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Why Does Our Memory Decline as We Age, and Could It Be Reversible?

A Penn State biologist explores the molecular relationship between aging and circadian changes in memory formation
8 June 2022
Janine Kwapis

Of the many ways in which aging affects our bodies, a deteriorating memory is among the most frustrating. Especially when you are expected to remember your login and secure password—upper and lowercase letters, numbers, and symbols—for umpteen different websites and apps! So, what is going on in our brains that makes remembering these types of things harder as we age?

Janine Kwapis, assistant professor of biology, has been interested in memory since her days as an undergraduate student studying psychology. Understanding the molecular mechanisms of memory formation is now the main focus of her lab at Penn State.

“Maybe it’s because I don’t have that good of a short-term memory, but I’ve always been fascinated by memory and how it works,” said Kwapis. “As my career has progressed, I have moved more toward trying to understand memory from a biological perspective. I want to understand the molecular mechanisms of memory formation. Because of the great core facilities, funding opportunities, and support for cross-disciplinary and collaborative research, Penn State is the ideal place to do this kind of research. Since I came to Penn State in 2019, I’ve been really impressed with the Department of Biology and how supportive my colleagues are both in and out of the lab.”

Kwapis recently received a grant from the Glenn Foundation for Medical Research and the American Federation for Aging Research (AFAR) to continue her study in mice of the relationship between age-related memory decline and circadian changes—those that happen across the 24-hour day—in memory.

As a postdoctoral researcher, Kwapis demonstrated that a gene known to be involved in helping to maintain circadian rhythms, called Period1 (Per1), is also involved in memory formation in the hippocampus—a region of the brain important in learning and memory. She further showed that Per1 expression declines with age and that this decline contributes to age-related memory loss.

“Per1 expression oscillates on a daily cycle,” she said. “It is higher during the day and lower at night. This pattern mirrors changes in memory formation across a 24-hour period. Both Per1 expression and memory formation peak during the day and are reduced at night. The age-related reduction in Per1 expression seems to mimic a persistent ‘nighttime state’ of low Per1 levels that limits memory. We now want to try to understand how this is happening on a molecular level.”

One possibility for the role of Per1 in memory formation is that it is involved in circadian control of memory allocation. Kwapis explained that when you learn something new, that information is stored in only a small percentage of the neurons in the hippocampus. Those neurons are allocated to that memory, and when you want to retrieve that information those neurons are activated together. The strength of the connection between those neurons is how the memory is stored.

“We’ve shown that more neurons are allocated to a memory during the day when Per1 levels are at their highest than at night,” said Kwapis. “We now want to know how age-related reduction in Per1 impacts these circadian patterns in memory allocation. To address this, we will measure how memory performance, memory allocation, and Per1 expression fluctuate across the day/night cycle in mice of varying ages. From these experiments, we hope to be able to learn at what age impairment begins.”

So, if age-related reduction in Per1 expression is at least partially responsible for impaired memory, an obvious question arises: Can this process be reversed? Kwapis and her lab will test this by overexpressing Per1 in young and old mice to see if artificially increasing Per1 increases memory performance and memory allocation.

“This research is aimed at understanding the molecular mechanisms that connect the circadian clock to memory,” said Kwapis. “If this works like we think it does, correcting Per1 levels in older individuals could help ameliorate age-related memory loss, and maybe other age-related cognitive impairments. Our research in mice will hopefully allow us to better understand these mechanisms, which are likely to be similar to the mechanisms in humans. Eventually, our findings could have implications for the treatment of a wide range of age-related neuropsychiatric disorders.”

That is still a long way off though, so in the meantime, use a password manager.