Opposing gene programs produced the same outcome in nine long-lived worm strains

Opposing gene programs produced the same outcome in nine long-lived worm strains

On August 20, researchers at McGill University published an eLife study of nine long-lived strains of the roundworm Caenorhabditis elegans. All nine lived longer than normal worms, but some shared genes changed activity in opposite directions in two groups. The authors then tested some of these genes in the animals themselves.

Mutations that extend lifespan are usually studied one strain at a time and under different conditions. Differences in gene activity can therefore reflect both the underlying biology and the experimental design. The authors first confirmed that all nine strains lived longer than normal worms, then compared them within a single experimental design. They collected at least six independent samples from each strain and 18 from the control worms.

The researchers measured gene activity using RNA-seq, a method that counts RNA molecules to determine how actively cells use each gene. The profiles fell into three groups. In the four strains in the first group, the activity of 507 genes increased. In the two strains in the second group, the activity of 188 of those same genes decreased, while only 12 showed increased activity. A similar difference appeared among genes regulated by DAF-16/FOXO, a protein that switches other genes on and off.

The authors tested whether these changes contributed to lifespan extension rather than merely accompanying it. Of 196 genes that were active in at least six strains, they were able to test 116 using RNA interference, a method that reduces the activity of a selected gene. Most interventions did not affect lifespan. Seven candidates passed a second round of testing. Suppressing any one of them shortened lifespan in both normal worms and a strain with impaired mitochondrial function. Increased activity of one candidate, C08F11.7, extended the lifespan of normal worms and made them more resistant to heat, oxidative stress, and a bacterial pathogen.

The same long lifespan in worms can depend on different combinations of active genes. A shared list of “longevity genes” therefore provides little evidence about causation by itself. The role of each candidate must be tested within the specific genetic program in which it operates.