erin M., Frantz, Marie-Céline, Bell-Temin, Harris, Pope-Varsalona, Hannah, Gurkar, Aditi U., Nasto, Luigi A., Robinson, Renã A.S., Fuhrmann-Stroissnigg, Heike, Czerwinska, Jolanta, McGowan, Sara J., Cantu-Medellin, Nadiezhda, Harris, Jamie B., Maniar, Salony, Ross, Mark A., Trussoni, Christy E., LaRusso, Nicholas F., Cifuentes-Pagano, Eugenia, Pagano, Patrick J., Tudek, Barbara, Vo, Nam V., Rigatti, Lora H., Opresko, Patricia L., Stolz, Donna B., Watkins, Simon C., Burd, Christin E., Croix, Claudette M. St., Siuzdak, Gary, Yates, Nathan A., Robbins, Paul D., Wang, Yinsheng, Wipf, Peter, Kelley, Eric E., and Niedernhofer, Laura J.

Published
2018
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19. Astaxanthin and meclizine extend lifespan in UM-HET3 male mice; fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate do not significantly affect lifespan in either sex at the doses and schedules used

Author

Acar, Murat (ORCID 0000-0003-3289-8751 & YÖK ID 384943), Harrison, David E.; Strong, Randy; Reifsnyder, Peter; Rosenthal, Nadia; Korstanje, Ron; Fernandez, Elizabeth; Flurkey, Kevin; Ginsburg, Brett C.; Murrell, Meredith D.; Javors, Martin A.; Lopez-Cruzan, Marisa; Nelson, James F.; Willcox, Bradley J.; Allsopp, Richard; Watumull, David M.; Watumull, David G.; Cortopassi, Gino; Kirkland, James L.; Tchkonia, Tamar; Choi, Young Geun; Yousefzadeh, Matthew J.; Robbins, Paul D.; Mitchell, James R.; Sarnoski, Ethan A.; Bene, Michael R.; Salmon, Adam; Kumar, Navasuja; Miller, Richard A., School of Medicine, Acar, Murat (ORCID 0000-0003-3289-8751 & YÖK ID 384943), Harrison, David E.; Strong, Randy; Reifsnyder, Peter; Rosenthal, Nadia; Korstanje, Ron; Fernandez, Elizabeth; Flurkey, Kevin; Ginsburg, Brett C.; Murrell, Meredith D.; Javors, Martin A.; Lopez-Cruzan, Marisa; Nelson, James F.; Willcox, Bradley J.; Allsopp, Richard; Watumull, David M.; Watumull, David G.; Cortopassi, Gino; Kirkland, James L.; Tchkonia, Tamar; Choi, Young Geun; Yousefzadeh, Matthew J.; Robbins, Paul D.; Mitchell, James R.; Sarnoski, Ethan A.; Bene, Michael R.; Salmon, Adam; Kumar, Navasuja; Miller, Richard A., and School of Medicine

Abstract

In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 x C3D2F1 cross, the Nrf2 activator astaxanthin (Asta) extended the median male lifespan by 12% (p = 0.003, log-rank test), while meclizine (Mec), an mTORC1 inhibitor, extended the male lifespan by 8% (p = 0.03). Asta was fed at 1840 +/- 520 (9) ppm and Mec at 544 +/- 48 (9) ppm, stated as mean +/- SE (n) of independent diet preparations. Both were started at 12 months of age. The 90th percentile lifespan for both treatments was extended in absolute value by 6% in males, but neither was significant by the Wang-Allison test. Five other new agents were also tested as follows: fisetin, SG1002 (hydrogen sulfide donor), dimethyl fumarate, mycophenolic acid, and 4-phenylbutyrate. None of these increased lifespan significantly at the dose and method of administration tested in either sex. Amounts of dimethyl fumarate in the diet averaged 35% of the target dose, which may explain the absence of lifespan effects. Body weight was not significantly affected in males by any of the test agents. Late life weights were lower in females fed Asta and Mec, but lifespan was not significantly affected in these females. The male-specific lifespan benefits from Asta and Mec may provide insights into sex-specific aspects of aging., This work was funded in part by NIA grants AG022308 (D.E.H.), AG022303 (R.A.M.), and AG022307 and AG013319 (R.S.), with important facilities supported by CA034196 (JAX). Some of the studies at UM were supported by the Glenn Foundation for Medical Research. RS is supported by a Senior Research Career Scientist Award from the Department of Veterans Affairs Office of Research and Development. We wish to thank Pam J. Krason, Vicki Ingalls, Nelson Durgin, Natalie Perry, Lori Roberts, Roxann Alonzo, Ilkim Erturk, Jacob Sheets, and Vivian Diaz for reliable technical assistance; Jesse Sanchez and Greg Friesenhahn for excellent technical support in Analytical Pharmacology; and Joanne M. Currer for editorial assistance. Dr Jennifer Fox served as the project officer for the National Institute on Aging and contributed to program development, experimental design, and analysis. Her contributions entitle her to co-authorship, but that is not allowed currently by the NIH.

