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Article ; Online: The million-molecule challenge: a moonshot project to rapidly advance longevity intervention discovery.

Lee, Mitchell B / Blue, Benjamin / Muir, Michael / Kaeberlein, Matt

2023 Volume 45, Issue 6, Page(s) 3103–3113

Abstract: Targeting aging is the future of twenty-first century preventative medicine. Small molecule interventions that promote healthy longevity are known, but few are well-developed and discovery of novel, robust interventions has stagnated. To accelerate ... ...

Abstract	Targeting aging is the future of twenty-first century preventative medicine. Small molecule interventions that promote healthy longevity are known, but few are well-developed and discovery of novel, robust interventions has stagnated. To accelerate longevity intervention discovery and development, high-throughput systems are needed that can perform unbiased drug screening and directly measure lifespan and healthspan metrics in whole animals. C. elegans is a powerful model system for this type of drug discovery. Combined with automated data capture and analysis technologies, truly high-throughput longevity drug discovery is possible. In this perspective, we propose the "million-molecule challenge", an effort to quantitatively assess 1,000,000 interventions for longevity within five years. The WormBot-AI, our best-in-class robotics and AI data analysis platform, provides a tool to achieve the million-molecule challenge for pennies per animal tested.
MeSH term(s)	Animals ; Longevity ; Caenorhabditis elegans ; Aging ; Robotics
Language	English
Publishing date	2023-07-11
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/s11357-023-00867-6
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Article ; Online: Deficiency of the RNA-binding protein Cth2 extends yeast replicative lifespan by alleviating its repressive effects on mitochondrial function.

Patnaik, Praveen K / Beaupere, Carine / Barlit, Hanna / Romero, Antonia María / Tsuchiya, Mitsuhiro / Muir, Michael / Martínez-Pastor, María Teresa / Puig, Sergi / Kaeberlein, Matt / Labunskyy, Vyacheslav M

Cell reports

2022 Volume 40, Issue 3, Page(s) 111113

Abstract: Iron dyshomeostasis contributes to aging, but little information is available about the molecular mechanisms. Here, we provide evidence that in Saccharomyces cerevisiae, aging is associated with altered expression of genes involved in iron homeostasis. ... ...

Abstract	Iron dyshomeostasis contributes to aging, but little information is available about the molecular mechanisms. Here, we provide evidence that in Saccharomyces cerevisiae, aging is associated with altered expression of genes involved in iron homeostasis. We further demonstrate that defects in the conserved mRNA-binding protein Cth2, which controls stability and translation of mRNAs encoding iron-containing proteins, increase lifespan by alleviating its repressive effects on mitochondrial function. Mutation of the conserved cysteine residue in Cth2 that inhibits its RNA-binding activity is sufficient to confer longevity, whereas Cth2 gain of function shortens replicative lifespan. Consistent with its function in RNA degradation, Cth2 deficiency relieves Cth2-mediated post-transcriptional repression of nuclear-encoded components of the electron transport chain. Our findings uncover a major role of the RNA-binding protein Cth2 in the regulation of lifespan and suggest that modulation of iron starvation signaling can serve as a target for potential aging interventions.
MeSH term(s)	Gene Expression Regulation, Fungal ; Iron/metabolism ; Longevity ; Mitochondria/metabolism ; RNA, Messenger/genetics ; RNA, Messenger/metabolism ; RNA-Binding Proteins/genetics ; RNA-Binding Proteins/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae/metabolism ; Saccharomyces cerevisiae Proteins/metabolism ; Tristetraprolin/genetics ; Tristetraprolin/metabolism
Chemical Substances	RNA, Messenger ; RNA-Binding Proteins ; Saccharomyces cerevisiae Proteins ; TIS11 protein, S cerevisiae ; Tristetraprolin ; Iron (E1UOL152H7)
Language	English
Publishing date	2022-07-16
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2022.111113
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article ; Online: Evidence that conserved essential genes are enriched for pro-longevity factors.

Oz, Naci / Vayndorf, Elena M / Tsuchiya, Mitsuhiro / McLean, Samantha / Turcios-Hernandez, Lesly / Pitt, Jason N / Blue, Benjamin W / Muir, Michael / Kiflezghi, Michael G / Tyshkovskiy, Alexander / Mendenhall, Alexander / Kaeberlein, Matt / Kaya, Alaattin

GeroScience

2022 Volume 44, Issue 4, Page(s) 1995–2006

Abstract: At the cellular level, many aspects of aging are conserved across species. This has been demonstrated by numerous studies in simple model organisms like Saccharomyces cerevisiae, Caenorhabdits elegans, and Drosophila melanogaster. Because most genetic ... ...

