The mechanisms that extend lifespan in humans are poorly understood. Studies in invertebrate and mammalian models suggest that the nervous system plays a role in the regulation of ageing. In the nematode C. elegans, ablation of specific sensory or neurosecretory neurons alters lifespan, and lifespan extension from reduced insulin/IGF-like signalling can be reversed by restoring function specifically in neurons.
Methods
C. elegans motility assay. Worms were treated for 24 h with the indicated drugs, and then 150 worms were transferred to 1.5 ml liquid nematode growth medium (NGM; 1 mM MgCl2, 1 mM CaCl2, 200 mM KH2PO4, 50 mM NaCl) and washed once to remove bacterial clumps. Worms were transferred in 100-μl volumes to a 96 u-shaped-well plate, and assayed in the WMicrotracker device.
Results
Calcium influx in ASH neurons increased during normal ageing from adult day 1–2 to day 12–16. To determine the effect of decreasing calcium influx on lifespan, worms were treated with nemadipine, an inhibitor of L-type calcium channels that reduces neural excitation. Continuous treatment with nemadipine beginning at adult day 1 extended lifespan. Moreover, incubation of worms with ivermectin, an agonist of invertebrate glutamate-gated chloride channels, suppressed neural excitation and resulted in a dose-dependent extension of mean lifespan. Nemadipine and ivermectin also extended lifespan when administered at day 8, when feeding activity has largely abated (Extended Data Fig. 2a), suggesting that the drugs do not act through caloric restriction. Furthermore, worm motility was preserved (Extended Data Fig. 2b). These results suggest that global inhibition of neural excitation extends lifespan in C. elegans.
Nature. 2019 Oct;574(7778):359-364. doi: 10.1038/s41586-019-1647-8. Epub 2019 Oct 16.
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.