Published
2023

22. Loss of DNA repair mechanisms in cardiac myocytes induce dilated cardiomyopathy

Author

Henpita, Chathurika, primary, Vyas, Rajesh, additional, Healy, Chastity L., additional, Kieu, Tra L., additional, Gurkar, Aditi U., additional, Yousefzadeh, Matthew J., additional, Cui, Yuxiang, additional, Lu, Aiping, additional, Angelini, Luise A., additional, O'Kelly, Ryan D., additional, McGowan, Sara J., additional, Chandrasekhar, Sanjay, additional, Vanderpool, Rebecca R., additional, Hennessy‐Wack, Danielle, additional, Ross, Mark A., additional, Bachman, Timothy N., additional, McTiernan, Charles, additional, Pillai, Smitha P. S., additional, Ladiges, Warren, additional, Lavasani, Mitra, additional, Huard, Johnny, additional, Beer‐Stolz, Donna, additional, St. Croix, Claudette M., additional, Watkins, Simon C., additional, Robbins, Paul D., additional, Mora, Ana L., additional, Kelley, Eric E., additional, Wang, Yinsheng, additional, O'Connell, Timothy D., additional, and Niedernhofer, Laura J., additional

Published
2023
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27. Novel small molecule inhibition of IKK/NF‐κB activation reduces markers of senescence and improves healthspan in mouse models of aging

Author

Zhang, Lei, primary, Zhao, Jing, additional, Mu, Xiaodong, additional, McGowan, Sara J., additional, Angelini, Luise, additional, O'Kelly, Ryan D., additional, Yousefzadeh, Matthew J., additional, Sakamoto, Ayumi, additional, Aversa, Zaira, additional, LeBrasseur, Nathan K., additional, Suh, Yousin, additional, Huard, Johnny, additional, Kamenecka, Theodore M., additional, Niedernhofer, Laura J., additional, and Robbins, Paul D., additional

Published
2021
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28. Metabolism in the Midwest: research from the Midwest Aging Consortium at the 49th Annual Meeting of the American Aging Association

Author

Murphy, Michaela E., primary, Narasimhan, Akilavalli, additional, Adrian, Alexis, additional, Kumar, Ankur, additional, Green, Cara L., additional, Soto-Palma, Carolina, additional, Henpita, Chathurika, additional, Camell, Christina, additional, Morrow, Christopher S., additional, Yeh, Chung-Yang, additional, Richardson, Claire E., additional, Hill, Cristal M., additional, Moore, Darcie L., additional, Lamming, Dudley W., additional, McGregor, Eric R., additional, Simmons, Heather A., additional, Pak, Heidi H., additional, Bai, Hua, additional, Denu, John M., additional, Clark, Josef, additional, Simcox, Judith, additional, Chittimalli, Kishore, additional, Dahlquist, Korbyn, additional, Lee, Kyoo-a, additional, Calubag, Mariah, additional, Bouska, Mark, additional, Yousefzadeh, Matthew J., additional, Sonsalla, Michelle, additional, Babygirija, Reji, additional, Yuan, Rong, additional, Tsuji, Tadataka, additional, Rhoads, Timothy, additional, Menon, Vinal, additional, Jarajapu, Yagna PR., additional, and Zhu, Yun, additional

Published
2021
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30. Case Report: Identification of a Heterozygous XPA c.553C>T Mutation Causing Neurological Impairment in a Case of Xeroderma Pigmentosum Complementation Group A

Author

García-Carmona, Juan Antonio, primary, Yousefzadeh, Matthew J., additional, Alarcón-Soldevilla, Fernando, additional, Fages-Caravaca, Eva, additional, Kieu, Tra L., additional, Witt, Mariah A., additional, López-Ávila, Ángel, additional, Niedernhofer, Laura J., additional, and Pérez-Vicente, José Antonio, additional

