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Article ; Online: Low-dose naltrexone and NAD+ for the treatment of patients with persistent fatigue symptoms after COVID-19.

Isman, Anar / Nyquist, Andy / Strecker, Bailey / Harinath, Girish / Lee, Virginia / Zhang, Xingyu / Zalzala, Sajad

Brain, behavior, & immunity - health

2024 Volume 36, Page(s) 100733

Abstract: A subset of patients experiences persistent fatigue symptoms after COVID-19, and patients may develop long COVID, which is characterized by lasting systemic symptoms. No treatments for this condition have been validated and are urgently warranted. In ... ...

Abstract	A subset of patients experiences persistent fatigue symptoms after COVID-19, and patients may develop long COVID, which is characterized by lasting systemic symptoms. No treatments for this condition have been validated and are urgently warranted. In this pilot study, we assessed whether treatment with low-dose naltrexone (LDN, 4.5 mg/day) and supplementation with NAD + through iontophoresis patches could improve fatigue symptoms and quality of life in 36 patients with persistent moderate/severe fatigue after COVID-19. We detected a significant increase from baseline in SF-36 survey scores after 12 weeks of treatment (mean total SF-36 score 36.5 [SD: 15.6] vs. 52.1 [24.8]; p < 0.0001), suggestive of improvement of quality of life. Furthermore, participants scored significantly lower on the Chalder fatigue scale after 12 weeks of treatment (baseline: 25.9 [4.6], 12 weeks: 17.4 [9.7]; p < 0.0001). We found a subset of 52 % of patients to be responders after 12 weeks of treatment. Treatment was generally safe, with mild adverse events previously reported for LDN, which could be managed with dose adjustments. The iontophoresis patches were associated with mild, short-lived skin irritation in 25 % of patients. Our data suggest treatment with LDN and NAD+ is safe and may be beneficial in a subset of patients with persistent fatigue after COVID-19. Larger randomized controlled trials will have to confirm our data and determine which patient subpopulations might benefit most from this strategy.
Language	English
Publishing date	2024-02-01
Publishing country	United States
Document type	Journal Article
ISSN	2666-3546
ISSN (online)	2666-3546
DOI	10.1016/j.bbih.2024.100733
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Article ; Online: The role of quality of life data as an endpoint for collecting real-world evidence within geroscience clinical trials.

Harinath, Girish / Zalzala, Sajad / Nyquist, Andy / Wouters, Maartje / Isman, Anar / Moel, Mauricio / Verdin, Eric / Kaeberlein, Matt / Kennedy, Brian / Bischof, Evelyne

Ageing research reviews

2024 Volume 97, Page(s) 102293

Abstract: With geroscience research evolving at a fast pace, the need arises for human randomized controlled trials to assess the efficacy of geroprotective interventions to prevent age-related adverse outcomes, disease, and mortality in normative aging cohorts. ... ...

Abstract	With geroscience research evolving at a fast pace, the need arises for human randomized controlled trials to assess the efficacy of geroprotective interventions to prevent age-related adverse outcomes, disease, and mortality in normative aging cohorts. However, to confirm efficacy requires a long-term and costly approach as time to the event of morbidity and mortality can be decades. While this could be circumvented using sensitive biomarkers of aging, current molecular, physiological, and digital endpoints require further validation. In this review, we discuss how collecting real-world evidence (RWE) by obtaining health data that is amenable for collection from large heterogeneous populations in a real-world setting can help speed up validation of geroprotective interventions. Further, we propose inclusion of quality of life (QoL) data as a biomarker of aging and candidate endpoint for geroscience clinical trials to aid in distinguishing healthy from unhealthy aging. We highlight how QoL assays can aid in accelerating data collection in studies gathering RWE on the geroprotective effects of repurposed drugs to support utilization within healthy longevity medicine. Finally, we summarize key metrics to consider when implementing QoL assays in studies, and present the short-form 36 (SF-36) as the most well-suited candidate endpoint.
Language	English
Publishing date	2024-04-03
Publishing country	England
Document type	Journal Article ; Review
ZDB-ID	2075672-0
ISSN	1872-9649 ; 1568-1637
ISSN (online)	1872-9649
ISSN	1568-1637
DOI	10.1016/j.arr.2024.102293
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Zs.A 5579: Show issues

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Article ; Online: The coupling between healthspan and lifespan in

Aging

2024 Volume 16, Issue 7, Page(s) 5829–5855

Abstract: Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in ...

