Antibiotics that Target Mitochondria Extend Lifespan in C. elegans

Abstract

This study investigates the role of mitochondria in aging by assessing the effects of mitochondrial inhibitors on the lifespan of Caenorhabditis elegans (C. elegans). The researchers treated the worms with doxycycline and azithromycin, antibiotics known to inhibit mitochondrial ribosomes, as well as diphenyleneiodonium (DPI), an inhibitor of mitochondrial complexes I and II. They observed that these treatments significantly extended the median lifespan of C. elegans, enhanced pharyngeal pumping rates, reduced lipofuscin accumulation, and decreased ATP levels. In contrast, treatment with vitamin C, a pro-oxidant, did not extend lifespan and increased ATP levels. The findings suggest that targeting mitochondrial function with specific antibiotics can abrogate aging processes and extend lifespan in C. elegans.

Key Findings

• Doxycycline Treatment: At concentrations of 13 μM and 130 μM, doxycycline extended the median lifespan of C. elegans by 72.8% and 63.64%, respectively, compared to controls. It also reduced lipofuscin accumulation by up to 90% and enhanced pharyngeal muscle contractions.
• Azithromycin Treatment: Administered at 25 μM and 50 μM, azithromycin increased lifespan by 50% and 17%, respectively. It also reduced lipofuscin levels, with a more pronounced effect at the higher concentration.
• DPI Treatment: DPI at 5 nM and 20 nM concentrations extended median lifespan by 28.6% and 14.3%, respectively, with a slight reduction in lipofuscin accumulation.
• Combination Therapy: A combination of 1 μM doxycycline and 1 μM azithromycin extended lifespan by 27% and maintained pharyngeal activity. However, adding 250 μM vitamin C to this combination negated the lifespan extension benefits.
• ATP Levels: Treatments with doxycycline, azithromycin, and their combination reduced ATP levels by up to 50%, indicating decreased metabolic activity. In contrast, vitamin C treatment increased ATP levels by more than 2.5-fold.

Methodology

The researchers utilized the C. elegans N2 (Bristol) strain, maintaining them on nematode growth medium (NGM) plates at 20°C. Lifespan assays involved synchronizing worm populations and treating them with specified concentrations of doxycycline, azithromycin, DPI, and vitamin C. Pharyngeal pumping rates were recorded to assess neuromuscular function. Lipofuscin accumulation, an aging marker, was measured using autofluorescence imaging. ATP levels were quantified using the CellTiter-Glo luminescent assay, providing insights into metabolic activity.

Conclusion

The study demonstrates that targeting mitochondrial function with specific antibiotics can effectively extend lifespan and improve health markers in C. elegans. These findings support the hypothesis that mitochondrial activity plays a crucial role in aging processes. The use of FDA-approved antibiotics like doxycycline and azithromycin offers a promising avenue for developing anti-aging therapies. However, the addition of pro-oxidants like vitamin C may counteract these benefits, highlighting the need for careful consideration in combination therapies.