Randy Strong

The University of Texas Health Science Center at San Antonio

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Co-Authors

James F. Nelson

The University of Texas Health Science Center at San Antonio

Martin A. Javors

The University of Texas Health Science Center at San Antonio

Elizabeth Fernández

South Texas Veterans Health Care System

Richard A. Miller

University of Michigan–Ann Arbor

Arlan Richardson

Oklahoma City VA Medical Center

David E. Harrison

Jackson Laboratory

Z. Dave Sharp

Mays Cancer Center at UT Health San Antonio

Adam B. Salmon

The University of Texas Health Science Center at San Antonio

Nancy L. Nadon

National Institutes of Health

Jonathan Gelfond

The University of Texas Health Science Center at San Antonio

Cooperative Institutions

The University of Texas Health Science Center at San Antonio

236

The University of Texas Health Science Center at Houston

117

South Texas Veterans Health Care System

The University of Texas at San Antonio

Geriatric Research Education and Clinical Center

National Institutes of Health

University of Michigan–Ann Arbor

University of Washington

Audie L. Murphy Memorial VA Hospital

Harvard University

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Lifespan effects in male UM-HET3 mice treated with sodium thiosulfate, 16-hydroxyestriol, and late-start canagliflozin

GeroScience (2024)

Richard A. Miller David Harrison Gino Cortopassi Ishmael Dehghan Elizabeth Fernández

Canagliflozin

10.1007/s11357-024-01176-2

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Citations (5)

Deciphering the Timing and Impact of Life-extending Drugs: A Novel Analytic Approach that Differentiates Early, Midlife, and Senescence Phase Efficacies.

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Nisi Jiang Catherine Cheng Qianqian Liu Randy Strong Jonathan Gelfond

Abstract Evidence that life-extending interventions are not uniformly effective across the lifespan calls for an analytic tool that can estimate age-specific treatment effects on mortality hazards. Here we report such a tool, applying it to mouse data from 42 agents tested in the NIA Interventions Testing Program. This tool identified agents that either reduced (22) or increased (16) mortality hazards or did both (6), all with marked variation in the duration of efficacy and magnitude of effect size. Only 7 reduced mortality hazards after the 90% mortality, when the burden of senescence is greatest. Sex differences were apparent in all parameters. This new analytic tool complements the commonly used log-rank test. It detects more potential life-extending candidates (22 versus 10) and indicates when during the life course they are effective. It also uncovers adverse effects. Most importantly, it identifies agents that specifically reduce mortality hazards during the senescent phase of life.

Senescence

10.1101/2024.03.27.585737

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Citations (0)

Detoxification of Biogenic Aldehydes in Parkinson¡¦s Disease

The FASEB Journal (2009)

Margaret Wey Elizabeth Fernández Carmen Hinojosa‐Laborde Randy Strong

It has been recognized for almost 20 years that idiopathic Parkinson's disease (PD) is linked to diminished NADH dehydrogenase (mitochondrial complex I) activity. How chronic complex I inhibition leads to the characteristic pathological features of PD is largely unknown. PD is accompanied by elevation of neurotoxic biogenic aldehydes, including 4‐hydroxynonenal, a product of lipid peroxidation, and 3, 4‐dyhydroxyphenylacetaldehyde, a product of dopamine metabolism. We hypothesize that impaired complex 1 activity reduces the availability of the NAD + co‐factor required by ALDHs to detoxify aldehydes. Aldh1a1 and Aldh2, are the only ALDH genes known to be expressed in midbrain brain dopamine neurons. Moreover, expression of ALDH1, the human homologue of Aldh1a1, is reduced in PD. Therefore, we tested the hypothesis that mice lacking both Aldh1a1 and Aldh2 would exhibit impaired motor function consequent to dopaminergic neurodegeneration. Compared to wild‐type controls, knockout mice exhibited significant age‐related decreases in the latency to fall during accelerated rotarod testing (no significant decrease at 7 months, 32% at 10 months, and 69% at 22 months). No age‐related deficits were observed in wild type controls. We will discuss neurochemical analyses of the nigrostriatal pathway in the double‐knockout mice. Supported by the VA Office of Research & Development (EF and RS) and PHS : AG022307 (RS) .

4-Hydroxynonenal

Neurochemical

ALDH2

10.1096/fasebj.23.1_supplement.963.4

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Citations (0)

NIA Interventions Testing Program: A collaborative approach for investigating interventions to promote healthy aging

Elsevier eBooks (2021)

Francesca Macchiarini Richard A. Miller Randy Strong Nadia Rosenthal David E. Harrison

Acarbose

Healthy aging

10.1016/b978-0-12-815962-0.00010-x

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Citations (11)

Acarbose, 17‐α‐estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in males

Aging Cell (2013)

David E. Harrison Randy Strong David B. Allison Bruce N. Ames Clinton M. Astle

Four agents--acarbose (ACA), 17-α-estradiol (EST), nordihydroguaiaretic acid (NDGA), and methylene blue (MB)--were evaluated for lifespan effects in genetically heterogeneous mice tested at three sites. Acarbose increased male median lifespan by 22% (P < 0.0001), but increased female median lifespan by only 5% (P = 0.01). This sexual dimorphism in ACA lifespan effect could not be explained by differences in effects on weight. Maximum lifespan (90th percentile) increased 11% (P < 0.001) in males and 9% (P = 0.001) in females. EST increased male median lifespan by 12% (P = 0.002), but did not lead to a significant effect on maximum lifespan. The benefits of EST were much stronger at one test site than at the other two and were not explained by effects on body weight. EST did not alter female lifespan. NDGA increased male median lifespan by 8-10% at three different doses, with P-values ranging from 0.04 to 0.005. Females did not show a lifespan benefit from NDGA, even at a dose that produced blood levels similar to those in males, which did show a strong lifespan benefit. MB did not alter median lifespan of males or females, but did produce a small, statistically significant (6%, P = 0.004) increase in female maximum lifespan. These results provide new pharmacological models for exploring processes that regulate the timing of aging and late-life diseases, and in particular for testing hypotheses about sexual dimorphism in aging and health.