Abstract	Aging is characterized by declining health that results in decreased cellular resilience and neuromuscular function. The relationship between lifespan and health, and the influence of genetic background on that relationship, has important implications in the development of pharmacological anti-aging interventions. Here we assessed swimming performance as well as survival under thermal and oxidative stress across a nematode genetic diversity test panel to evaluate health effects for three compounds previously studied in the
MeSH term(s)	Animals ; Longevity/drug effects ; Longevity/genetics ; Oxidative Stress/drug effects ; Caenorhabditis elegans/drug effects ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/physiology ; Resveratrol/pharmacology ; Aging/drug effects ; Aging/genetics ; Genetic Background ; Swimming ; Piperazines/pharmacology ; Stilbenes/pharmacology
Chemical Substances	Resveratrol (Q369O8926L) ; Piperazines ; Stilbenes
Language	English
Publishing date	2024-04-12
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ISSN	1945-4589
ISSN (online)	1945-4589
DOI	10.18632/aging.205743
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Article ; Online: Single swim sessions in C. elegans induce key features of mammalian exercise.

Laranjeiro, Ricardo / Harinath, Girish / Burke, Daniel / Braeckman, Bart P / Driscoll, Monica

BMC biology

2017 Volume 15, Issue 1, Page(s) 30

Abstract: Background: Exercise exerts remarkably powerful effects on metabolism and health, with anti-disease and anti-aging outcomes. Pharmacological manipulation of exercise benefit circuits might improve the health of the sedentary and the aging populations. ... ...

Abstract	Background: Exercise exerts remarkably powerful effects on metabolism and health, with anti-disease and anti-aging outcomes. Pharmacological manipulation of exercise benefit circuits might improve the health of the sedentary and the aging populations. Still, how exercised muscle signals to induce system-wide health improvement remains poorly understood. With a long-term interest in interventions that promote animal-wide health improvement, we sought to define exercise options for Caenorhabditis elegans. Results: Here, we report on the impact of single swim sessions on C. elegans physiology. We used microcalorimetry to show that C. elegans swimming has a greater energy cost than crawling. Animals that swam continuously for 90 min specifically consumed muscle fat supplies and exhibited post-swim locomotory fatigue, with both muscle fat depletion and fatigue indicators recovering within 1 hour of exercise cessation. Quantitative polymerase chain reaction (qPCR) transcript analyses also suggested an increase in fat metabolism during the swim, followed by the downregulation of specific carbohydrate metabolism transcripts in the hours post-exercise. During a 90 min swim, muscle mitochondria matrix environments became more oxidized, as visualized by a localized mitochondrial reduction-oxidation-sensitive green fluorescent protein reporter. qPCR data supported specific transcriptional changes in oxidative stress defense genes during and immediately after a swim. Consistent with potential antioxidant defense induction, we found that a single swim session sufficed to confer protection against juglone-induced oxidative stress inflicted 4 hours post-exercise. Conclusions: In addition to showing that even a single swim exercise bout confers physiological changes that increase robustness, our data reveal that acute swimming-induced changes share common features with some acute exercise responses reported in humans. Overall, our data validate an easily implemented swim experience as C. elegans exercise, setting the foundation for exploiting the experimental advantages of this model to genetically or pharmacologically identify the exercise-associated molecules and signaling pathways that confer system-wide health benefits.
MeSH term(s)	Animals ; Caenorhabditis elegans/genetics ; Caenorhabditis elegans/physiology ; Energy Metabolism/physiology ; Exercise/physiology ; Glucose/metabolism ; Humans ; Lipid Metabolism ; Mammals/physiology ; Mitochondria/metabolism ; Movement/physiology ; Muscles/metabolism ; Oxidative Stress ; Physical Conditioning, Animal ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; Swimming/physiology ; Transcription, Genetic
Chemical Substances	RNA, Messenger ; Glucose (IY9XDZ35W2)
Language	English
Publishing date	2017-04-10
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2133020-7
ISSN	1741-7007 ; 1741-7007
ISSN (online)	1741-7007
ISSN	1741-7007
DOI	10.1186/s12915-017-0368-4
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Article ; Online: Spaceflight affects neuronal morphology and alters transcellular degradation of neuronal debris in adult

Laranjeiro, Ricardo / Harinath, Girish / Pollard, Amelia K / Gaffney, Christopher J / Deane, Colleen S / Vanapalli, Siva A / Etheridge, Timothy / Szewczyk, Nathaniel J / Driscoll, Monica

iScience

2021 Volume 24, Issue 2, Page(s) 102105

Abstract: Extended space travel is a goal of government space agencies and private companies. However, spaceflight poses risks to human health, and the effects on the nervous system have to be better characterized. Here, we exploited the unique experimental ... ...

