Ethan A. Sarnoski

Yale University

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Murat Açar

Koç University

Ruijie Song

Shenzhen University

Tolga T. Ölmez

Yale University

Thomas Young

Yale University

Ping Liu

Jiangsu Agri-animal Husbandry Vocational College

Noelle L Koonce

Yale University

Ege Ertekin

University of Sydney

G. Chin

University of California, San Francisco

Kevin Flurkey

Jackson Laboratory

Guste Urbonaite

Yale University

Cooperative Institutions

Yale University

The University of Texas Health Science Center at Houston

The University of Texas Health Science Center at San Antonio

Buck Institute for Research on Aging

Jackson Laboratory

The University of Texas at San Antonio

University of California, San Francisco

Harvard University

University of Michigan–Ann Arbor

Longevity Biotech (United States)

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Characterization of the impact of GMP/GDP synthesis inhibition on replicative lifespan extension in yeast

Current Genetics (2020)

Ping Liu Ethan A. Sarnoski Tolga T. Ölmez Thomas Young Murat Açar

10.1007/s00294-020-01068-w

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Citations (4)

Mitochondrial Dysfunction Induces Senescence with a Distinct Secretory Phenotype

Cell Metabolism (2015)

Christopher D. Wiley Michael C. Velarde Pacôme Lecot Su Liu Ethan A. Sarnoski

Senescence

10.1016/j.cmet.2015.11.011

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Citations (950)

Antibiotic-dependent expression of early transcription factor subunits leads to stringent control of vaccinia virus replication

Virus Research (2014)

Caitlin J. Hagen Allison Titong Ethan A. Sarnoski Paulo H. Verardi

The use of vaccinia virus (VACV) as the vaccine against variola virus resulted in the eradication of smallpox. VACV has since been used in the development of recombinant vaccine and therapeutic vectors, but complications associated with uncontrolled viral replication have constrained its use as a live viral vector. We propose to improve the safety of VACV as a live-replicating vector by using elements of the tet operon to control the transcription of genes that are essential for viral growth. Poxviruses encode all enzymes and factors necessary for their replication within the host cell cytoplasm. One essential VACV factor is the vaccinia early transcription factor (VETF) packaged into the viral core. This heterodimeric protein is required for expression of early VACV genes. VETF is composed of a large subunit encoded by the A7L gene and a small subunit encoded by the D6R gene. Two recombinant VACVs were generated in which either the A7L or D6R gene was placed under the control of tet operon elements to allow their transcription, and therefore viral replication, to be dependent on tetracycline antibiotics such as doxycycline. In the absence of inducers, no plaques were produced but abortively infected cells could be identified by expression of a reporter gene. In the presence of doxycycline, both recombinant viruses replicated indistinguishably from the wild-type strain. This stringent control of VACV replication can be used for the development of safer, next-generation VACV vaccines and therapeutic vectors. Such replication-inducible VACVs would only replicate when administered with tetracycline antibiotics, and if adverse events were to occur, treatment would be as simple as antibiotic cessation.

Transcription

Recombinant virus

10.1016/j.virusres.2013.12.033

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Citations (14)

Inhibition of GMP synthesis extends yeast replicative lifespan

bioRxiv (Cold Spring Harbor Laboratory) (2019)

Ethan A. Sarnoski Pangfeng Liu Guste Urbonaite Tolga T. Ölmez Thomas Young

ABSTRACT Aging, the time-dependent accumulation of molecular damage, is the primary limiting factor of human lifespan. Slowing down damage accumulation or its prevention therefore represents a promising therapeutic paradigm to combat aging-related disease and death. While several chemical compounds extend lifespan in model organisms, their mechanism of action is often unknown, reducing their therapeutic potential. Using a systematic approach, here we show that inhibition of GMP synthesis is a novel lifespan extension mechanism in yeast. We further discover that proteasome activation extends lifespan in part through GMP insufficiency. GMP synthesis inhibition exerts its lifespan extension effect independently of the canonical nutrient-sensing and sirtuin pathways regulating lifespan. Exposing longitudinally aging yeast cells to GMP synthesis inhibition in an age-dependent manner, we demonstrate that the lifespan extension by GMP insufficiency is facilitated by slowing, rather than reversing, the aging process in cells. While GMP and its downstream metabolites are involved in many cellular processes in cells, our results rule out the combined effect of global transcription and translation on cellular lifespan. These findings elucidate the involvement of nucleotide metabolism in the aging process. The existence of clinically-approved GMP synthesis inhibitors elicits the potential of a new class of therapeutics for aging-related disorders.