Published
2021
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31. The Second Annual Symposium of the Midwest Aging Consortium: The Future of Aging Research in the Midwestern United States

Author

Green, Cara L, primary, Englund, Davis A, additional, Das, Srijit, additional, Herrerias, Mariana M, additional, Yousefzadeh, Matthew J, additional, Grant, Rogan A, additional, Clark, Josef, additional, Pak, Heidi H, additional, Liu, Peiduo, additional, Bai, Hua, additional, Prahlad, Veena, additional, Lamming, Dudley W, additional, and Chusyd, Daniella E, additional

Published
2021
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32. Senolytics reduce coronavirus-related mortality in old mice

Author

Camell, Christina D., primary, Yousefzadeh, Matthew J., additional, Zhu, Yi, additional, Prata, Larissa G. P. Langhi, additional, Huggins, Matthew A., additional, Pierson, Mark, additional, Zhang, Lei, additional, O’Kelly, Ryan D., additional, Pirtskhalava, Tamar, additional, Xun, Pengcheng, additional, Ejima, Keisuke, additional, Xue, Ailing, additional, Tripathi, Utkarsh, additional, Espindola-Netto, Jair Machado, additional, Giorgadze, Nino, additional, Atkinson, Elizabeth J., additional, Inman, Christina L., additional, Johnson, Kurt O., additional, Cholensky, Stephanie H., additional, Carlson, Timothy W., additional, LeBrasseur, Nathan K., additional, Khosla, Sundeep, additional, O’Sullivan, M. Gerard, additional, Allison, David B., additional, Jameson, Stephen C., additional, Meves, Alexander, additional, Li, Ming, additional, Prakash, Y. S., additional, Chiarella, Sergio E., additional, Hamilton, Sara E., additional, Tchkonia, Tamara, additional, Niedernhofer, Laura J., additional, Kirkland, James L., additional, and Robbins, Paul D., additional

Published
2021
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33. Exercise reduces circulating biomarkers of cellular senescence in humans

Author

Englund, Davis A., primary, Sakamoto, Ayumi E., additional, Fritsche, Chad M., additional, Heeren, Amanda A., additional, Zhang, Xu, additional, Kotajarvi, Brian R., additional, Lecy, Denise R., additional, Yousefzadeh, Matthew J., additional, Schafer, Marissa J., additional, White, Thomas A., additional, Atkinson, Elizabeth J., additional, and LeBrasseur, Nathan K., additional

Published
2021
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34. Influences of circulatory factors on intervertebral disc aging phenotype

Author

Lei, Changbin, primary, Colangelo, Debora, additional, Patil, Prashanti, additional, Li, Vivian, additional, Ngo, Kevin, additional, Wang, Dong, additional, Dong, Qing, additional, Yousefzadeh, Matthew J., additional, Lin, Hongsheng, additional, Lee, Joon, additional, Kang, James, additional, Sowa, Gwendolyn, additional, Wyss-Coray, Tony, additional, Niedernhofer, Laura J., additional, Robbins, Paul D., additional, Huffman, Derek M., additional, and Vo, Nam, additional

Published
2020
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35. ATM is a key driver of NF-κB-dependent DNA-damage-induced senescence, stem cell dysfunction and aging

Author

Zhao, Jing, primary, Zhang, Lei, additional, Lu, Aiping, additional, Han, Yingchao, additional, Colangelo, Debora, additional, Bukata, Christina, additional, Scibetta, Alex, additional, Yousefzadeh, Matthew J., additional, Li, Xuesen, additional, Gurkar, Aditi U., additional, McGowan, Sara J., additional, Angelini, Luise, additional, O’Kelly, Ryan, additional, Li, Hongshuai, additional, Corbo, Lana, additional, Sano, Tokio, additional, Nick, Heather, additional, Pola, Enrico, additional, Pilla, Smitha P.S., additional, Ladiges, Warren C., additional, Vo, Nam, additional, Huard, Johnny, additional, Niedernhofer, Laura J., additional, and Robbins, Paul D., additional

Published
2020
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36. Tissue specificity of senescent cell accumulation during physiologic and accelerated aging of mice

Author

Yousefzadeh, Matthew J., primary, Zhao, Jing, additional, Bukata, Christina, additional, Wade, Erin A., additional, McGowan, Sara J., additional, Angelini, Luise A., additional, Bank, Michael P., additional, Gurkar, Aditi U., additional, McGuckian, Collin A., additional, Calubag, Mariah F., additional, Kato, Jonathan I., additional, Burd, Christin E., additional, Robbins, Paul D., additional, and Niedernhofer, Laura J., additional

