Zinc levels fall by almost 90% in aging roundworms. A low dose restored ribosome function, extended healthy lifespan and slowed disease progression in models resembling Alzheimer’s and Huntington’s diseases
Zinc levels fall by almost 90% in aging roundworms. A low dose restored ribosome function, extended healthy lifespan and slowed disease progression in models resembling Alzheimer’s and Huntington’s diseases
On October 9, biologists at the Institute of Biochemistry and Biophysics of the Polish Academy of Sciences posted a preprint on bioRxiv reporting a sharp decline in zinc levels in the roundworm Caenorhabditis elegans, measured at different ages. A low dose of zinc chloride extended the lifespan of aged worms, improved muscle function and increased resistance to heat and oxidative stress. A dose one hundred times higher was lethal.
In adult worms, zinc levels initially rise slightly, then fall sharply: by 33% on day seven, 60% on day ten and 90% on day thirteen, remaining at that level thereafter. The authors measured the zinc-to-sulfur ratio to distinguish zinc loss from changes in body mass. Of the six metals tested, zinc alone showed such a sustained decline. Iron and calcium accumulate with age, manganese and copper rise temporarily before returning to their earlier levels, and magnesium remains virtually unchanged.
Zinc chloride had a narrow dose window between benefit and toxicity: 10 micromoles restored normal zinc levels and extended lifespan (the median increased from 9 to 12 days), whereas a dose one hundred times higher killed the worms within one day. When the researchers used a chelating agent to bind free zinc inside cells, the benefit disappeared completely, indicating that zinc itself was responsible for the effect, rather than the salt.
An earlier study from the same laboratory suggested a mechanism: the cysteine residues that bind structural zinc in ribosomal proteins become oxidized during aging. This gave the researchers a reason to examine the ribosome itself. Proteomics supported their hypothesis: zinc supplementation had its strongest effects on the structural proteins of the ribosome, the molecular machinery that builds proteins from RNA instructions. Levels of the ribosomal RNA precursor, a starting material for assembling new ribosomes, remained unchanged. Zinc therefore repairs existing ribosomes rather than building new ones, and the worms synthesized 36% more protein. To test whether the benefit came from the ribosome itself rather than a general improvement in the worms’ health, the researchers treated them with paromomycin, an antibiotic that reduces the accuracy with which ribosomes read RNA. Even under these conditions, zinc substantially improved survival after heat shock, and the same chelating agent again abolished this protection.
Reducing protein synthesis usually extends lifespan in worms; here, increased synthesis extended it. The findings can be reconciled through the accuracy of protein synthesis: a ribosomal protein mutation that improves accuracy without increasing the rate of synthesis had already been shown to extend lifespan in yeast, flies and worms. Zinc acted across several cellular systems, restoring antioxidant defenses, chaperones (proteins that help other proteins fold), energy metabolism and the machinery that disposes of damaged proteins to youthful levels. Without this coordination, the effect could have been reversed. In another study, accelerating protein synthesis in cells without a corresponding chaperone response reduced the recovery of damaged proteins after heat shock by almost threefold. Worms with the same imbalance showed faster deterioration in a model of toxic protein accumulation resembling Huntington’s disease.
In two models of human disease, a polyglutamine model resembling Huntington’s disease and an amyloid model resembling Alzheimer’s disease, zinc significantly slowed the accumulation of toxic protein aggregates and the progression of muscle paralysis. Clearance was selective: expression of a gene involved in capturing toxic cargo nearly doubled, while expression of a gene involved in general cellular clearance decreased.
These results differ from an earlier study in the same field, in which zinc deficiency extended worm lifespan and supplementation shortened it. The distinction lies in the starting conditions: the earlier study varied zinc levels in healthy worms from deficiency to excess, whereas the current study replenishes zinc already lost through aging, within a narrow, nontoxic dose window. So far, these experiments have been conducted in roundworms. The same dose window has not been tested in mammals, in which excess zinc is already known to be toxic.