About

Jeffrey S. Smith is a Professor of Biochemistry and Molecular Genetics at the University of Virginia School of Medicine. His research focuses on understanding how chromatin structure influences DNA-mediated processes, including gene expression, DNA replication, repair, and recombination. A significant aspect of his work involves studying transcriptional silencing in yeast, particularly the role of the SIR2 gene, which encodes a conserved NAD+-dependent protein deacetylase known as a Sirtuin. His lab investigates the mechanisms of silencing at the yeast rDNA locus, the regulation of rDNA transcription, and the impact of chromatin-modifying enzymes on these processes, with implications for diseases such as cancer and cardiac hypertrophy. Smith's research also explores the regulation of NAD+ biosynthesis and salvage pathways, which are critical for Sirtuin activity and cellular processes like aging. His work extends to using yeast as a model system for aging and caloric restriction, aiming to identify genes and pathways involved in lifespan extension. The ultimate goal of his research is to translate findings from yeast to mammalian systems, where Sirtuins are implicated in aging-related diseases including diabetes, cancer, and neurodegeneration.

Research topics

• Surgery
• Medicine
• Computer Science
• Radiology
• Artificial Intelligence
• Anesthesia
• Physical medicine and rehabilitation
• Computational chemistry
• Chemistry
• Computational science
• Organic chemistry
• Anatomy
• Parallel computing
• Physical therapy
• Orthodontics
• Intensive care medicine

Selected publications

• Chronological lifespan extension and nucleotide salvage inhibition in yeast by isonicotinamide supplementation

  Journal of Biological Chemistry · 2026-01-13

  articleOpen accessSenior author

  <h2>Abstract</h2> Isonicotinamide (INAM) is an isomer of the NAD⁺ precursor nicotinamide (NAM) that stimulates the enzymatic activity of Sir2, an NAD⁺-dependent histone deacetylase from the budding yeast, <i>Saccharomyces cerevisiae</i>. Supplementing INAM into growth media promotes the replicative lifespan (RLS) of this single cell organism by maintaining intracellular NAD⁺ homeostasis. INAM also extends yeast chronological lifespan (CLS), but the underlying mechanisms remain largely uncharacterized. To identify cellular pathways potentially impacted by INAM, in this study we perform a chemical genomics screen of the yeast knockout (YKO) collection for mutants sensitized to growth inhibition by INAM. Significant Gene Ontology (GO) terms for candidate genes include transcription elongation factors, metabolic pathways converging on one-carbon metabolism, and de novo purine biosynthesis, collectively suggesting that INAM perturbs nucleotide metabolism. Indeed, INAM causes dose-dependent depletion of intracellular cytidine, uridine, and guanosine, ribonucleosides derived from the breakdown of nucleotide monophosphates (NMPs) via nucleotidases (Phm8, Sdt1, Isn1) or the alkaline phosphatase Pho8. We also find that INAM directly inhibits recombinant nucleotidase activity using cytidine or nicotinamide mononucleotide (NMN) as substrates and inhibits alkaline phosphatase activity quantitated from whole cell extracts. Lastly, we find that Phm8 and Pho8 are specifically required for INAM-induced CLS extension, implicating them as likely functional targets in vivo. Taken together, the findings suggest a model whereby partial impairment of nucleotide and/or NAD⁺ salvage pathways by INAM can trigger a hormetic stress response that supports enhanced quiescence during chronological aging.

  PublisherOA PDFDOI

• Age-dependent topoisomerase I depletion alters recruitment of rDNA silencing complexes

