In worms, a low-oxygen alarm in a few brain cells is enough to lengthen life

When oxygen runs low, cells switch on an emergency program called the hypoxic response. Its master switch is a protein called HIF-1. Normally another protein, VHL-1, tags HIF-1 for destruction as soon as it is made; when oxygen is scarce, HIF-1 survives and turns on genes that help cells cope.

In the tiny roundworm C. elegans, a favourite animal for aging research because it lives only a few weeks, keeping this switch on lengthens life. But in mammals the same program has a dark side: faults in it are linked to cancer and heart disease. So simply turning it on everywhere is not an option. The team behind this study, published in the journal eLife, wanted to find out exactly which cells and signals carry the life-lengthening part, in the hope of one day targeting only that part.

Earlier work by the same group had shown that HIF-1 acting in nerve cells that use the messenger serotonin can lengthen worm life, and that the signal ends in the gut, where it switches on a gene called fmo-2.

What they did

The researchers bred worms in which HIF-1 could not be broken down, but only in one type of serotonin-making nerve cell at a time. In other worms they turned off VHL-1, which lengthens life, and then asked which cells and chemicals had to be present for that to work. They did this by removing the ability of single cell types to make a messenger, by killing specific nerve cells, by blocking receptors, and by putting genes back into only one cell type. As a quick read-out they also measured how strongly the gut gene fmo-2 came on.

What they found

• A few nerve cells are enough. Keeping HIF-1 active only in one type of serotonin cell, called ADF, lengthened lifespan by 26%; in another type, NSM, by 23%; in a third type by 9%.
• One cell type is essential. When worms could make serotonin only in their ADF cells, turning off VHL-1 still lengthened life; when ADF cells could not make it, the gain was lost.
• A relay of messengers. The serotonin signal is picked up by a single nerve cell called RIS, which uses the messenger GABA. Worms also needed tyramine (the worm's version of adrenaline), made in a nerve cell called RIM, and a little-known signalling protein called NLP-17. Without any of these, the lifespan gain shrank or disappeared.
• Oxygen sensors are part of it. Killing the worm's oxygen- and carbon-dioxide-sensing nerve cells also blocked the effect, even when HIF-1 was kept active in the ADF cells.
• Healthier movement, in part. HIF-1 in the NSM cells, but not the ADF cells, prevented the drop in feeding and swimming movements seen in older worms that lacked HIF-1.

What to keep in mind

• Worms, not people. The work was done entirely in roundworms. Whether a similar circuit exists in mammals, and whether it could be targeted safely, is unknown.
• Genetic tricks, not real low oxygen. The authors note that turning off VHL-1 does not mimic low oxygen exactly: HIF-1 ends up in a slightly different chemical state, which can change which genes it turns on.
• The order of the relay is partly guessed. The team shows which signals are needed, but the order in which they act is mostly predicted from the worm's wiring diagram. Whether tyramine and NLP-17 act before, after or alongside the serotonin cells remains unclear.
• Some steps are less well tested. The role of the RIM cell was shown only by putting tyramine back in that cell, not by removing it there, and some results rest on gene knock-down methods that were not all confirmed with full gene knock-outs. Cell-specific tricks can also leak into neighbouring cells.
• No drug yet. The authors point out that no longevity treatment currently targets the hypoxic response.

Why it matters

Many ways of lengthening life in the lab, such as eating less or mild stress, seem to work partly through the nervous system, which senses trouble and tells the rest of the body to prepare. This study maps one such alarm line in unusual detail, from a handful of nerve cells to the gut. The authors hope that knowing the individual links could one day point to drug targets that capture the benefits of the low-oxygen response without its risks. That is a long road, and for now the finding is about how aging is controlled in a worm.