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Consuming Aspartame Impairs Learning and Memory in Mice

A person ripping open a packet of sweetener.
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First authorized for human consumption by the US Food and Drug Administration (FDA) in 1981, aspartame is used as a sugar alternative in over 5,000 food products. As it is ~200 times sweeter than sucrose, its introduction to the food market was intended to tackle obesity rates and support patients with diabetes by reducing sugar consumption.

While the consumption of non-nutritive sweeteners – including aspartame – continues to rise, so too does the body of scientific work assessing their impact on the human body and long-term safety. Some of these studies are required by regulatory bodies; the European Food Safety Authority (EFSA) is obliged to re-evaluate all food additives that were permitted for use prior to 2009, for example. Others are conducted by laboratories with specific interests relating to sweeteners, like that of Pradeep Bhide, the Jim and Betty Ann Rodgers Eminent Scholar Chair of Developmental Neuroscience in the department of biomedical sciences at Florida State University College of Medicine.

Aspartame intake recommendations

The advised daily intake (ADI) for aspartame is 40 mg/kg of body weight per day.

Bhide’s research is in the field of epigenetics, which explores how modifications to our genetic code can alter how genes are read, transcribed and translated into proteins by our cell’s machinery. Emerging research suggests that such modifications may be passed down to future generations. “Our lab has been interested in examining how environmental exposures influence traits (behavioral, cellular, molecular, etc.) not only in directly exposed individuals but also in their un-exposed descendants. This research falls into a field of biology that examines heritable effects of environmental exposures, often ancestral exposures,” Bhide said in a previous interview with Technology Networks.

Aspartame induced anxiety-like behaviors in mice, which were heritable

Environmental exposures include the foods that we eat as part of our lifestyle. In 2022, Bhide and colleagues published a study that demonstrated anxiety-like behavior in mice, induced by aspartame consumption, is heritable through the paternal line. In behavioral tests, the children and grandchildren of aspartame-exposed mice spent significantly less time in the center of an open-field test, a hallmark of fear and stress in mouse models. Delving into the molecular mechanisms behind this response, RNA sequencing revealed altered gene expression in the amygdala, an area of the brain associated with fear responses. “We believe that aspartame produces a shift in the excitation–inhibition balance, in favor of excitation,” Bhide said.

Bhide and team’s newest study, published in Scientific Reports, questioned whether aspartame consumption affects learning and memory deficits in mice, and whether such effects could also be inherited by future generations.

Aspartame exposure leads to working and spatial memory deficits in mice

For the experiment, mice were divided into three groups: a control group that consumed just water, and two groups that consumed either 7% or 15% of the FDA’s recommended DIA of aspartame in water over a 16-week period. These levels were replicated from Bhide and colleagues’ previous study exploring anxiety.

At 4-, 8- and 12-week intervals, the mice undertook the Y-maze test that assesses spatial working and reference memory. “Aspartame’s effects on working memory were present as early as 4 weeks of exposure and persisted over the entire 12-week duration,” the authors wrote.

After 14 weeks, all groups of mice undertook the Barnes maze, where they learn the location of a “safe” escape box out of 40 possible boxes organized in a circular arena. The control group mice discovered the safe box quickly, while the mice that had consumed aspartame took longer to learn the task. “We’re seeing they use a different strategy, but they do find the escape box,” co-author Deirdre McCarthy, research faculty in the department of biomedical sciences and the Center for Brain Repair, said. “They compensate in some sort of way.”

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“They can function, but they need longer time, or may need extra help,” Bhide added. “The second thing we noticed here, unlike the anxiety (research), this went only one generation.” The effects were only observed in the children of male mice, not the grandchildren, which Bhide stated as further evidence that these “kinds of transmissions” are occurring due to epigenetic changes in the sperm. The exact mechanisms underlying this heritability are not yet clear.

FDA urged to take a closer look at the effects of aspartame

Bhide and colleagues emphasize that the cognitive functions tested in this study are distinct from anxiety behaviors. The findings of the work therefore imply that the effects of aspartame could be more widespread than their previous paper suggested – in mice at least. The data cannot be directly extrapolated to humans, and research investigating such effects on learning and memory in the human brain is currently limited.

Aspartame has already received a fair amount of attention this year, most recently through its classification as “possibly carcinogenic” by the International Agency for Research on Cancer. In July, the FDA released a statement expressing its disagreement with this decision. “Aspartame is one of the most studied food additives in the human food supply. FDA scientists do not have safety concerns when aspartame is used under the approved conditions,” the statement read. “FDA scientists reassess the science about the exposure and safety of a sweetener each time the agency files a food additive petition or a generally recognized as safe notice for that sweetener. We also stay abreast of published literature and the current level of consumer exposure and participate in international scientific and standard-setting activities related to food ingredient safety.”

Based on its findings, the Bhide team suggested that the FDA take a closer “multi-generational” perspective on the effects of aspartame.

Reference: Jones SK, McCarthy DM, Stanwood GD, Schatschneider C, Bhide PG. Learning and memory deficits produced by aspartame are heritable via the paternal lineage. Sci Rep. 2023;13(1):14326. doi: 10.1038/s41598-023-41213-2