Zullo JM, Drake D, Aron L, O'Hern P, Dhamne SC, Davidsohn N, Mao CA, Klein WH, Rotenberg A, Bennett DA, Church GM, Colaiácovo MP, Yankner BA. Regulation of lifespan by neural excitation and REST. Nature. 2019 Oct;574(7778):359-364. Epub 2019 Oct 16 PubMed.

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  1. The need to understand drivers of healthy aging is critically important for today’s society, one that invests heavily in promoting longevity but continues to be burdened by age-associated impairments. In their recent paper, Zullo, Drake, and colleagues show that neural excitation increases with age in C. elegans, and that neural inhibition in turn increases mean lifespan of the worm population. The authors use a multidisciplinary approach, combining C. elegans genetics and pharmacology along with a rich human transcriptomic dataset, to robustly link neural excitation to longevity.

    Extending lifespan by altering a cellular feature specifically in neurons is an impressive feat that points to the importance of brain health for an organism’s overall health. This work suggests that promoting the health of inhibitory cells during aging might be therapeutically beneficial and therefore an interesting target for future translational research. Additionally, the authors further elucidate a line of work initiated in Bruce Yankner’s lab identifying the transcription factor REST as an anti-aging factor (Lu et al., 2014). They again use a combinatorial approach to show that REST expression bidirectionally regulates excitation and lifespan in C. elegans, and that REST-deficiency is sufficient to reduce the lifespan of the well-known long-lived daf-2 mutant (Kenyon et al., 1993). We are very excited to follow this research to see if neuronal REST also promotes longevity in mammalian species. Ultimately, this work nicely points to an additional longevity factor that may be relevant to humans.

    Scarlett Jazmine Barker of MIT is a co-author of this comment.

    References:

    Lu T, Aron L, Zullo J, Pan Y, Kim H, Chen Y, Yang TH, Kim HM, Drake D, Liu XS, Bennett DA, Colaiácovo MP, Yankner BA. REST and stress resistance in ageing and Alzheimer's disease. Nature. 2014 Mar 27;507(7493):448-54. Epub 2014 Mar 19 PubMed.

    Kenyon C, Chang J, Gensch E, Rudner A, Tabtiang R. A C. elegans mutant that lives twice as long as wild type. Nature. 1993 Dec 2;366(6454):461-4. PubMed.

    View all comments by Li-Huei Tsai

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