Published
2020
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37. Adenoviral gene transfer of a single‐chain IL‐23 induces psoriatic arthritis–like symptoms in NOD mice

Author

Flores, Rafael R., primary, Carbo, Lana, additional, Kim, Eun, additional, Van Meter, Montina, additional, De Padilla, Consuelo M. Lopez, additional, Zhao, Jing, additional, Colangelo, Debora, additional, Yousefzadeh, Matthew J., additional, Angelini, Luise A., additional, Zhang, Lei, additional, Pola, Enrico, additional, Vo, Nam, additional, Evans, Christopher H., additional, Gambotto, Andrea, additional, Niedernhofer, Laura J., additional, and Robbins, Paul D., additional

Published
2019
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39. Fisetin is a senotherapeutic that extends health and lifespan

Author

Yousefzadeh, Matthew J., primary, Zhu, Yi, additional, McGowan, Sara J., additional, Angelini, Luise, additional, Fuhrmann-Stroissnigg, Heike, additional, Xu, Ming, additional, Ling, Yuan Yuan, additional, Melos, Kendra I., additional, Pirtskhalava, Tamar, additional, Inman, Christina L., additional, McGuckian, Collin, additional, Wade, Erin A., additional, Kato, Jonathon I., additional, Grassi, Diego, additional, Wentworth, Mark, additional, Burd, Christin E., additional, Arriaga, Edgar A., additional, Ladiges, Warren L., additional, Tchkonia, Tamara, additional, Kirkland, James L., additional, Robbins, Paul D., additional, and Niedernhofer, Laura J., additional

Published
2018
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40. Adenoviral Gene Transfer of a Single Chain IL-23 Induces Psoriatic Arthritis-Like Symptoms in NOD Mice

Author

Flores, Rafael R., primary, Carbo, Lana, additional, Kim, Eun, additional, Van Meter, Montina, additional, Lopez De Padilla, Consuelo M., additional, Zhao, Jing, additional, Colangelo, Debora, additional, Yousefzadeh, Matthew J., additional, Angelini, Luise A, additional, Zhang, Lei, additional, Pola, Enrico, additional, Vo, Nam, additional, Evans, Christopher H., additional, Gambotto, Andrea, additional, Niedernhofer, Laura J., additional, and Robbins, Paul D., additional

Published
2018
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41. Circulating levels of monocyte chemoattractant protein‐1 as a potential measure of biological age in mice and frailty in humans

Author

Yousefzadeh, Matthew J., primary, Schafer, Marissa J., additional, Noren Hooten, Nicole, additional, Atkinson, Elizabeth J., additional, Evans, Michele K., additional, Baker, Darren J., additional, Quarles, Ellen K., additional, Robbins, Paul D., additional, Ladiges, Warren C., additional, LeBrasseur, Nathan K., additional, and Niedernhofer, Laura J., additional

Published
2017
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42. Analysis of DNA polymerase ν function in meiotic recombination, immunoglobulin class-switching, and DNA damage tolerance

Author

Takata, Kei-ichi, primary, Reh, Shelley, additional, Yousefzadeh, Matthew J., additional, Zelazowski, Maciej J., additional, Bhetawal, Sarita, additional, Trono, David, additional, Lowery, Megan G., additional, Sandoval, Maria, additional, Takata, Yoko, additional, Lu, Yue, additional, Lin, Kevin, additional, Shen, Jianjun, additional, Kusewitt, Donna F., additional, McBride, Kevin M., additional, Cole, Francesca, additional, and Wood, Richard D., additional

Published
2017
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43. Metabolism in the Midwest: research from the Midwest Aging Consortium at the 49thAnnual Meeting of the American Aging Association

Author

Murphy, Michaela E., Narasimhan, Akilavalli, Adrian, Alexis, Kumar, Ankur, Green, Cara L., Soto-Palma, Carolina, Henpita, Chathurika, Camell, Christina, Morrow, Christopher S., Yeh, Chung-Yang, Richardson, Claire E., Hill, Cristal M., Moore, Darcie L., Lamming, Dudley W., McGregor, Eric R., Simmons, Heather A., Pak, Heidi H., Bai, Hua, Denu, John M., Clark, Josef, Simcox, Judith, Chittimalli, Kishore, Dahlquist, Korbyn, Lee, Kyoo-a, Calubag, Mariah, Bouska, Mark, Yousefzadeh, Matthew J., Sonsalla, Michelle, Babygirija, Reji, Yuan, Rong, Tsuji, Tadataka, Rhoads, Timothy, Menon, Vinal, Jarajapu, Yagna PR., and Zhu, Yun

Published
2021
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44. Circulating levels of monocyte chemoattractant protein‐1 as a potential measure of biological age in mice and frailty in humans.

