Annual Report 2020

A New Simons Collaboration Probes How the Brain Ages

Life Sciences

The African turquoise killifish is unusual for a vertebrate, especially among those typically found in research labs. All told, it lives about six months, a life cycle adapted to the ephemeral ponds of Zimbabwe and Mozambique. Ironically, their short life span makes these fish ideal candidates with which to study the science of aging: Their life stages appear predictably and rapidly and, as research on aging progresses, will eventually permit quick evaluation of genetic and other interventions.

Bérénice Benayoun knows this. As a postdoctoral researcher with Anne Brunet at Stanford University, Benayoun helped piece together the killifish genome and then edit it to recapitulate known hallmarks of aging-related disorders. Now a Simons Collaboration on Plasticity and the Aging Brain (SCPAB) investigator and a researcher at the University of Southern California, Benayoun continues to collaborate with Brunet to manipulate other under-studied molecular pathways, to understand how they control aging processes including cognitive decline. Given that the world’s population of people 65 and older will double in the next few decades, these questions are increasingly relevant.

The killifish is just one of a handful of organisms used to study aging. Coleen Murphy, a Princeton University professor of molecular biology and genomics and director of the SCPAB, has long been interested in using the tiny Caenorhabditis elegans roundworm to understand why and how we age. Her team is working to untangle multiple molecular pathways underlying aging, including those involving CREB (cAMP response element-binding protein), a transcription factor involved in neural plasticity whose abundance declines with age in both worms and humans. In 2019, Murphy’s team showed that they could manipulate the CREB pathway to rescue the ability of old worms to learn and remember. 

Driven by the goal of understanding the aging brain, the SCPAB has so far pledged support to 21 investigators to search for mechanisms underlying aging and investigate whether they can be slowed or reversed. The SCPAB was begun with the belief that cognitive decline and aging are worth understanding per se, as well as for their connections to neurodegenerative disorders. All animals age, and though there is plenty of research on conditions such as Alzheimer’s disease, much less is known about the ‘normal’ aging process that most of us will experience. SCPAB funding is distributed across seven projects, each tackling the question of aging from a different angle. Groups are investigating aging at the genetic, molecular, systems and behavioral levels — and in different species. 

All of the projects rely on animal models that have been underutilized in aging research thus far. Although research on different animal models has thrived, until the SCPAB collaboration, studies were usually performed without reference to one another. “We all knew of each other’s work, but there was never an opportunity for us to work together,” Benayoun says. “Simons funding gave us a platform and a common project to work on.” 

Most of the SCPAB projects require expertise across multiple domains. For example, one project focuses on the role of bloodborne factors shown to affect aging processes. To fully understand these mechanisms, the SCPAB team will use multiple approaches: proteomics and RNA sequencing to understand which proteins can cross from blood into the brain, high-resolution imaging to understand structural changes caused in blood vessels, and behavioral assays to assess how these bloodborne factors alter cognition. Injecting such bloodborne factors may be a viable way to extend our healthy, cognitively active years.

A common goal across SCPAB projects is to find similarities and differences across species, beginning with defining what should be considered “old” for each organism. “We want to understand the molecular changes that take place with age in the brains of all these organisms — and which changes are conserved in different species and which are unique,” Murphy says. 

“It’s not going to be enough to say I found one thing that changes with aging,” says Gerald Fischbach, distinguished scientist and fellow at the Simons Foundation, who initiated the SCPAB in 2017. “The question is: Are there common features of aging across species?”

To truly compare results between species, one SCPAB project is dedicated to designing a database that will standardize data collected across all organisms studied, as well as from all SCPAB projects, becoming the first database on aging of its kind. The database will also feature data from humans: initially neuroimaging data from the U.K. Biobank, and later many types of human data from other sources.

Males and females age differently. Benayoun’s team developed a mouse model to study the influence of hormonal regulation on our aging genomes and brains. But as a trained genomicist, she was a fish out of water when attempting to understand what was happening to the brain as these mice aged. Facilitated by SCPAB workshops intended to harmonize the way researchers collect and annotate data, she traded expertise with fellow SCPAB researchers like Dena Dubal, who specializes in neuroscience and behavior. 

Studying the aging process in animals requires studying an organism throughout its life cycle. African killifish are more closely related to humans than other animals with short life cycles, such as fruit flies and nematode worms, while still having only a monthslong life span. Credit: A. Wang et al./Cell 2015

This type of collaborative approach, especially starting from the inception of a project, is truly unprecedented. “With traditional funding mechanisms, you are already about 90 percent done with the project in question when you apply for support — which means that your ability to adjust course is really very limited,” Benayoun says.

Sometimes, this involves getting into the nitty-gritty about what’s working and what’s not — even down to specific experimental time points — ultimately saving each other the time and effort of working out the kinks themselves. “This is not something you’re going to see at a conference,” Benayoun says.

“I’ve rarely been involved in such a collaborative project where people are so committed at such an early stage,” says Fischbach. Importantly, the SCPAB leadership values and listens to everyone on the project, even students and junior investigators. “It’s a true collaboration,” Benayoun says. “It feels very original.” 

Ultimately, the goal of this harmonization is to develop clear insight about why we age and how we might reduce cognitive decline. In Benayoun’s words, “How do we best design what each lab is doing so that we can learn something that transcends what each lab is doing?”

For octogenarian Fischbach, the scientific and humanitarian implications of the SCPAB work have deeply personal importance. He notes that although the present focus is on using simple organisms to test causality, these findings may ultimately lead to genetic or therapeutic interventions in humans. “It’s going to be hard to do such genetic manipulation in higher vertebrates,” he cautions, “but it’s coming.”