Abstract	At the cellular level, many aspects of aging are conserved across species. This has been demonstrated by numerous studies in simple model organisms like Saccharomyces cerevisiae, Caenorhabdits elegans, and Drosophila melanogaster. Because most genetic screens examine loss of function mutations or decreased expression of genes through reverse genetics, essential genes have often been overlooked as potential modulators of the aging process. By taking the approach of increasing the expression level of a subset of conserved essential genes, we found that 21% of these genes resulted in increased replicative lifespan in S. cerevisiae. This is greater than the ~ 3.5% of genes found to affect lifespan upon deletion, suggesting that activation of essential genes may have a relatively disproportionate effect on increasing lifespan. The results of our experiments demonstrate that essential gene overexpression is a rich, relatively unexplored means of increasing eukaryotic lifespan.
MeSH term(s)	Animals ; Longevity/genetics ; Saccharomyces cerevisiae/genetics ; Genes, Essential/genetics ; Drosophila melanogaster/genetics ; Aging/physiology
Language	English
Publishing date	2022-06-13
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Research Support, N.I.H., Extramural
ZDB-ID	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-022-00604-5
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Article: Organic complexation of U(VI) in reducing soils at a natural analogue site: Implications for uranium transport

Fuller, Adam J / Leary, Peter / Gray, Neil D / Davies, Helena S / Mosselmans, J. Frederick W / Cox, Filipa / Robinson, Clare H / Pittman, Jon K / McCann, Clare M / Muir, Michael / Graham, Margaret C / Utsunomiya, Satoshi / Bower, William R / Morris, Katherine / Shaw, Samuel / Bots, Pieter / Livens, Francis R / Law, Gareth T.W

Chemosphere. 2020 Sept., v. 254

2020

Abstract: Understanding the long-term fate, stability, and bioavailability of uranium (U) in the environment is important for the management of nuclear legacy sites and radioactive wastes. Analysis of U behavior at natural analogue sites permits evaluation of U ... ...

Abstract	Understanding the long-term fate, stability, and bioavailability of uranium (U) in the environment is important for the management of nuclear legacy sites and radioactive wastes. Analysis of U behavior at natural analogue sites permits evaluation of U biogeochemistry under conditions more representative of long-term equilibrium. Here, we have used bulk geochemical and microbial community analysis of soils, coupled with X-ray absorption spectroscopy and μ-focus X-ray fluorescence mapping, to gain a mechanistic understanding of the fate of U transported into an organic-rich soil from a pitchblende vein at the UK Needle’s Eye Natural Analogue site. U is highly enriched in the Needle’s Eye soils (∼1600 mg kg⁻¹). We show that this enrichment is largely controlled by U(VI) complexation with soil organic matter and not U(VI) bioreduction. Instead, organic-associated U(VI) seems to remain stable under microbially-mediated Fe(III)-reducing conditions. U(IV) (as non-crystalline U(IV)) was only observed at greater depths at the site (>25 cm); the soil here was comparatively mineral-rich, organic-poor, and sulfate-reducing/methanogenic. Furthermore, nanocrystalline UO₂, an alternative product of U(VI) reduction in soils, was not observed at the site, and U did not appear to be associated with Fe-bearing minerals. Organic-rich soils appear to have the potential to impede U groundwater transport, irrespective of ambient redox conditions.
Keywords	X-radiation ; X-ray absorption spectroscopy ; administrative management ; behavior ; bioavailability ; biogeochemistry ; environment ; eyes ; fluorescence ; groundwater flow ; microbial communities ; minerals ; nanocrystals ; radioactive waste ; soil ; soil organic matter ; uranium
Language	English
Dates of publication	2020-09
Publishing place	Elsevier Ltd
Document type	Article
Note	NAL-light
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2020.126859
Database	NAL-Catalogue (AGRICOLA)

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Article ; Online: Organic complexation of U(VI) in reducing soils at a natural analogue site: Implications for uranium transport.