Abstract	Extended space travel is a goal of government space agencies and private companies. However, spaceflight poses risks to human health, and the effects on the nervous system have to be better characterized. Here, we exploited the unique experimental advantages of the nematode
Language	English
Publishing date	2021-01-29
Publishing country	United States
Document type	Journal Article
ISSN	2589-0042
ISSN (online)	2589-0042
DOI	10.1016/j.isci.2021.102105
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Article ; Online: Swim exercise in

Laranjeiro, Ricardo / Harinath, Girish / Hewitt, Jennifer E / Hartman, Jessica H / Royal, Mary Anne / Meyer, Joel N / Vanapalli, Siva A / Driscoll, Monica

Proceedings of the National Academy of Sciences of the United States of America

2019 Volume 116, Issue 47, Page(s) 23829–23839

Abstract: Regular physical exercise is the most efficient and accessible intervention known to promote healthy aging in humans. The molecular and cellular mechanisms that mediate system-wide exercise benefits, however, remain poorly understood, especially as ... ...

Abstract	Regular physical exercise is the most efficient and accessible intervention known to promote healthy aging in humans. The molecular and cellular mechanisms that mediate system-wide exercise benefits, however, remain poorly understood, especially as applies to tissues that do not participate directly in training activity. The establishment of exercise protocols for short-lived genetic models will be critical for deciphering fundamental mechanisms of transtissue exercise benefits to healthy aging. Here we document optimization of a long-term swim exercise protocol for
MeSH term(s)	Adaptation, Physiological ; Animals ; Caenorhabditis elegans/physiology ; Intestines/physiology ; Learning ; Muscles/physiology ; Nervous System Physiological Phenomena ; Neuroprotection ; Swimming
Language	English
Publishing date	2019-11-04
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S.
ZDB-ID	209104-5
ISSN	1091-6490 ; 0027-8424
ISSN (online)	1091-6490
ISSN	0027-8424
DOI	10.1073/pnas.1909210116
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Zs.A 1148: Show issues

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Article ; Online: Antioxidants green tea extract and nordihydroguaiaretic acid confer species and strain-specific lifespan and health effects in Caenorhabditis nematodes.

Banse, Stephen A / Sedore, Christine A / Johnson, Erik / Coleman-Hulbert, Anna L / Onken, Brian / Hall, David / Jackson, E Grace / Huynh, Phu / Foulger, Anna C / Guo, Suzhen / Garrett, Theo / Xue, Jian / Inman, Delaney / Morshead, Mackenzie L / Plummer, W Todd / Chen, Esteban / Bhaumik, Dipa / Chen, Michelle K / Harinath, Girish /

Chamoli, Manish / Quinn, Rose P / Falkowski, Ron / Edgar, Daniel / Schmidt, Madeline O / Lucanic, Mark / Guo, Max / Driscoll, Monica / Lithgow, Gordon J / Phillips, Patrick C

GeroScience

2023 Volume 46, Issue 2, Page(s) 2239–2251

Abstract: The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust ... ...

