A recent study published in Nature uncovered the genetic basis of natural variation in aging rate. This work was carried out by researchers from Dr. CAI Shiqing’s lab at the Institute of Neuroscience and State Key Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences.

Aging is characterized by progressive declines in physiological functions with age and is a major risk factor for neurodegenerative disorders, cancer, and diabetes. Previous studies on aging mainly focus on the regulation of longevity. Over the past three decades, more than 100 genes and numerous small compounds have been identified to regulate lifespan from yeast to mammals. However, recent studies suggest that lifespan extension induced by gene mutations does not necessarily delay the age-related behavioral decline, thus longevity and behavioral aging may be two dissociable processes. With the increase of life expectancy, prevention of age-related functional impairment has emerged as a major medical challenge. However, despite the great advance in understanding the genetic control of animal lifespan, little is known on the mechanism underlying regulation of healthy aging, that is, aging with limited loss of physiological functions.

The rate of aging is highly variable among individuals. It is believed that this variation is governed by environmental and genetic factors. Despite the great interest in studying natural variation in aging rate to identify factors that control healthy aging, no such factor has yet been found. Researchers from Dr. CAI Shiqing’s lab sought to study the genetic origin of variability in the rate of aging using Caenorhabditis elegans as an animal model.

C. elegans is a tiny free-living nematode, about 1 mm in length. Due to its short lifespan and clear genetic background, C. elegans has been widely used in aging research. Many conserved longevity pathways were firstly identified in C. elegans. The researchers found that natural isolates of C elegans from different parts of the world show distinct rates of declines in virility, feeding behavior, and locomotion during aging. They found that genetic variations in a novel neuropeptide coding gene (named rgba-1) and its receptor gene npr-28 regulate aging rate of worm behaviors among wild isolates. RGBA-1 from glial cells activates NPR-28 signaling in serotonergic and dopaminergic neurons to regulate behavioral decline in aging animals. The function of RGBA-1/NPR-28 signaling on behavioral aging depends on the SIR-2.1-mediated activation of mitochondrial unfolded protein response, a pathway known to modulate aging. The researchers also performed population genetic analysis of rgba-1 and npr-28 and found that these two genes might have been subjected to recent selective sweep, a natural selection that leads to the reduction or elimination of genetic variations among individuals.

This study reveals the first genetic pathway underlying natural variation in the rate of aging, and uncovers an important role of neuropeptide-mediated glia-neuron signaling in controling aging rate. Further studies on natural variation in the rate of aging will pave an avenue to comprehensively understand the biological regulation of healthy aging. Antagonistic pleiotropy theory for the evolution of aging proposes that the naturally selected genes promote survival and reproductive success in early life, but accelerate aging in late life. This study suggests that the evolutionary selection of genes that offer benefits in early life could also result in a concomitant extension of lifespan or extension of healthspan, or both. In addition, this study indicates that aging rates may have been affected by emergence of new genes, natural selection, and the interaction between different genetic loci. Thus, this study provides new insights into the evolution theory of aging.

This work entitled “Genetic variation in glia-neuron signalling modulates ageing rate” is now published in Nature on November 9, 2017 as a research article. YIN Jiangan and Gao Ge are co-first authors of this paper. This work was supported by grants from the Chinese Academy of Sciences and the National Natural Science Foundation of China.