Genetic switch could be key to increased health, lifespan

• Stressing mitochondria in worm, C. elegans, triggers epigenetic changes that last lifetime

Newly discovered genetic switches that increase lifespan and boost fitness in worms are also linked to increased lifespan in mammals, offering hope that drugs to flip these switches could improve human metabolic function and increase longevity.

These so-called epigenetic switches, discovered by scientists at the University of California, Berkeley, United States (U.S.), and the École Polytechnique Fédérale de Lausanne in Switzerland, are enzymes that are ramped up after mild stress during early development and continue to affect the expression of genes throughout the animal’s life.

When the researchers looked at strains of inbred mice that have radically different lifespans, those with the longest lifespans had significantly higher expression of these enzymes than did the short-lived mice.

“Two of the enzymes we discovered are highly, highly correlated with lifespan; it is the biggest genetic correlation that has ever been found for lifespan in mice, and they’re both naturally occurring variants,” said Andrew Dillin, a University of Carlifornia (U.C.) Berkeley, U.S., professor of molecular and cell biology. “Based on what we see in worms, boosting these enzymes could reprogram your metabolism to create better health, with a possible side effect of altering lifespan.”

These are the first epigenetic modifiers known to affect metabolic function and longevity, though others are known to affect either metabolism or lifespan.

The discoveries will be reported in two papers to appear in the May 19 issue of the journal Cell. Both are now available online. Dillin and Johan Auwerx at the EPFL led an international team that is publishing one paper, while Dillin and his UC Berkeley colleagues, including Barbara Meyer, a professor of molecular and cell biology, authored the second.
Starvation leads to longer life spans

For decades, researchers have found correlations between nutrient availability during early development and adult health and metabolism. Brief changes in the energy available to the cell — caused by restricting diet, for example — seem to reshape animal physiology for years to come, even affecting lifespan.

The brain’s hunger switch

The first set of enzymes — methylases, in particular LIN-65 — add methyl groups to the DNA, which can silence promoters and thus suppress gene expression. By also opening up the mitochondrial genes, these methylases set the stage for the second set of enzymes — demethylases, in this case jmjd-1.2 and jmjd-3.1 — to ramp up transcription of the mitochondrial genes. When the researchers artificially increased production of the demethylases in worms, all lived longer, a result identical to what is observed after mitochondrial stress.

*Culled from ScienceDaily