  bioRxiv (Cold Spring Harbor Laboratory) · 2025-08-01

  preprintOpen accessSenior authorCorresponding

  Genomic instability and loss of proteostasis are two of the primary Hallmarks of Aging. Although these hallmarks are well-defined in the literature, the mechanisms that drive genomic instability and loss of proteostasis as cells age are still largely unknown. Using budding yeast replicative lifespan as a model for aging in actively dividing cells, we identified nuclear proteins that were depleted in the earliest stages of aging. We found that many age-depleted proteins were involved in ribosome biogenesis, specifically in ribosome processing, or in maintenance of chromatin stability. We focused on topoisomerase I (Top1) as a novel age-depleted nuclear protein and found that its depletion in the early stages of aging was not a result of transcriptional changes or changes in protein turnover. Despite the stark depletion of Top1 in early aging, rescue of this age-dependent depletion was actually harmful to replicative lifespan. We found that Top1, when overexpressed, disrupts the stoichiometry of the RENT complex by pulling Sir2 away from the ribosomal DNA (rDNA), a phenotype which is further enhanced when the overexpressed Top1 is catalytically dead. Loss of Sir2 from the rDNA via the overexpression of catalytically dead Top1 decreases RNA Pol II silencing of a reporter gene inside or adjacent to the rDNA, consistent with the lifespan defect. Finally, we found that the catalytic activity of Top1 plays an important role in the establishment of rDNA silencing, raising the possibility that rDNA secondary structure/DNA topology is important for RNA Pol I-dependent spreading of silent chromatin across the rDNA locus.

  PublisherOA PDFDOI

• Exploring Acetyl-CoA-Mediated Beta-Hydroxybutyrate Enrichment in Yeast: A Mechanistic Link to Longevity

  Innovation in Aging · 2025-12-01

  articleOpen accessSenior author

  Abstract Aging predisposes organisms to diseases ranging from diabetes to Alzheimer’s, driving interest in interventions like Caloric Restriction (CR), which extends lifespan across species. While CR’s benefits are well-documented, its metabolic mechanisms remain incompletely understood. This study investigates β-hydroxybutyrate (βHB), a ketone body, in CR-mediated longevity using Saccharomyces cerevisiae. Despite the absence of canonical ketogenesis enzymes (HMG-CoA lyase, OXCT1) in yeast, we detect βHB for the first time in stationary-phase and CR conditions via metabolomics, GC-MS, and luminescence assays. Alternative carbon sources and supplementing yeast media with acetoacetate drive βHB levels. In addition, we identify mitochondrial acetyl-CoA metabolism (ACS1) and mtFAS pathways to be critical for βHB enrichment during CR. βHB supplementation extends chronological lifespan dose-dependently, mirroring CR’s effects, and combined CR + βHB yields additive lifespan extension. Transcriptomic profiling reveals 156 overlapping genes and 268 βHB-exclusive targets, suggesting shared (TCA cycle, amino acid metabolism) and βHB-specific mechanisms (mitochondrial translation, stress response). These findings resolve yeast’s unexpected capacity for ketogenesis and establish it as a model for dissecting βHB’s role in aging. This work also elucidates conserved nodes linking ketogenesis to longevity and positions yeast as a platform for exploring CR-mimicking therapeutics.

  PublisherOA PDFDOI

• Age-dependent topoisomerase I depletion alters recruitment of rDNA silencing complexes

  Journal of Biological Chemistry · 2025-12-17

  articleOpen accessSenior author

  Genomic instability and loss of proteostasis are two of the primary Hallmarks of Aging. Although these hallmarks are well-defined in the literature, the mechanisms that drive genomic instability and loss of proteostasis as cells age are still incompletely understood. Using budding yeast replicative lifespan as a model for aging in actively dividing cells, we identify nuclear proteins that are depleted in the earliest stages of aging. We find that many age-depleted proteins are involved in ribosome biogenesis, specifically in ribosome processing, or in maintenance of chromatin stability. We focus on topoisomerase I (Top1) as a novel age-depleted nuclear protein and determine that its depletion in the early stages of aging is not a result of transcriptional changes or changes in protein turnover. Despite the stark depletion of Top1 in early aging, we find that rescue of this age-dependent depletion is harmful to replicative lifespan. When overexpressed, Top1 disrupts the stoichiometry of the RENT complex by pulling Sir2 away from the ribosomal DNA (rDNA), a phenotype that is further enhanced when the overexpressed Top1 is catalytically dead. Loss of Sir2 from the rDNA via the overexpression of catalytically dead Top1 decreases RNA Pol II silencing of a reporter gene inside or adjacent to the rDNA, consistent with the lifespan defect. Finally, we show that the catalytic activity of Top1 plays an important role in the establishment of rDNA silencing, raising the possibility that rDNA secondary structure/DNA topology is important for RNA Pol I-dependent spreading of silent chromatin across the rDNA locus.

