Frederick W. Alt

Research summary

Work characterizes the mammalian sirtuin family of NAD-dependent deacetylases and their roles in stress response, autophagy, and mitochondrial regulation. SIRT1, the mammalian Sir2 homolog, was shown to form a complex with the FOXO3 forkhead transcription factor in response to oxidative stress and to deacetylate FOXO3 both in vitro and in cells; SIRT1 exerted a dual effect on FOXO3, modulating its capacity to induce stress-response gene expression and thereby coupling NAD-dependent deacetylation to insulin/longevity signaling [1]. Acute increases in SIRT1 expression were sufficient to stimulate basal autophagy, while Sirt1^-/- mouse embryonic fibroblasts failed to fully activate starvation-induced autophagy; reconstitution with wild-type but not catalytically inactive SIRT1 restored the response, and SIRT1 was shown to form molecular complexes with autophagy components Atg5, Atg7, and Atg8 and to deacetylate them in an NAD-dependent manner, linking nutrient sensing to the autophagy machinery [2]. Endogenous mouse SIRT3 was identified as a soluble mitochondrial protein; SIRT3-knockout animals exhibited pronounced mitochondrial protein hyperacetylation while no comparable hyperacetylation arose in mice lacking other tested sirtuins, establishing SIRT3 as a major mitochondrial deacetylase in vivo and providing genetic tools for studying mitochondrial energy metabolism [3]. The three studies provide complementary entry points for sirtuin biology spanning cytosolic stress response, lysosomal degradation, and mitochondrial acetylation.

Recent publications

1. Stress-Dependent Regulation of FOXO Transcription Factors by the SIRT1 Deacetylase2004 · Science · 3215 citationsDOI
2. SIRT3 regulates mitochondrial fatty-acid oxidation by reversible enzyme deacetylation2010 · Nature · 1659 citationsDOI
3. Genomic Instability and Aging-like Phenotype in the Absence of Mammalian SIRT62006 · Cell · 1616 citationsDOI
4. A role for the NAD-dependent deacetylase Sirt1 in the regulation of autophagy2008 · Proceedings of the National Academy of Sciences · 1436 citationsDOI
5. An early haematopoietic defect in mice lacking the transcription factor GATA-21994 · Nature · 1433 citationsDOI
6. SIRT1 Regulates Circadian Clock Gene Expression through PER2 Deacetylation2008 · Cell · 1353 citationsDOI
7. Plasma cell differentiation requires the transcription factor XBP-12001 · Nature · 1283 citationsDOI
8. Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC‐1α2007 · The EMBO Journal · 1276 citationsDOI
9. Mammalian Sir2 Homolog SIRT3 Regulates Global Mitochondrial Lysine Acetylation2007 · Molecular and Cellular Biology · 1213 citationsDOI
10. SIRT4 Inhibits Glutamate Dehydrogenase and Opposes the Effects of Calorie Restriction in Pancreatic β Cells2006 · Cell · 1144 citationsDOI

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Email Frederick W. Alt 6-12 months before your application deadline. Read several recent papers and reference specific work in your message. Use our how to email a Japanese professor guide for the proven email structure.

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External profiles

• ORCID: https://orcid.org/0000-0002-0583-1271
• OpenAlex: openalex.org

Profile compiled from public sources (Researchmap, OpenAlex, Hokkaido University faculty directory). Last refreshed 2026-05. Report incorrect information.