Abstract	The Caenorhabditis Intervention Testing Program (CITP) is an NIH-funded research consortium of investigators who conduct analyses at three independent sites to identify chemical interventions that reproducibly promote health and lifespan in a robust manner. The founding principle of the CITP is that compounds with positive effects across a genetically diverse panel of Caenorhabditis species and strains are likely engaging conserved biochemical pathways to exert their effects. As such, interventions that are broadly efficacious might be considered prominent compounds for translation for pre-clinical research and human clinical applications. Here, we report results generated using a recently streamlined pipeline approach for the evaluation of the effects of chemical compounds on lifespan and health. We studied five compounds previously shown to extend C. elegans lifespan or thought to promote mammalian health: 17α-estradiol, acarbose, green tea extract, nordihydroguaiaretic acid, and rapamycin. We found that green tea extract and nordihydroguaiaretic acid extend Caenorhabditis lifespan in a species-specific manner. Additionally, these two antioxidants conferred assay-specific effects in some studies-for example, decreasing survival for certain genetic backgrounds in manual survival assays in contrast with extended lifespan as assayed using automated C. elegans Lifespan Machines. We also observed that GTE and NDGA impact on older adult mobility capacity is dependent on genetic background, and that GTE reduces oxidative stress resistance in some Caenorhabditis strains. Overall, our analysis of the five compounds supports the general idea that genetic background and assay type can influence lifespan and health effects of compounds, and underscores that lifespan and health can be uncoupled by chemical interventions.
MeSH term(s)	Animals ; Humans ; Aged ; Antioxidants/pharmacology ; Masoprocol/pharmacology ; Masoprocol/metabolism ; Caenorhabditis elegans/genetics ; Caenorhabditis ; Longevity ; Health Promotion ; Plant Extracts/pharmacology ; Tea/metabolism ; Mammals
Chemical Substances	Antioxidants ; Masoprocol (7BO8G1BYQU) ; Plant Extracts ; Tea
Language	English
Publishing date	2023-11-04
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-023-00978-0
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Zs.A 1502: Show issues

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Article ; Online: Metformin treatment of diverse Caenorhabditis species reveals the importance of genetic background in longevity and healthspan extension outcomes.

Aging cell

2021 Volume 21, Issue 1, Page(s) e13488

Abstract: Metformin, the most commonly prescribed anti-diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, ... ...

Abstract	Metformin, the most commonly prescribed anti-diabetes medication, has multiple reported health benefits, including lowering the risks of cardiovascular disease and cancer, improving cognitive function with age, extending survival in diabetic patients, and, in several animal models, promoting youthful physiology and lifespan. Due to its longevity and health effects, metformin is now the focus of the first proposed clinical trial of an anti-aging drug-the Targeting Aging with Metformin (TAME) program. Genetic variation will likely influence outcomes when studying metformin health effects in human populations. To test for metformin impact in diverse genetic backgrounds, we measured lifespan and healthspan effects of metformin treatment in three Caenorhabditis species representing genetic variability greater than that between mice and humans. We show that metformin increases median survival in three C. elegans strains, but not in C. briggsae and C. tropicalis strains. In C. briggsae, metformin either has no impact on survival or decreases lifespan. In C. tropicalis, metformin decreases median survival in a dose-dependent manner. We show that metformin prolongs the period of youthful vigor in all C. elegans strains and in two C. briggsae strains, but that metformin has a negative impact on the locomotion of C. tropicalis strains. Our data demonstrate that metformin can be a robust promoter of healthy aging across different genetic backgrounds, but that genetic variation can determine whether metformin has positive, neutral, or negative lifespan/healthspan impact. These results underscore the importance of tailoring treatment to individuals when testing for metformin health benefits in diverse human populations.
MeSH term(s)	Aging/genetics ; Animals ; Caenorhabditis elegans/drug effects ; Humans ; Hypoglycemic Agents/pharmacology ; Hypoglycemic Agents/therapeutic use ; Longevity/genetics ; Metformin/pharmacology ; Metformin/therapeutic use ; Treatment Outcome
Chemical Substances	Hypoglycemic Agents ; Metformin (9100L32L2N)
Language	English
Publishing date	2021-11-27
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2113083-8
ISSN	1474-9726 ; 1474-9718
ISSN (online)	1474-9726
ISSN	1474-9718
DOI	10.1111/acel.13488
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Zs.A 6581: Show issues

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Article ; Online: Analysis of microRNA-target interactions across diverse cancer types.

Jacobsen, Anders / Silber, Joachim / Harinath, Girish / Huse, Jason T / Schultz, Nikolaus / Sander, Chris

Nature structural & molecular biology

2013 Volume 20, Issue 11, Page(s) 1325–1332

Abstract: Little is known about the extent to which individual microRNAs (miRNAs) regulate common processes of tumor biology across diverse cancer types. Using molecular profiles of >3,000 tumors from 11 human cancer types in The Cancer Genome Atlas, we ... ...