  PublisherDOI

• Accuracy of a Second-Year Dermatology Resident’s Pre-Biopsy Diagnoses

  medRxiv · 2025-05-21

  preprintOpen accessSenior authorCorresponding

  Skin biopsies are heavily relied upon in dermatology to diagnose cutaneous malignancies. Mastering skin biopsies and recognizing skin cancer is a core component of dermatology residency training. However, limited data exists on evaluative standards for biopsy training and residents' accuracy in diagnosing skin cancer. This study aimed to analyze pre- and post-biopsy diagnostic accuracy of a second-year resident in the Harvard Combined Dermatology Residency Program from July 2021 to June 2022. This resident recorded biopsies performed in specialty dermatology clinics across three large academic centers with attending oversight and the hypothesized pre-biopsy diagnosis and the subsequent histopathologically confirmed diagnosis. Stratifying lesions into categories of squamous cell carcinoma (SCC), basal cell carcinoma (BCC), and benign and subsequently comparing the recorded pre- and post-biopsy diagnoses, it was determined that this resident correctly identified the diagnosis in 64% of the cases and correctly diagnosed all histologically confirmed skin cancers as SCC or BCC. The specificity of this resident in identifying an SCC or BCC was 56%. This study provides a preliminary foundational dataset for developing evidence-based residency training guidelines to better prepare residents for independent clinical practice. It serves as a model for providing trainees and programs with information on variations in practice patterns.

  PublisherOA PDFDOI

• VEXAS in a patient with hypereosinophilia and Sweet’s-like lesions

  JAAD Case Reports · 2024-09-07 · 2 citations

  articleOpen access
  PublisherDOI

• Parasiticide use and obesity in dogs with sudden acquired retinal degeneration syndrome

  Journal of the American Veterinary Medical Association · 2024-09-13 · 4 citations

  article

  OBJECTIVE: To investigate parasiticide use and describe signalment features in patients with sudden acquired retinal degeneration syndrome (SARDS). ANIMALS: Retrospective case-control study of dogs with (n = 71) and without (136) SARDS. METHODS: Parasiticide use, presentation season, weight, body condition, and signalment were compared between dogs diagnosed with SARDS and the reference population by use of descriptive statistics and logistic regression. RESULTS: Animals with SARDS were at a 5.99 times higher odds of having previously used imidacloprid (95% CI, 1.6 to 22.2; P = .003). However, time of last imidocloprid administration was > 6 years prior to diagnosis in 6 SARDS-affected individuals and 15, 26, or 42 months before diagnosis (n = 1 each). No other class of parasiticide had a significant association with SARDS. Seasonal variation was observed with a negative association identified between incidence of SARDS and tick season (October to January; P < .001). Overweight and obese dogs were 4.42 (95% CI, 1.9 to 10.4) and 4.96 (95% CI, 2.1 to 11.6) times more likely to have SARDS (P ≤ .001). History of polyphagia or weight gain was not associated with an increased likelihood of being overweight or obese within the SARDS-affected population (P > .108). CLINICAL RELEVANCE: While a statistically significant association was found between imidacloprid use and SARDS, this is unlikely to be clinically significant given the lack of a temporal association, sparse exposure numbers, and low point estimate of the OR. A positive association between being overweight or obese and a diagnosis of SARDS was found independent of polyphagia and weight gain, suggesting that it may be a risk factor for the development of SARDS.

