Related Experiment Video

Updated: Jun 20, 2026

Revealing the Ferroptotic Phenotype of Medulloblastoma
04:01

Revealing the Ferroptotic Phenotype of Medulloblastoma

Published on: March 15, 2024

Atypical Tetracyclines Promote Longevity and Ferroptotic Neuroprotection via Translation Attenuation

Khalyd J Clay1,2, Manuel Sanchez-Alavez1,2, Ian Newman1,2

  • 1Department of Molecular and Cellular Biology, The Scripps Research Institute, La Jolla, California, USA.

Aging Cell
|June 18, 2026
PubMed

Insights

New tetracycline compounds extend lifespan by reducing protein synthesis, a key aging mechanism. These drugs offer a novel druggable target for longevity and neuroprotection, independent of antibiotic effects.

Area of Science:

  • Biogerontology
  • Pharmacology
  • Molecular Biology

Background:

  • Reducing protein synthesis is a conserved mechanism for extending lifespan across diverse species.
  • Pharmacological strategies to safely attenuate protein translation (the process of making proteins) are limited.
  • Tetracyclines, known antibiotics, show potential benefits in age-related diseases and lifespan extension, but their mechanisms are unclear.

Purpose of the Study:

  • To systematically profile tetracyclines for their ability to attenuate protein translation.
  • To identify novel tetracycline derivatives that can reduce protein synthesis independently of antibiotic activity and integrated stress response (ISR) activation.
  • To evaluate the efficacy of these compounds in promoting longevity and protecting against neuronal stress.

Main Methods:

  • Systematic profiling of commercially available tetracyclines.
  • Identification and characterization of atypical tetracyclines (4-epiminocycline and 12-aminominocycline).
  • Assessment of translation attenuation in human induced neurons and in vivo hippocampal protein synthesis.
  • Evaluation of lifespan extension in C. elegans and neuroprotection assays.

Main Results:

  • Translation attenuation is a general property of the tetracycline class.
  • 4-epiminocycline and 12-aminominocycline attenuate translation independently of antibiotic activity and ISR activation.
  • These compounds extend lifespan in C. elegans, reduce protein synthesis in human neurons and mouse hippocampus, and protect against ferroptotic stress.

Conclusions:

  • Pharmacological attenuation of protein translation is sufficient to promote longevity.
  • Translation attenuation represents a druggable mechanism for promoting longevity in mammals.
  • Atypical tetracyclines offer a promising therapeutic avenue for age-associated diseases and longevity.
Keywords:
agingferroptosisintegrated stress responselongevityneuroprotectionproteostasistetracyclinestranslation inhibition

Related Concept Videos

Translation01:31

Translation

Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Translation01:31

Translation

Lesson: Translation
Translation is the process of synthesizing proteins from the genetic information carried by messenger RNA (mRNA). Following transcription, it constitutes the final step in the expression of genes. This process is carried out by ribosomes, complexes of protein and specialized RNA molecules. Ribosomes, transfer RNA (tRNA), and other proteins produce a chain of amino acids—the polypeptide—as the end product of translation.
Translation Produces the Building Blocks of Life
Transcription Attenuation in Prokaryotes02:42

Transcription Attenuation in Prokaryotes

Transcriptional attenuation occurs when RNA transcription is prematurely terminated due to the formation of a terminator mRNA hairpin structure.  Bacteria use these hairpins to regulate the transcription process and control the synthesis of several amino acids including histidine, lysine, threonine, and phenylalanine. Transcription attenuation takes place in the non-coding regions of mRNA.
There are several different mechanisms used to attenuate transcription. In ribosome mediated...
Inhibitors of Bacterial Protein Synthesis01:25

Inhibitors of Bacterial Protein Synthesis

Aminoglycosides constitute a highly potent class of bactericidal antibiotics that exert their antimicrobial effects by targeting the bacterial ribosome, specifically disrupting protein synthesis. These polycationic molecules consist of amino-modified sugars linked via glycosidic bonds to an aminocyclitol core such as 2-deoxystreptamine or streptamine. Their strong positive charges facilitate tight binding to the negatively charged phosphate backbone of ribosomal RNA (rRNA), primarily at the 16S...
Drugs Affecting Neurotransmitter Synthesis01:29

Drugs Affecting Neurotransmitter Synthesis

Drugs affecting neurotransmitter synthesis can impact the adrenergic neuron and the synthesis of neurotransmitters. For example, α-methyltyrosine and carbidopa target specific enzymes involved in catecholamine synthesis. α-methyltyrosine inhibits the enzyme tyrosine hydroxylase, which converts tyrosine into dopamine. By blocking this enzyme, α-methyltyrosine reduces dopamine production and other catecholamines. Carbidopa, on the other hand, inhibits the enzyme dopa decarboxylase, which converts...