Author

Yousefzadeh, Matthew J., Schafer, Marissa J., Noren Hooten, Nicole, Atkinson, Elizabeth J., Evans, Michele K., Baker, Darren J., Quarles, Ellen K., Robbins, Paul D., Ladiges, Warren C., LeBrasseur, Nathan K., and Niedernhofer, Laura J.

Subjects
*BIOMARKERS, *DISEASE risk factors, *CLINICAL trials, *MONOCYTES, *CHEMOKINES
Abstract

Summary: A serum biomarker of biological versus chronological age would have significant impact on clinical care. It could be used to identify individuals at risk of early‐onset frailty or the multimorbidities associated with old age. It may also serve as a surrogate endpoint in clinical trials targeting mechanisms of aging. Here, we identified MCP‐1/CCL2, a chemokine responsible for recruiting monocytes, as a potential biomarker of biological age. Circulating monocyte chemoattractant protein‐1 (MCP‐1) levels increased in an age‐dependent manner in wild‐type (WT) mice. That age‐dependent increase was accelerated in Ercc1−/Δ and Bubr1H/H mouse models of progeria. Genetic and pharmacologic interventions that slow aging of Ercc1−/Δ and WT mice lowered serum MCP‐1 levels significantly. Finally, in elderly humans with aortic stenosis, MCP‐1 levels were significantly higher in frail individuals compared to nonfrail. These data support the conclusion that MCP‐1 can be used as a measure of mammalian biological age that is responsive to interventions that extend healthy aging. [ABSTRACT FROM AUTHOR]

Published
2018
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45. <italic>ERCC4</italic> variants identified in a cohort of patients with segmental progeroid syndromes.

Author

Mori, Takayasu, Yousefzadeh, Matthew J., Faridounnia, Maryam, Chong, Jessica X., Hisama, Fuki M., Hudgins, Louanne, Mercado, Gabriela, Wade, Erin A., Barghouthy, Amira S., Lee, Lin, Martin, George M., Nickerson, Deborah A., Bamshad, Michael J., University of Washington Center for Mendelian Genomics, Niedernhofer, Laura J., and Oshima, Junko

Abstract

Abstract: Pathogenic variants in genes, which encode DNA repair and damage response proteins, result in a number of genomic instability syndromes with features of accelerated aging. ERCC4 (XPF) encodes a protein that forms a complex with ERCC1 and is required for the 5′ incision during nucleotide excision repair. ERCC4 is also FANCQ, illustrating a critical role in interstrand crosslink repair. Pathogenic variants in this gene cause xeroderma pigmentosum, XFE progeroid syndrome, Cockayne syndrome (CS), and Fanconi anemia. We performed massive parallel sequencing for 42 unsolved cases submitted to the International Registry of Werner Syndrome. Two cases, each carrying two novel heterozygous ERCC4 variants, were identified. The first case was a compound heterozygote for: c.2395C > T (p.Arg799Trp) and c.388+1164_792+795del (p.Gly130Aspfs*18). Further molecular and cellular studies indicated that the ERCC4 variants in this patient are responsible for a phenotype consistent with a variant of CS. The second case was heterozygous for two variants in cis: c.[1488A > T; c.2579C > A] (p.[Gln496His; Ala860Asp]). While the second case also had several phenotypic features of accelerated aging, we were unable to provide biological evidence supporting the pathogenic roles of the associated ERCC4 variants. Precise genetic causes and disease mechanism of the second case remains to be determined. [ABSTRACT FROM AUTHOR]

Published
2018
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47. Mechanism of suppression of chromosomal instability by DNA polymerase POLQ

Author

Yousefzadeh, Matthew J, Wyatt, David W, Takata, Kei-Ichi, Mu, Yunxiang, Hensley, Sean C, Tomida, Junya, Bylund, Göran O, Doublié, Sylvie, Johansson, Erik, Ramsden, Dale A, McBride, Kevin M, Wood, Richard D, Yousefzadeh, Matthew J, Wyatt, David W, Takata, Kei-Ichi, Mu, Yunxiang, Hensley, Sean C, Tomida, Junya, Bylund, Göran O, Doublié, Sylvie, Johansson, Erik, Ramsden, Dale A, McBride, Kevin M, and Wood, Richard D

