In roundworms, damaging different sites of the mitochondrial respiratory chain extends lifespan through two incompatible pathways, and metformin amplifies one while canceling the other
In roundworms, damaging different sites of the mitochondrial respiratory chain extends lifespan through two incompatible pathways, and metformin amplifies one while canceling the other
A new preprint from biochemists at Mahidol University and Ghent University, published on September 17, compared what happens in C. elegans roundworms when Complex I and Complex IV, two sites within the mitochondrial respiratory chain, are suppressed. Lifespan extension from Complex I inhibition depended entirely on the protein ATFS-1 and did not require the enzyme AAK-2 (AMPK), while extension from Complex IV inhibition showed the opposite pattern. Metformin, which inhibits Complex I and activates AAK-2, sharply extended lifespan further in one set of these worms while eliminating the effect in the other.
Mild impairment of the mitochondrial respiratory chain, the part of the cell that converts oxygen and nutrients into energy, extends lifespan in yeast, flies, mice, and roundworms. The effect is called mitohormesis: a small amount of damage activates a protective program rather than causing harm. Two such examples in C. elegans, weakening nuo-6 in Complex I and cco-1 in Complex IV, were for decades treated as interchangeable models of the same phenomenon.
The impetus came from a finding by the same laboratory last year: in different mutants, the protective cellular response to metformin did not match whether metformin actually extended their lifespan.
The biochemists separately suppressed nuo-6 and cco-1 in worms and measured anew which genes sustained the lifespan extension. Complex I suppression raised median lifespan from 17 to 19 days. Complex IV suppression produced a larger increase, to 24 days. Both knockdowns triggered the same stress response, the mitochondrial unfolded protein response (UPRmt), which activates production of protective chaperone proteins through the regulator ATFS-1.
From there, the pathways diverged. In worms with Complex I impairment, disabling ATFS-1 collapsed median lifespan to 15 days, below the level of controls: without this protein, the organism cannot survive Complex I deficiency itself. In worms with Complex IV impairment, disabling ATFS-1 left median lifespan unchanged at 24 days, even though chaperone production still dropped. Here, the protective response and lifespan extension were uncoupled.
AAK-2 is the worm homolog of the human enzyme AMPK, which activates when the cell runs low on energy. The pattern with AAK-2 was the mirror image: disabling AAK-2 slightly enhanced the lifespan extension from Complex I, raising median lifespan to 21 days, while in worms with Complex IV impairment, the same disruption collapsed lifespan nearly to control levels, to 15 days.
The authors attribute the difference to where in the chain the damage occurs. Complex IV is the terminal link, transferring electrons to oxygen, and blocking it shuts down electron flow immediately and completely, forcing the cell to rely on AAK-2. Complex I has an alternative electron entry point through Complex II, so the crisis is milder and AAK-2 is dispensable. Only ATFS-1 operates in that context.
Metformin is a diabetes drug and one of the most extensively tested candidates for an anti-aging medication in humans. In worms with Complex I impairment and AAK-2 disabled, metformin delivers a second hit to the same node of the respiratory chain and drops median lifespan from 21 to 18 days. In worms with Complex IV impairment, metformin produces the largest extension observed, from 24 to 30 days, and even without AAK-2 it extends lifespan from 15 to 20 days, bypassing this enzyme.
This divergence resolves a longstanding contradiction in geroscience. A 2018 study showed that ATFS-1 extends lifespan in worms with Complex I impairment. A 2014 study showed that worms with Complex IV impairment live longer even without active ATFS-1. The new work demonstrates that both sides were correct, simply describing different nodes of the same respiratory chain, and that drugs like metformin need to be tested separately for each.