Fuller, Adam J / Leary, Peter / Gray, Neil D / Davies, Helena S / Mosselmans, J Frederick W / Cox, Filipa / Robinson, Clare H / Pittman, Jon K / McCann, Clare M / Muir, Michael / Graham, Margaret C / Utsunomiya, Satoshi / Bower, William R / Morris, Katherine / Shaw, Samuel / Bots, Pieter / Livens, Francis R / Law, Gareth T W

Chemosphere

2020 Volume 254, Page(s) 126859

Abstract	Understanding the long-term fate, stability, and bioavailability of uranium (U) in the environment is important for the management of nuclear legacy sites and radioactive wastes. Analysis of U behavior at natural analogue sites permits evaluation of U biogeochemistry under conditions more representative of long-term equilibrium. Here, we have used bulk geochemical and microbial community analysis of soils, coupled with X-ray absorption spectroscopy and μ-focus X-ray fluorescence mapping, to gain a mechanistic understanding of the fate of U transported into an organic-rich soil from a pitchblende vein at the UK Needle's Eye Natural Analogue site. U is highly enriched in the Needle's Eye soils (∼1600 mg kg
MeSH term(s)	Ferric Compounds ; Groundwater/chemistry ; Radioactive Waste/analysis ; Soil/chemistry ; Soil Microbiology ; Uranium/analysis ; Uranium/chemistry ; Uranium Compounds/analysis ; Water Pollutants, Radioactive/analysis ; X-Ray Absorption Spectroscopy
Chemical Substances	Ferric Compounds ; Radioactive Waste ; Soil ; Uranium Compounds ; Water Pollutants, Radioactive ; Uranium (4OC371KSTK)
Language	English
Publishing date	2020-04-28
Publishing country	England
Document type	Journal Article
ZDB-ID	120089-6
ISSN	1879-1298 ; 0045-6535 ; 0366-7111
ISSN (online)	1879-1298
ISSN	0045-6535 ; 0366-7111
DOI	10.1016/j.chemosphere.2020.126859
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Article ; Online: Taurine deficiency as a driver of aging.

Singh, Parminder / Gollapalli, Kishore / Mangiola, Stefano / Schranner, Daniela / Yusuf, Mohd Aslam / Chamoli, Manish / Shi, Sting L / Lopes Bastos, Bruno / Nair, Tripti / Riermeier, Annett / Vayndorf, Elena M / Wu, Judy Z / Nilakhe, Aishwarya / Nguyen, Christina Q / Muir, Michael / Kiflezghi, Michael G / Foulger, Anna / Junker, Alex / Devine, Jack /

Sharan, Kunal / Chinta, Shankar J / Rajput, Swati / Rane, Anand / Baumert, Philipp / Schönfelder, Martin / Iavarone, Francescopaolo / di Lorenzo, Giorgia / Kumari, Swati / Gupta, Alka / Sarkar, Rajesh / Khyriem, Costerwell / Chawla, Amanpreet S / Sharma, Ankur / Sarper, Nazan / Chattopadhyay, Naibedya / Biswal, Bichitra K / Settembre, Carmine / Nagarajan, Perumal / Targoff, Kimara L / Picard, Martin / Gupta, Sarika / Velagapudi, Vidya / Papenfuss, Anthony T / Kaya, Alaattin / Ferreira, Miguel Godinho / Kennedy, Brian K / Andersen, Julie K / Lithgow, Gordon J / Ali, Abdullah Mahmood / Mukhopadhyay, Arnab / Palotie, Aarno / Kastenmüller, Gabi / Kaeberlein, Matt / Wackerhage, Henning / Pal, Bhupinder / Yadav, Vijay K

Science (New York, N.Y.)

2023 Volume 380, Issue 6649, Page(s) eabn9257

Abstract: Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine ... ...

Abstract	Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.
MeSH term(s)	Animals ; Humans ; Mice ; Aging/blood ; Aging/drug effects ; Aging/metabolism ; Cellular Senescence ; Haplorhini ; Longevity/drug effects ; Longevity/physiology ; Taurine/blood ; Taurine/deficiency ; Taurine/pharmacology ; Dietary Supplements ; DNA Damage/drug effects ; Telomerase/metabolism
Chemical Substances	Taurine (1EQV5MLY3D) ; Telomerase (EC 2.7.7.49)
Language	English
Publishing date	2023-06-09
Publishing country	United States
Document type	Journal Article
ZDB-ID	128410-1
ISSN	1095-9203 ; 0036-8075
ISSN (online)	1095-9203
ISSN	0036-8075
DOI	10.1126/science.abn9257
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Article ; Online: Loss of vacuolar acidity results in iron-sulfur cluster defects and divergent homeostatic responses during aging in Saccharomyces cerevisiae.