Abstract

Although a defect in the DNA polymerase POLQ leads to ionizing radiation sensitivity in mammalian cells, the relevant enzymatic pathway has not been identified. Here we define the specific mechanism by which POLQ restricts harmful DNA instability. Our experiments show that Polq-null murine cells are selectively hypersensitive to DNA strand breaking agents, and that damage resistance requires the DNA polymerase activity of POLQ. Using a DNA break end joining assay in cells, we monitored repair of DNA ends with long 3' single-stranded overhangs. End joining events retaining much of the overhang were dependent on POLQ, and independent of Ku70. To analyze the repair function in more detail, we examined immunoglobulin class switch joining between DNA segments in antibody genes. POLQ participates in end joining of a DNA break during immunoglobulin class-switching, producing insertions of base pairs at the joins with homology to IgH switch-region sequences. Biochemical experiments with purified human POLQ protein revealed the mechanism generating the insertions during DNA end joining, relying on the unique ability of POLQ to extend DNA from minimally paired primers. DNA breaks at the IgH locus can sometimes join with breaks in Myc, creating a chromosome translocation. We found a marked increase in Myc/IgH translocations in Polq-defective mice, showing that POLQ suppresses genomic instability and genome rearrangements originating at DNA double-strand breaks. This work clearly defines a role and mechanism for mammalian POLQ in an alternative end joining pathway that suppresses the formation of chromosomal translocations. Our findings depart from the prevailing view that alternative end joining processes are generically translocation-prone.

Published
2014
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48. Mechanism of Suppression of Chromosomal Instability by DNA Polymerase POLQ

Author

Yousefzadeh, Matthew J., primary, Wyatt, David W., additional, Takata, Kei-ichi, additional, Mu, Yunxiang, additional, Hensley, Sean C., additional, Tomida, Junya, additional, Bylund, Göran O., additional, Doublié, Sylvie, additional, Johansson, Erik, additional, Ramsden, Dale A., additional, McBride, Kevin M., additional, and Wood, Richard D., additional

Published
2014
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50. The Ercc1−/Δ mouse model of XFE progeroid syndrome undergoes accelerated retinal degeneration.

Author

Narasimhan, Akilavalli, Min, Seok Hong, Johnson, Laura L., Roehrich, Heidi, Cho, William, Her, Tracy K., Windschitl, Caeden, O'Kelly, Ryan D., Angelini, Luise, Yousefzadeh, Matthew J., McLoon, Linda K., Hauswirth, William W., Robbins, Paul D., Skowronska‐Krawczyk, Dorota, and Niedernhofer, Laura J.

Subjects
*DNA ligases, *MACULAR degeneration, *MACULA lutea, *CELLULAR aging, *RHODOPSIN
Abstract

Age‐related macular degeneration (AMD) is a major cause of vision loss in older adults. AMD is caused by degeneration in the macula of the retina. The retina is the highest oxygen consuming tissue in our body and is prone to oxidative damage. DNA damage is one hallmark of aging implicated in loss of organ function. Genome instability has been associated with several disorders that result in premature vision loss. We hypothesized that endogenous DNA damage plays a causal role in age‐related retinal changes. To address this, we used a genetic model of systemic depletion of expression of the DNA repair enzyme ERCC1‐XPF. The neural retina and retinal pigment epithelium (RPE) from Ercc1−/Δ mice, which models a human progeroid syndrome, were compared to age‐matched wild‐type (WT) and old WT mice. By 3‐months‐of age, Ercc1−/Δ mice presented abnormal optokinetic and electroretinogram responses consistent with photoreceptor dysfunction and visual impairment. Ercc1−/Δ mice shared many ocular characteristics with old WT mice including morphological changes, elevated DNA damage markers (γ‐H2AX and 53BP1), and increased cellular senescence in the neural retinal and RPE, as well as pathological angiogenesis. The RPE is essential for the metabolic health of photoreceptors. The RPE from Ercc1−/Δ mice displayed mitochondrial dysfunction causing a compensatory glycolytic shift, a characteristic feature of aging RPE. Hence, our study suggests spontaneous endogenous DNA damage promotes the hallmarks of age‐related retinal degeneration. [ABSTRACT FROM AUTHOR]

Published
2024
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