  PublisherDOI

• Feline distichiasis treated with cryoepilation: A retrospective study of 15 cats (27 eyes)

  Veterinary Ophthalmology · 2024-02-29

  articleOpen accessSenior author

  OBJECTIVE: To describe the clinical features of cats diagnosed with distichiasis and report on the outcomes following cryoepilation. ANIMALS STUDIED: Fifteen cats (27 eyes). PROCEDURES: Medical records of domestic cats with distichiasis that underwent a double freeze-thaw cycle with a -80°C cryoprobe applied to the palpebral conjunctiva, with hair then epilated were retrospectively studied. The patient signalment, distichiae locations, concurrent ocular diseases, recurrences, complications, and outcomes were recorded. RESULTS: The mean (std dev) age at the time of diagnosis and treatment was 2.2 years (2.8 years). All (15/15) cats were of the domestic shorthair (DSH) breed. Concurrent ocular findings at the initial examination were observed in 17/27 (63%) eyes, with upper lateral eyelid hypoplasia the most prevalent, present in 9/27 (33.3%) eyes. Recurrence of distichiae occurred in 8/27 (29.6%) eyes. The clinical presentation in the instances of recurrence was judged as asymptomatic and not of a clinical concern in 3/27 (11.1%) eyes, with a second procedure deemed necessary to alleviate symptoms in 5/27 (18.5%) eyes. All eyes treated with a second procedure had no recurrence of distichiae or symptoms. Complications following cryoepilation occurred in 4/27 (14.8%) eyes, with two cats developing bilateral entropion post-procedure. CONCLUSIONS: Treatment of distichiasis in cats utilizing cryoepilation was effective at alleviating symptoms, though some cats needed a second procedure. The development of post-procedural entropion was seen occasionally.

  PublisherOA PDFDOI

• Fob1-dependent condensin recruitment and loop extrusion on yeast chromosome III

  PLoS Genetics · 2023-04-14 · 15 citations

  articleOpen accessSenior authorCorresponding

  Despite recent advances in single-molecule and structural analysis of condensin activity in vitro, mechanisms of functional condensin loading and loop extrusion that lead to specific chromosomal organization remain unclear. In Saccharomyces cerevisiae, the most prominent condensin loading site is the rDNA locus on chromosome XII, but its repetitiveness deters rigorous analysis of individual genes. An equally prominent non-rDNA condensin site is located on chromosome III (chrIII). It lies in the promoter of a putative non-coding RNA gene called RDT1, which is in a segment of the recombination enhancer (RE) that dictates MATa-specific chrIII organization. Here, we unexpectedly find that condensin is recruited to the RDT1 promoter in MATa cells through hierarchical interactions with Fob1, Tof2, and cohibin (Lrs4/Csm1), a set of nucleolar factors that also recruit condensin to the rDNA. Fob1 directly binds to this locus in vitro, while its binding in vivo depends on an adjacent Mcm1/α2 binding site that provides MATa cell specificity. We also uncover evidence for condensin-driven loop extrusion anchored by Fob1 and cohibin at RDT1 that unidirectionally extends toward MATa on the right arm of chrIII, supporting donor preference during mating-type switching. S. cerevisiae chrIII therefore provides a new platform for the study of programmed condensin-mediated chromosome conformation.

  PublisherOA PDFDOI

• Increased alcohol dehydrogenase 1 activity promotes longevity

  Current Biology · 2023-02-17 · 14 citations

  articleOpen access
  PublisherOA PDFDOI

Recent grants

• NIH Grant F32CA113039

  NIH · $53k · 2006

Frequent coauthors

• Christopher I. Shaffrey

  Duke University

  3253 shared

• Virginie Lafage

  2981 shared

• Christopher P. Ames

  2828 shared

• Shay Bess

  Twin Cities Spine Center

  2612 shared

• Frank J. Schwab

  2364 shared

• Peter G. Passias

  Neurological Surgery

  2203 shared

• Eric O. Klineberg

  1988 shared

• Themistocles S. Protopsaltis

  1976 shared

Education

• PhD/Biochemistry, Biochemistry

  Rutgers Robert Wood Johnson Medical School

  1994

• BS/Marine Biology

  Long Island University-Southampton Campus

  1989