Mechanism of Action

10.1101/629428

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The Systems Biology of Single-Cell Aging

iScience (2018)

Ruijie Song Ethan A. Sarnoski Murat Açar

Aging is a leading cause of human morbidity and mortality, but efforts to slow or reverse its effects are hampered by an incomplete understanding of its multi-faceted origins. Systems biology, the use of quantitative and computational methods to understand complex biological systems, offers a toolkit well suited to elucidating the root cause of aging. We describe the known components of the aging network and outline innovative techniques that open new avenues of investigation to the aging research community. We propose integration of the systems biology and aging fields, identifying areas of complementarity based on existing and impending technological capabilities. Aging is a leading cause of human morbidity and mortality, but efforts to slow or reverse its effects are hampered by an incomplete understanding of its multi-faceted origins. Systems biology, the use of quantitative and computational methods to understand complex biological systems, offers a toolkit well suited to elucidating the root cause of aging. We describe the known components of the aging network and outline innovative techniques that open new avenues of investigation to the aging research community. We propose integration of the systems biology and aging fields, identifying areas of complementarity based on existing and impending technological capabilities.

Complementarity (molecular biology)

Healthy aging

Modelling biological systems

Cellular Aging

10.1016/j.isci.2018.08.023

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Citations (29)

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

GeroScience (2023)

David Harrison Randy Strong Peter C. Reifsnyder Nadia Rosenthal Ron Korstanje

Abstract In genetically heterogeneous (UM-HET3) mice produced by the CByB6F1 × 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.

Dimethyl fumarate

Affect

10.1007/s11357-023-01011-0

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Citations (14)

Biomarkers to identify and isolate senescent cells

Ageing Research Reviews (2016)

Mantas Matjusaitis G. Chin Ethan A. Sarnoski Alexandra Stolzing

Senescence

Cell type

10.1016/j.arr.2016.05.003

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Citations (129)

A High-Throughput Screen for Yeast Replicative Lifespan Identifies Lifespan-Extending Compounds

Cell Reports (2017)

Ethan A. Sarnoski Ping Liu Murat Açar

Progress in aging research is constrained by the time requirement of measuring lifespans. Even the most rapid model for eukaryotic aging, the replicative lifespan of Saccharomyces cerevisiae, is technically limited to only several lifespan measurements each day. Here we report a 384-well plate-based technique to measure replicative lifespan, termed High-Life. Using the High-Life technique, a single researcher can compare lifespan for more than 1,000 conditions per day. We validated the technique with long-lived mutant strains and the lifespan-extending compound ibuprofen. We also applied this technique to screen a small compound library for lifespan extension. Two hits, terreic acid and mycophenolic acid, were validated on our single-cell replicator device and found to extend mean replicative lifespan by 15% and 20%, respectively. Together, we report a technique for high-throughput lifespan measurement, and we identify two lifespan-extending compounds. Our technique could be used to efficiently drive early-stage discovery of pro-longevity therapeutics.

Cellular Aging

High-Throughput Screening

10.1016/j.celrep.2017.11.002

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Citations (33)

Fundamental Characteristics of Single-Cell Aging in Diploid Yeast

iScience (2018)

Ethan A. Sarnoski Ruijie Song Ege Ertekin Noelle L Koonce Murat Açar

Single-cell-level experimentation can elucidate key biological insights about cellular aging that are masked in population-level studies. However, the extensive time requirement of tracking single cells has historically prevented their long-term longitudinal observation. Using a microfluidic device that automates microscopic monitoring of diploid Saccharomyces cerevisiae cells throughout their replicative lifespan, here we report the fundamental characteristics of single-cell aging for diploid yeast. We find that proteins with short versus long half-lives exhibit distinct dynamics as cells age and that the intercellular gene expression noise increases during aging, whereas the intracellular noise stays unchanged. A stochastic model provides quantitative mechanistic insights into the observed noise dynamics and sheds light on the age-dependent intracellular noise differences between diploid and haploid yeast. Our work elucidates how a set of canonical phenotypes dynamically change while the host cells are aging in real time, providing essential insights for a comprehensive understanding on and control of lifespan at the single-cell level.

Single-Cell Analysis

Model Organism

10.1016/j.isci.2018.08.011

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Citations (36)