Genetic variation in a neuropeptide signalling pathway regulates age-related declines in health in nematode worms. This discovery points to a mechanism that influences individual differences in ageing. See Article p.198
The human genome was published1,2 in 2001, but the DNA sequence of any individual does not exactly match this reference sequence. Each individual genome contains millions of polymorphisms — variable sites that differ from the reference. Much research is dedicated to understanding how polymorphisms influence biological traits, but this remains a formidable challenge, because the underlying genetic basis of traits is typically complex. On page 198, Yin et al.3 add to our understanding of the genetic basis of ageing. The authors report that, in the nematode worm Caenorhabditis elegans, naturally occurring genetic variation in two genes modifies age-related declines in mating and feeding traits. They further show that this variation acts to modulate a signalling pathway that controls neuronal activity.
In classic genetics, genes that regulate traits of interest are identified by screening numerous animals that have been subject to mutation such that each harbours a different genetic change. This approach has long been used in model organisms to identify single, damaging changes that cause inactivation of a gene, regulating biological traits. However, natural trait differences between individuals are more typically influenced by a host of genetic changes, each of which perturbs gene expression or function only slightly. This is probably attributable, at least in part, to evolutionary forces, which purge mutations that have a strong negative effect on evolutionary fitness from the population.
Caenorhabditis elegans is often used for genetic studies of ageing, because it has a lifespan of only about two weeks. Yin et al. set out to study differences in the rate of ageing in wild strains of the worm (a strategy that is comparable to studying naturally occurring differences in individuals in a population). Instead of focusing only on lifespan, the authors measured the rates of age-related decline in traits associated with mating, feeding and locomotion, to examine how healthy the worms remained in later life.
Some of the authors of the current paper had previously demonstrated4 that changes in expression of the enzyme BAS-1 correlate with age-related declines in two traits — mating virility and pumping of the pharynx, which brings food into the intestine from the environment. In the current study, the researchers mapped the genetic variants that modulate BAS-1 expression, and found polymorphisms in a single gene that were responsible for about half of the variation in age-related decline in these two traits between strains. The authors dubbed the gene rgba-1 (regulatory-gene-for-behavioural-ageing-1), and showed that mutations that cause loss of rgba-1 function prevent age-related declines in mating behaviour.
The rgba-1 gene seems to be unique to C. elegans (it is not present in even closely related nematodes), suggesting that it evolved in the C. elegans lineage. Yin et al. showed that the gene encodes four protein fragments called neuropeptides. Neuropeptides can act either as neurotransmitters, which pass signals between neurons, or as slow-acting signalling molecules called neuromodulators that modify neuronal dynamics and neurotransmission5. Through a variety of experiments, the authors identified neuropeptide receptor 28 (NPR-28) as the receptor for one of the rgba-1 neuropeptides, RGBA-1-2b. Although the rgba-1 neuropeptides are specific to C. elegans, NPR-28 is not — it is related to receptors for the human neuropeptides somatostatin and nociceptin. Like NPR-28, the human receptors modulate neuronal function.
Yin and colleagues found that npr-28 also harboured polymorphisms that modified age-related declines in mating in wild strains of worm. Although ageing has been extensively studied in C. elegans, npr-28 and rgba-1 have not been identified as age-associated genes by any classic genetic approach, suggesting that this neuropeptide pathway might be particularly relevant to genetic variation that causes subtle behavioural changes. Indeed, neuropeptide signalling systems have already been shown to have a role in behavioural variation in several settings6,7 — for example, in promoting social-attachment behaviour between mating partners in certain species of vole8.
Because neuromodulators have a major role in regulating the activity of long-range neuronal signalling between brain regions, expression of neuropeptides and their receptors is an important genetic substrate on which evolutionary forces can act to optimize behaviours9. The ageing traits that rgba-1 and npr-28 regulate are not expected to be under evolutionary selection, because they regulate behaviours in older adult animals, after most reproduction has occurred. However, this signalling system probably also regulates behavioural traits in younger animals that are under evolutionary pressure — the ageing-related decline associated with these genes is merely a side effect.
Yin et al. went on to show that one or more of the neuropeptides encoded by rgba-1 is released by glial cells (Fig. 1). These cells were originally identified for their role in providing physical and nutritional support to neurons. However, they can also directly modify neuronal circuits by releasing glial signalling molecules10.
Finally, the authors demonstrated that npr-28 is expressed in neurons that produce the neurotransmitters serotonin and dopamine. When activated by RGBA-1-2b, the receptor represses the activity of a stress response — the mitochondrial unfolded protein response (mtUPR) — that occurs in metabolic organelles called mitochondria.
It is tempting to speculate that the release of rgba-1 neuropeptides is triggered when glia sense age-induced changes in the function or health of the neuronal cells they support. Such a mechanism could link age-dependent deterioration in neuronal function with regulated changes to neuronal circuits. For instance, dopamine signalling declines in ageing humans owing to the death of dopamine-releasing neurons, and it is thought that this decline contributes to neurological symptoms of ageing, including loss of cognitive control and memory11. Perhaps declining dopamine levels are mediated by neuropeptide signalling — increased action of the mtUPR could delay this process. However, the authors did not demonstrate that the mtUPR acts in dopamine-producing neurons, so it is also possible that the activity of dopamine- and serotonin-producing neurons modulates the mtUPR pathway in downstream cells.
Yin and colleagues' paper serves as a valuable mechanistic example of how genetic variation can modify age-dependent decline. A major remaining challenge is to determine whether neuropeptides have a similar role in regulating healthy lifespan in humans. Neuropeptide receptors are members of the G-protein-coupled receptor family, which are often targeted by drugs in the treatment of disease. Focusing on neuropeptide signalling in human ageing could lead to the development of drugs that ameliorate ageing-related declines in health. Although the mechanisms that regulate healthy ageing are likely to involve more than simple neuropeptide signalling, such developments might eventually extend the time each individual spends in a healthy, youthful state.Footnote 1
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Science Signaling (2017)