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. These observations led to the idea that reducing cellular energy production could slow the aging process and make organisms live longer.

Puzzlingly, these energy restrictions had to occur during a specific window of development in order to affect the aging process, suggesting the existence of a critical metabolic switch that could remodel cellular functions throughout the organism´s entire lifespan. The mechanisms of how these changes were sensed and perpetuated, however, remained elusive, though researchers have focused their search on the power factory of the cell, the mitochondria.

Malfunctioning mitochondria have been reported as a cause or a consequence of nearly every single age-onset human disease, including Alzheimer's and Parkinson's disease, heart disease, type 2 diabetes and cancer. When mitochondrial function is shut down during a specific period of development in model organisms, the animals live longer. These transient metabolic changes appear capable of restructuring the way our cells read our DNA, shutting down the use of some genes, while amplifying the expression of others - ultimately affecting health into adulthood.

Researchers found that mitochondrial stress activates enzymes in the brain that affect DNA folding, exposing a segment of DNA that contains the 1,500 genes involved in the work of the mitochondria. A second set of enzymes then tags these genes, affecting their activation for much or all of the lifetime of the animal and causing permanent changes in how the mitochondria generates energy.

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. Researchers artificially increased production of the demethylases in worms and found that all lived longer, a result identical to what is observed after mitochondrial stress.

"By changing the epigenetic state, these enzymes are able to switch genes on and off," author said. This happens only in the brain of the worm, however, in areas that sense hunger or satiety.

"These genes are expressed in neurons that are sensing the nutritional status of the animal, and these signals emanate out to the periphery to change peripheral metabolism," author said.

When they profiled enzymes in short- and long-lived mice, they found up-regulation of these genes in the brains of long-lived mice, but not in other tissues or in the brains of short-lived mice.

"These genes are expressed in the hypothalamus, exactly where, when you eat, the signals are generated that tell you that you are full. And when you are hungry, signals in that region tell you to go and eat," author said. "These genes are all involved in peripheral feedback. "

Among the mitochondrial genes activated by these enzymes are those involved in the body's response to proteins that unfold, which is a sign of stress. Increased activity of the proteins that refold other proteins is another hallmark of longer life.

These observations suggest that the reversal of aging by epigenetic enzymes could also take place in humans.

http://www.cell.com/cell/fulltext/S0092-8674(16)30403-2