Nordihydroguaiaretic acid

Acarbose

Sexual dimorphism

10.1111/acel.12170

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Citations (385)

Identification of a glucocorticoid‐responsive element in the promoter region of the mouse tyrosine hydroxylase gene

Journal of Neurochemistry (2001)

Timothy Hagerty W. W. Morgan N Elango Randy Strong

It has been known for nearly 30 years that glucocorticoid receptor stimulation induces increased tyrosine hydroxylase (TH) gene expression. However, the mechanism mediating this effect has remained elusive. Sequences with homology to known glucocorticoid‐responsive elements (GRE) have been identified in the 5′ flanking region of the TH gene of several vertebrate species, but none has been shown to be functional. To identify the GRE element(s) in the TH promoter, we generated chimeric constructs in which different lengths of the 5′ flanking sequences of the mouse TH gene (3.6, 1.1 and 0.8 kb) were ligated to a luciferase reporter gene. Dexamethasone treatment increased luciferase expression only in cells transiently transfected with the construct containing 3.6 kb of the TH 5′ flanking DNA. Co‐administration of mifepristone (RU486), a glucocorticoid receptor antagonist, blocked this effect. We identified a TH‐GRE sequence (5′‐GGCACAGTGTGGTCT) in the mouse 5′ flanking DNA between −2435 and −2421 from the transcription start. Responsiveness to dexamethasone was lost following deletion of this sequence. To determine the ability of this element to function in a heterologous promoter, we prepared a chimeric construct in which the TH‐GRE sequence was cloned just upstream of a minimal thymidine kinase (TK) promoter. Promoter activity was increased 2‐fold in dexamethasone‐treated PC12 cells transfected with the TH‐GRE‐TK construct. These results provide strong evidence that the 15 base‐pair sequence in the 5′ flanking DNA of the mouse TH gene functions as a glucocorticoid response element. This is the first report identifying a functional glucocorticoid response element in the promoter region of the TH gene of any species.

Hormone response element

Response element

Thymidine kinase

Chimeric gene

Transcription

10.1046/j.1471-4159.2001.00072.x

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Citations (52)

Adaptations to chronic rapamycin in mice

Pathobiology of Aging & Age-related Diseases (2016)

Sherry G. Dodds Carolina B. Livi Manish Parihar Hang-Kai Hsu Adriana D. Benavides

Rapamycin inhibits mechanistic (or mammalian) target of rapamycin (mTOR) that promotes protein production in cells by facilitating ribosome biogenesis (RiBi) and eIF4E-mediated 5'cap mRNA translation. Chronic treatment with encapsulated rapamycin (eRapa) extended health and life span for wild-type and cancer-prone mice. Yet, the long-term consequences of chronic eRapa treatment are not known at the organ level. Here, we report our observations of chronic eRapa treatment on mTORC1 signaling and RiBi in mouse colon and visceral adipose. As expected, chronic eRapa treatment decreased detection of phosphorylated mTORC1/S6K substrate, ribosomal protein (rpS6) in colon and fat. However, in colon, contrary to expectations, there was an upregulation of 18S rRNA and some ribosomal protein genes (RPGs) suggesting increased RiBi. Among RPGs, eRapa increases rpl22l1 mRNA but not its paralog rpl22. Furthermore, there was an increase in the cap-binding protein, eIF4E relative to its repressor 4E-BP1 suggesting increased translation. By comparison, in fat, there was a decrease in the level of 18S rRNA (opposite to colon), while overall mRNAs encoding ribosomal protein genes appeared to increase, including rpl22, but not rpl22l1 (opposite to colon). In fat, there was a decrease in eIF4E relative to actin (opposite to colon) but also an increase in the eIF4E/4E-BP1 ratio likely due to reductions in 4E-BP1 at our lower eRapa dose (similar to colon). Thus, in contrast to predictions of decreased protein production seen in cell-based studies, we provide evidence that colon from chronically treated mice exhibited an adaptive 'pseudo-anabolic' state, which is only partially present in fat, which might relate to differing tissue levels of rapamycin, cell-type-specific responses, and/or strain differences.

EIF4E

ribosome biogenesis

Ribosomal protein s6

Ribosomal protein

Translational efficiency

10.3402/pba.v6.31688

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Citations (14)

Chronic Rapamycin Restores Brain Vascular Integrity and Function Through NO Synthase Activation and Improves Memory in Symptomatic Mice Modeling Alzheimer’s Disease

Carolina Digital Repository (University of North Carolina at Chapel Hill) (2013)

Ai‐Ling Lin Wei Zheng Jonathan J Halloran Raquel R Burbank Stacy A. Hussong

Brain Function