Abstract	Little is known about the extent to which individual microRNAs (miRNAs) regulate common processes of tumor biology across diverse cancer types. Using molecular profiles of >3,000 tumors from 11 human cancer types in The Cancer Genome Atlas, we systematically analyzed expression of miRNAs and mRNAs across cancer types to infer recurrent cancer-associated miRNA-target relationships. As we expected, the inferred relationships were consistent with sequence-based predictions and published data from miRNA perturbation experiments. Notably, miRNAs with recurrent target relationships were frequently regulated by genetic and epigenetic alterations across the studied cancer types. We also identify new examples of miRNAs that coordinately regulate cancer pathways, including the miR-29 family, which recurrently regulates active DNA demethylation pathway members TET1 and TDG. The online resource http://cancerminer.org allows exploration and prioritization of miRNA-target interactions that potentially regulate tumorigenesis.
MeSH term(s)	Computational Biology/methods ; DNA Methylation ; Epigenesis, Genetic ; Gene Expression Profiling ; Gene Expression Regulation ; Humans ; MicroRNAs/genetics ; MicroRNAs/metabolism ; Neoplasms/genetics ; RNA, Messenger/genetics ; RNA, Messenger/metabolism
Chemical Substances	MicroRNAs ; RNA, Messenger
Language	English
Publishing date	2013-10-06
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	2126708-X
ISSN	1545-9985 ; 1545-9993
ISSN (online)	1545-9985
ISSN	1545-9993
DOI	10.1038/nsmb.2678
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Zs.A 4101: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: C. elegans neurons jettison protein aggregates and mitochondria under neurotoxic stress.

Melentijevic, Ilija / Toth, Marton L / Arnold, Meghan L / Guasp, Ryan J / Harinath, Girish / Nguyen, Ken C / Taub, Daniel / Parker, J Alex / Neri, Christian / Gabel, Christopher V / Hall, David H / Driscoll, Monica

Nature

2017 Volume 542, Issue 7641, Page(s) 367–371

Abstract: The toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease. Accordingly, neurons invest considerable cellular resources in chaperones, protein ...

Abstract	The toxicity of misfolded proteins and mitochondrial dysfunction are pivotal factors that promote age-associated functional neuronal decline and neurodegenerative disease. Accordingly, neurons invest considerable cellular resources in chaperones, protein degradation, autophagy and mitophagy to maintain proteostasis and mitochondrial quality. Complicating the challenges of neuroprotection, misfolded human disease proteins and mitochondria can move into neighbouring cells via unknown mechanisms, which may promote pathological spread. Here we show that adult neurons from Caenorhabditis elegans extrude large (approximately 4 μm) membrane-surrounded vesicles called exophers that can contain protein aggregates and organelles. Inhibition of chaperone expression, autophagy or the proteasome, in addition to compromising mitochondrial quality, enhances the production of exophers. Proteotoxically stressed neurons that generate exophers subsequently function better than similarly stressed neurons that did not produce exophers. The extruded exopher transits through surrounding tissue in which some contents appear degraded, but some non-degradable materials can subsequently be found in more remote cells, suggesting secondary release. Our observations suggest that exopher-genesis is a potential response to rid cells of neurotoxic components when proteostasis and organelle function are challenged. We propose that exophers are components of a conserved mechanism that constitutes a fundamental, but formerly unrecognized, branch of neuronal proteostasis and mitochondrial quality control, which, when dysfunctional or diminished with age, might actively contribute to pathogenesis in human neurodegenerative disease and brain ageing.
MeSH term(s)	Aging/metabolism ; Aging/pathology ; Animals ; Autophagy ; Caenorhabditis elegans/cytology ; Caenorhabditis elegans/metabolism ; Cell-Derived Microparticles/metabolism ; Cytoplasm/metabolism ; Mitochondria/metabolism ; Molecular Chaperones/metabolism ; Neurodegenerative Diseases/metabolism ; Neurodegenerative Diseases/pathology ; Neurons/metabolism ; Neurons/pathology ; Neuroprotection/physiology ; Oxidation-Reduction ; Proteasome Endopeptidase Complex/metabolism ; Protein Aggregates
Chemical Substances	Molecular Chaperones ; Protein Aggregates ; Proteasome Endopeptidase Complex (EC 3.4.25.1)
Language	English
Publishing date	2017-02-08
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	120714-3
ISSN	1476-4687 ; 0028-0836
ISSN (online)	1476-4687
ISSN	0028-0836
DOI	10.1038/nature21362
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