Neural Activity Levels and REST Regulate Longevity
Post by Sarah Hill
What's the science?
The global population is aging, with the number of adults over 80 years of age expected to triple by 2050. Consequently, the prevalence of aging-related neurological diseases such as dementia is predicted to increase in years to come. To this end, determining the biological mechanisms that mediate healthy aging is a key objective for many researchers. Past research has shown clear gene expression differences in the brains of aged individuals compared to those that are younger. However, whether activity levels in the brain affect the aging process is unknown. This week in Nature, Zullo and colleagues identify key neurobiological processes that regulate aging and longevity, demonstrating for the first time that neural activity levels influence lifespan.
How did they do it?
The authors carried out three major investigations to identify the neurobiological processes that govern longevity. In the first investigation, they analyzed gene expression datasets from three different human sample cohorts to characterize gene expression differences in the brains of aged individuals compared to younger adults. Finding that many of the differentially expressed genes associated with longevity (defined as >85 years of age) were related to neural excitation, they subsequently tested how neural activity levels affect aging using the worm Caenorhabditis elegans (C. elegans) as a model organism. In this investigation, they either boosted or suppressed neuronal activity through chemical and genetic manipulation and recorded resultant neural excitation levels through calcium imaging, allowing them to identify the specific populations of neurons responsible for longevity. In a third investigation, they shifted focus to the processes regulating differential gene expression in advanced age. Having previously found that REST, an inhibitor of gene expression in mammals, is upregulated in the aged brain, they investigated whether this regulatory transcription factor directs neural activity levels. First, they looked at whether REST was associated with any of the differentially expressed genes in the human sample cohorts. They then examined whether the C. elegans REST orthologs SPR-3 and SPR-4 regulate longevity and neural activity levels by comparing lifespans and evaluating gene expression in normal worms versus those lacking either or both of the SPR-3 and SPR-4 genes. Finally, they carried out calcium imaging of SPR-3/-4 mutant worms to confirm whether SPR-3 and SPR-4 regulate neural excitation.
What did they find?
Analysis of the human gene expression datasets revealed an association between longevity and reduced expression of genes related to neural excitation and synaptic function, suggesting diminished excitatory neurotransmission is a feature of longevity. Indeed, manipulation and calcium imaging of neural activity levels in C. elegans confirmed that suppression of neural excitation lengthens lifespan, while neural overexcitation shortens lifespan. Specifically, inhibition of glutamatergic and cholinergic neurons, both of which are excitatory neuronal cell types, led to extended lifespan in the worms. When looking at whether REST is involved in dampening neural excitation and regulating longevity, the authors found negative associations between the gene expression repressor and many of the differentially expressed genes in the aged human subjects, suggesting that as REST is upregulated in the brain during aging, and genes related to neural excitation are selectively downregulated. This was validated in the worm model, in which the REST orthologs SPR-3 and SPR-4 were found to specifically downregulate the expression of neuronal genes associated with neural excitation and synaptic function. Interestingly, genetic manipulation of SPR-3 and SPR-4 expression in neurons was associated with dramatic differences in worm lifespans, with SPR-3/-4 affecting the insulin/IGF signaling pathway and activating an additional regulator of gene expression, DAF-16, to extend longevity. Finally, calcium imaging of SPR-3/-4 mutants demonstrated that both the C. elegans REST orthologs contribute to inhibition of neural excitation, a key feature of extended longevity.
What's the impact?
This is the first study to show that brain activity levels influence aging and lifespan in worms. Given the expected increase in population aging, identification of the neurobiological processes governing longevity is critical for developing interventions to promote healthy aging and extend lifespan. Findings from this study may thus be an important step in this effort.
Zullo et al. Regulation of lifespan by neural excitation and REST. Nature (2019). Access the original scientific publication here.