As we age, memory and other cognitive functions start to decline, even outside the context of Alzheimer’s disease and other types of dementia. A new effort, funded by the Simons Foundation, will search for the molecular mechanisms that underlie these changes and investigate whether they can be slowed or reversed. SCPAB has pledged $42 million over five years.
“People have the idea that cognitive aging is inevitable,” says Coleen Murphy, SCPAB’s director and a scientist at Princeton University. “We want to ask — does it have to happen?”
Most research into brain aging has focused on the changes linked to Alzheimer’s and other neurological diseases. “Aging in the normal brain is like an orphan disease — there is very little NIH or industry money devoted to it,” says Gerald Fischbach, distinguished scientist and fellow at the Simons Foundation, who initiated and developed the program. “And yet it is a huge public health problem.”
In the United States, the number of people ages 65 and older is expected to reach almost 84 million by 2050, almost double the 2012 number. Roughly 10 percent of this group will develop Alzheimer’s disease. But the other 90 percent will also experience significant decline in memory, attention, processing speed and other cognitive functions.
We know that plasticity — the brain’s ability to rewire — declines with age, as do blood flow and the birth of new brain cells. These changes likely contribute to worsening memory and other issues that accompany normal aging. But scientists don’t yet know the molecular mechanisms underlying these changes or whether they can be modified. A central goal of the collaboration will be to characterize the molecular and cellular changes that occur in typical aging and to identify genes that regulate these processes. This will establish a baseline that researchers can then use to test potential interventions.
Aging across species
Researchers will study aging in a range of species, from short-lived worms and fish to longer-lived rodents, nonhuman primates and humans. These organisms share some of the same basic neurological components and show similar changes with age. A protein called CREB, for example, which is essential for plasticity and long-term memory, declines with age and is present in many species from worms to humans.
“Attacking the problem from different angles and in different organisms will get at the heart of the aging brain in a way that has not been done before,” Murphy says. “We want to understand the molecular changes that take place with age in the brain in all of these organisms — which changes are conserved in different species and which are unique.”
Scientists will compare findings in model organisms and in humans to find the most promising molecular targets for slowing age-related cognitive decline. For example, researchers can determine whether a gene whose expression changes with age in worms has a genetic variation linked to brain aging in humans. They can then examine whether modifying that gene in worms, fish or mice reduces cognitive decline. Short-lived animals offer the opportunity to quickly test hypotheses for which molecular mechanisms are essential to cognitive aging and whether they can be modified.
The SCPAB will help unite two fields — neuroscience and longevity research — that have not traditionally interacted much outside of disease research. Most labs have focused either on aging or on brain development and disease, Murphy says. “I think people assume that the same mechanisms regulate aging all over the body, but entirely different mechanisms may be at play in the brain,” she says. “The assumption is that if you slow aging, you will also slow brain aging, but we don’t know if that’s true.”
Blood, sex and sleep
The first round of funding will support 21 investigators working on six projects exploring different aspects of aging in the brain, including bloodborne factors that influence the brain, age-related changes in sleep, and how aging differs between the sexes. For example, previous research in rodents has shown that blood from young animals can enhance brain function in older animals, restoring plasticity and boosting the birth of new blood cells. Researchers have already identified several factors within blood that can trigger these rejuvenating effects, each of which comes from different tissue and operates through different mechanisms. The team is now exploring how each of these factors — some of which act directly in the brain and some outside the brain — affects brain tissue, brain function and blood flow, and how the function of the blood-brain barrier, which regulates what chemicals can enter the brain, changes with age.
Differences in how men and women age may also provide new insight. Women live longer than men worldwide, and in many populations, women show less cognitive decline and lose less brain tissue compared to men over time. Understanding what makes one sex more vulnerable or resilient to aging will reveal novel targets for treatment that could benefit both sexes. One potential source of this discrepancy is genes that lie on the X chromosome. In people with two X chromosomes, one copy of most X-linked genes is silenced, a process known as X-linked inactivation. But some genes escape this silencing, resulting in the presence of two active copies. Researchers will track which genes escape X inactivation in the brain and determine if this changes with age and how it affects cognitive decline.
All the SCPAB projects will contribute to a central database that will bring together data on how gene expression and other factors change with age in different species and different cell types. “The database will allow researchers to easily explore the diverse effects of age,” says Randy Buckner, a scientist at Harvard University and a member of the SCPAB executive committee. Integrating data across species and tissue types will help researchers decide which targets to prioritize in their experiments. The database will be publicly accessible to the broader scientific community.
The SCPAB’s full mission statement is available here.
More information on each of the SCPAB projects is available here.