18 Oct 2019

Why do some people age better than others? In the October 16 Nature, researchers led by Bruce Yankner at Harvard Medical School once again credit the repressor element 1-silencing transcription factor (REST). People who lived to a ripe old age had much higher levels of REST protein in their neurons when they died than did people who died younger. Boosting expression of a REST ortholog in roundworms quieted neural transmission and extended lifespan, while knocking it down shortened lifespan. Similarly, pharmacologically quenching neural excitability in worms lengthened life, while amping up neural transmission shortened it. “Neural activity may be a player in the regulation of aging. That’s encouraging, because [activity] is very plastic,” Yankner told Alzforum. He is investigating drugs that suppress neural excitation. He believes they might help ward off Alzheimer’s disease as well, because neurons become hyperactive early in this disorder.

Other researchers found the implications intriguing. “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,” Li-Huei Tsai and Scarlett Barker at Massachusetts Institute of Technology, Cambridge, wrote to Alzforum (see comment below). Chris Link at the University of Colorado in Boulder said the worm data are convincing. “Those experiments were particularly elegant,” he told Alzforum. However, Link noted that so far, the human data are merely correlative. More studies will be needed to determine if the same factors affect human aging, he said.

Yankner has long been interested in brain aging. His lab previously reported reduced expression of synaptic plasticity genes in aged human cortex (Jun 2004 news). Now, with a wealth of transcriptomic and aging data available across a wide age range from the Religious Orders Study and Rush Memory and Aging Project (ROSMAP), the Common Mind Consortium, and the Baltimore Longitudinal Study of Aging, the scientists took a fresh look. First authors Joseph Zullo and Derek Drake analyzed gene-expression data from the frontal cortices of 573 participants whose cognitive function was still normal when they died.

In this combined dataset, the authors found two distinct gene-expression profiles, one for people who had died between the ages of 60 and 80 and one for those who had lived longer than 85 years. The longer-lived group expressed lower levels of transcripts involved in excitatory synaptic transmission, such as glutamate receptors, ion channels, and synaptic structural components. Many of these transcripts, it turns out, are regulated by REST. In keeping with this, the more REST a person had in his or her brain, the less the expression of proteins involved in excitatory transmission. In addition, REST levels rose with age. People who lived to be centenarians had almost twice as much in their neuronal nuclei as did those who died in their 70s (see image at right).

Was REST helping drive longevity, or merely a consequence of it? To address this question, the authors turned to C. elegans, a widely used model of aging. These tiny worms normally live only three weeks. First, the researchers examined the relationship of excitatory synaptic transmission with age. They found that glutaminergic neuronal activity ramped up as worms neared the end of their lives. Suppressing this excitatory neuronal activity with a pharmacological agent extended lifespan by a third. Stimulating inhibitory neurons had the same effect, suggesting that the overall level of neural activity was the key factor. The authors next used transgenes to selectively modulate neural activity. Again, silencing excitatory neurons lengthened life, while silencing inhibitory neurons shortened it.

“Increased neuronal activity in the aging brain might reflect an imbalance between excitation and inhibition,” Yankner suggested. It is unclear what relationship this cellular-level imbalance has to higher-order brain functions, such as cognition, anxiety, or behavior.

To find out how REST functions in worm aging, the authors boosted expression of the ortholog, SPR-4, by nearly twofold. This quieted excitatory neurotransmission and kept the worms alive a few days longer. SPR-4’s effects depended on DAF-16, a forkhead transcription factor suppressed by insulin signaling in worms. Insulin signaling shortens worm lifespan while suppressing it increases DAF-16 and extends lifespan. Without DAF-16, SPR-4 did not extend life, demonstrating that the REST ortholog acts through the same pathway as does insulin. Notably, a lack of SPR-4 shortened the life of long-lived DAF-2 mutant worms, which have weak insulin signaling, demonstrating further interaction between metabolism and neural activity (Oct 2003 news; Mar 2008 news). Suppressing neural excitation increased DAF-16 expression, in keeping with excitatory activity reducing lifespan. 

“Insulin signaling and neural activity may be parallel longevity pathways that converge on DAF-16,” Yankner told Alzforum. He believes these findings would hold up in people as well. In mammals, the DAF-16 ortholog is FOXO1. In the cortical brain samples from the three aging cohorts, REST levels correlated with FOXO1, but not with other forkhead transcription factors. In addition, REST and FOXO1 were found together in neuronal nuclei, with their protein levels closely linked.

To further test this relationship in mammals, the authors dampened glutamatergic transmission in cultured mouse primary cortical neurons. This boosted FOXO1 expression, suggesting the transcription factor is regulated by neuronal activity. In addition, the authors found that old REST knockout mice have more epileptiform activity and less FOXO1 than age-matched wild-types.

Still, any association between neural activity and longevity in mammals remains unproven, Link noted. REST and FOXO1 are expressed throughout the body, particularly in the gastrointestinal tract, and so could affect many aspects of physiology. Link said additional experiments in mice will help define REST’s effects and connection to longevity.

For his part, Yankner is interested in how REST might affect Alzheimer’s disease. Previously, his lab identified REST as a neuroprotective factor that shields neurons from oxidative stress and cell death. In postmortem human brain samples riddled with plaques and tangles, people who had high levels of the protein in neuronal nuclei maintained better episodic memory than did those with less of it (Mar 2014 news). More recently, the lab found that a lack of REST depletes neurogenesis in AD brain (Feb 2019 news). In ongoing research, he is testing how drugs that suppress neuronal excitation and REST affect mouse models of amyloidosis.

Others agree this is a fruitful area for research. “REST and other molecules that control neural excitability are possible targets for interventions aimed at battling the decline and maladies of old age,” Nektarios Tavernarakis at the University of Crete School of Medicine in Greece wrote in an accompanying Nature editorial.—Madolyn Bowman Rogers

Comments

1. • Li-Huei Tsai
     Picower Institute of MIT
   • Posted: 18 Oct 2019

   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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References

News Citations

1. After 40, DNA Damage Accrues in Genes, Hampering Expression 11 Jun 2004
2. Pushing Longevity to the Max 24 Oct 2003
3. How Sweet It Is! Longevity Linked to Insulin-like Growth Factor Signaling 6 Mar 2008
4. No REST for Weary Neurons: Protective Factor Stems Cognitive Decline 19 Mar 2014
5. In Alzheimer’s, Too Little REST Spurs Too Much Neurogenesis 4 Feb 2019

Further Reading

News

1. No REST for the Brainy: Human Evolution Linked to Diseases of Aging 25 May 2018
2. The Mutation You Want: It Protects the Brain, Extends Life 31 May 2019
3. Is Klotho’s Partner FGF23 a Cognition Protein? 20 Mar 2019