Chen, Kenneth L / Ven, Toby N / Crane, Matthew M / Brunner, Matthew L C / Pun, Adrian K / Helget, Kathleen L / Brower, Katherine / Chen, Dexter E / Doan, Ha / Dillard-Telm, Justin D / Huynh, Ellen / Feng, Yen-Chi / Yan, Zili / Golubeva, Alexandra / Hsu, Roy A / Knight, Raheem / Levin, Jessie / Mobasher, Vesal / Muir, Michael /

Omokehinde, Victor / Screws, Corey / Tunali, Esin / Tran, Rachael K / Valdez, Luz / Yang, Edward / Kennedy, Scott R / Herr, Alan J / Kaeberlein, Matt / Wasko, Brian M

GeroScience

2020 Volume 42, Issue 2, Page(s) 749–764

Abstract: The loss of vacuolar/lysosomal acidity is an early event during aging that has been linked to mitochondrial dysfunction. However, it is unclear how loss of vacuolar acidity results in age-related dysfunction. Through unbiased genetic screens, we ... ...

Abstract	The loss of vacuolar/lysosomal acidity is an early event during aging that has been linked to mitochondrial dysfunction. However, it is unclear how loss of vacuolar acidity results in age-related dysfunction. Through unbiased genetic screens, we determined that increased iron uptake can suppress the mitochondrial respiratory deficiency phenotype of yeast vma mutants, which have lost vacuolar acidity due to genetic disruption of the vacuolar ATPase proton pump. Yeast vma mutants exhibited nuclear localization of Aft1, which turns on the iron regulon in response to iron-sulfur cluster (ISC) deficiency. This led us to find that loss of vacuolar acidity with age in wild-type yeast causes ISC defects and a DNA damage response. Using microfluidics to investigate aging at the single-cell level, we observe grossly divergent trajectories of iron homeostasis within an isogenic and environmentally homogeneous population. One subpopulation of cells fails to mount the expected compensatory iron regulon gene expression program, and suffers progressively severe ISC deficiency with little to no activation of the iron regulon. In contrast, other cells show robust iron regulon activity with limited ISC deficiency, which allows extended passage and survival through a period of genomic instability during aging. These divergent trajectories suggest that iron regulation and ISC homeostasis represent a possible target for aging interventions.
MeSH term(s)	Homeostasis ; Iron/metabolism ; Saccharomyces cerevisiae/genetics ; Saccharomyces cerevisiae Proteins/genetics ; Sulfur
Chemical Substances	Saccharomyces cerevisiae Proteins ; Sulfur (70FD1KFU70) ; Iron (E1UOL152H7)
Language	English
Publishing date	2020-01-23
Publishing country	Switzerland
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	2886586-8
ISSN	2509-2723 ; 2509-2715
ISSN (online)	2509-2723
ISSN	2509-2715
DOI	10.1007/s11357-020-00159-3
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Book: An electronic Cash and credit System

Anderson, Allan H / Cannell, Donald T / Gibbons, Terrance A / Grote, G. Peter / Henn, John / Kennedy, J. Bradley / Muir, Michael B / Potter, Norman D / Whitby, Robert H

1966

Author's details	authors: Allan H. Anderson; Donald T. Cannell; Terrance A. Gibbons; G. Peter Grote; John Henn; J. Bradley Kennedy; Michael B. Muir; Norman D. Potter; Robert H. Whitby
Size	142 S. 8"
Publisher	American Management Assoc
Publishing place	New York
Document type	Book
Note	Literaturverz. S. 137-141
Database	Former special subject collection: coastal and deep sea fishing

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Book: An electronic Cash and credit System

Anderson, Allan H / Cannell, Donald T / Gibbons, Terrance A / Grote, G. Peter / Henn, John / Kennedy, J. Bradley / Muir, Michael B / Potter, Norman D / Whitby, Robert H

1966

Author's details	authors: Allan H. Anderson; Donald T. Cannell; Terrance A. Gibbons; G. Peter Grote; John Henn; J. Bradley Kennedy; Michael B. Muir; Norman D. Potter; Robert H. Whitby
Keywords	Elektronik ; Bankbetrieb ; Kredit
Language	Undetermined
Size	142 S. 8"
Document type	Book
Note	Literaturverz. S. 137-141
Database	ECONomics Information System

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