Spermidine Supplementation and Cognition in Older Adults: A Clinical Trial

Aging is often accompanied by cognitive decline, and researchers are exploring potential interventions to preserve memory function. In their study, Effects of Spermidine Supplementation on Cognition and Biomarkers in Older Adults With Subjective Cognitive Decline: A Randomized Clinical Trial, Schwarz et al. investigated whether spermidine, a naturally occurring polyamine known for its role in cellular maintenance and autophagy, could improve memory performance in older adults with subjective cognitive decline (SCD). Previous research suggested that spermidine supplementation might enhance brain health, but long-term effects in humans remained unclear. This 12-month, randomized, placebo-controlled trial aimed to assess the impact of spermidine on memory, neuropsychological function, and biomarkers associated with cognitive health.

As people age, memory, and cognitive function tend to decline, and conditions like Alzheimer’s disease become a growing concern. Scientists are actively looking for ways to slow down memory loss and improve brain health in older adults. One promising area of research involves spermidine, a naturally occurring compound found in foods like wheat germ, mushrooms, and aged cheese.

Spermidine is known to support autophagy, the body’s natural process of cleaning out damaged cells and maintaining cellular health. Animal studies have shown that spermidine can enhance memory and protect brain function. A smaller human study even suggested that short-term spermidine supplementation might improve memory performance in older adults with subjective cognitive decline (SCD)—a condition where individuals feel their memory is worsening, even though standard tests don’t always detect major issues.

This study aimed to determine whether 12 months of spermidine supplementation could provide long-term cognitive benefits in older adults with SCD. The researchers wanted to see if taking a daily spermidine-rich supplement could improve memory performance and influence biological markers related to brain health.

This study was a randomized, double-masked, placebo-controlled trial—meaning neither the participants nor the researchers knew who received the active supplement or the placebo. Conducted at an academic research center in Germany, the study followed 100 participants aged 60 to 90 who had reported subjective cognitive decline.

Participants were randomly assigned to one of two groups:

• One group received a spermidine-rich wheat germ supplement (0.9 mg of spermidine per day).
• The other group received a placebo (microcrystalline cellulose).

The primary goal was to measure changes in memory performance over 12 months using a test called the Mnemonic Similarity Task (MST), which evaluates how well a person can distinguish between similar-looking objects.

Secondary outcomes included other cognitive tests, behavioral assessments, and physiological measures such as inflammation markers and vascular health indicators. Researchers also monitored safety by tracking adverse events (AEs) and serious adverse events (SAEs) throughout the study.

After 12 months, the results showed no significant difference in memory performance between the spermidine and placebo groups. The mnemonic discrimination performance score change was nearly identical for both groups:

“The adjusted mean change of mnemonic discrimination performance from baseline to postintervention assessment was −0.02 in the spermidine group and 0.01 in the placebo group.”

This means that participants who took the spermidine supplement did not show noticeable improvement in their ability to distinguish between similar objects compared to those who took a placebo. Since the Mnemonic Similarity Task (MST) is designed to detect subtle memory changes, these results suggest that spermidine at the tested dose and duration does not significantly enhance memory function in older adults with subjective cognitive decline.

Similarly, secondary neuropsychological and behavioral tests showed no substantial differences between the two groups. These included assessments of executive function, attention, sensorimotor speed, and quality of life. Behavioral measures, such as lifestyle and psychological well-being, were also unaffected.

However, when researchers conducted additional exploratory analyses, they found two interesting results that suggest spermidine might still have some benefits.

Participants in the spermidine group showed reduced soluble intercellular adhesion molecule-1 (sICAM-1) levels, which are linked to inflammation and blood vessel health. Since chronic inflammation is a key factor in aging and neurodegenerative diseases, this could indicate a potential protective role of spermidine.

“The adjusted mean change of sICAM-1 concentration in peripheral blood from baseline to 12-month postintervention assessment was −30.5 ng/mL in the spermidine group and 25.7 ng/mL in the placebo group, resulting in an adjusted intervention effect of −56.2 ng/mL.”

This suggests that spermidine supplementation may reduce inflammation-related vascular injury, which is a known contributor to cognitive decline.

Some participants in the spermidine group showed slight gains in verbal learning and recall tests, particularly those older or who had a higher dietary intake of spermidine before the study. However, these findings were not statistically significant, meaning they could have occurred by chance.

“Subgroup analyses showed effects of the intervention on memory performance and executive function/processing speed in individuals aged 70 years and older, in men, in individuals with higher baseline dietary spermidine intake, and in individuals with more severe subjective cognitive complaints.”

Although these findings do not provide strong evidence that spermidine directly enhances memory, they suggest that certain groups of people might benefit more than others. Future studies could investigate whether higher doses or longer supplementation periods might lead to greater effects, especially in individuals with higher inflammation levels or more noticeable cognitive decline.

The study found that spermidine supplementation was well tolerated, with no significant differences in adverse events (AEs) or serious adverse events (SAEs) between the supplement and placebo groups. Most side effects were mild and related to age-related conditions, such as joint pain or arthritis, rather than the supplement itself.

“During the 12-month intervention time, 19 SAEs were documented among all participants, 7 in the spermidine group and 12 in the placebo group. All SAEs were rated as not related to the intervention and mild to severe in intensity.”

While this study did not confirm a clear cognitive benefit, it provided valuable insights into spermidine’s potential anti-inflammatory properties and long-term safety in older adults. Future research will be needed to determine whether different doses, longer treatment periods, or specific subgroups of people might experience stronger effects.

These findings suggest that taking a daily spermidine supplement for 12 months does not significantly improve memory in older adults with subjective cognitive decline. While spermidine has shown promise in animal studies and short-term human trials, this longer-term study did not find strong evidence of cognitive benefits.

However, the potential anti-inflammatory effects are intriguing. Chronic inflammation is linked to many age-related diseases, including Alzheimer’s, so future studies could explore whether spermidine might have long-term protective effects against cognitive decline. The study authors also noted that a higher dosage or a longer intervention period might be needed to see measurable benefits.

“Positive results from per-protocol and subgroup analyses regarding memory function and anti-inflammatory actions, combined with the excellent safety profile of the supplementation, endorse future trials with higher dosage.”

While this study did not find a direct memory-boosting effect from spermidine supplements, it did highlight potential anti-inflammatory benefits that could be important for long-term brain health. The results suggest that spermidine is safe for older adults and may still prevent cognitive decline, especially if taken at higher doses or for extended periods.

More research is needed to fully understand how spermidine affects brain function, but this study contributes valuable insights into its potential and limitations. For now, a healthy diet rich in natural sources of spermidine—such as whole grains, mushrooms, and aged cheese—may still be a good strategy for overall well-being. Future studies will help determine whether spermidine can be an effective tool in the fight against age-related memory loss.