The findings from the Bruneck study mesh with those of another study led by Miranka Wirth and Agnes Flöel of the German Center for Neurodegenerative Diseases in Dresden and Greifswald (Schwarz et al., 2020). Within a cohort of 160 participants aged 60–90, including 108 with subjective cognitive complaints, these researchers found that dietary spermidine intake was tied to hippocampal volume and cortical thickness. Adherence to a Mediterranean diet also correlated with these structural features of brain health, and the researchers reported that spermidine intake substantially contributed to this association.

A recent Japanese study used a more pungent vehicle to deliver dietary spermidine. Natto is a traditional Japanese breakfast staple made of fermented soybeans. An acquired taste, it nonetheless oozes with spermidine. Curiously though, this study found that blood levels of spermine, not spermidine, gradually rose in people who noshed on natto every day. This rise, possibly due to conversion of spermidine to spermine in the body, correlated with reduced markers of inflammation in circulating monocytes, suggesting the polyamines had an anti-inflammatory effect (Soda et al., 2021).

Flöel and colleagues are testing spermidine supplements in clinical trials for cognitive aging. After a small pilot study hinted that 1 mg spermidine daily gave adults with subjective cognitive decline a slight advantage in memory performance over those taking placebo, the researchers began the SmartAge study (Wirth et al., 2018). This Phase 2b trial will evaluate how one year of 2 mg/day of spermidine supplementation affects memory in cognitively healthy older adults with subjective memory complaints (clinical trials.gov; clinical trials.gov; Wirth et al., 2019). Estimates of dietary spermidine intake around the world range from 5 mg to 12 mg per day (Buyukuslu et al., 2014; Nishibori et al., 2007; Zoumas-Morse et al., 2007).

Despite the paucity of clinical trial data, spermidine is already being marketed to the public. Longevity Labs+, an Austrian company founded by Madeo, sells a month’s supply of wheat germ extract capsules on Amazon for $98. Each contain 0.5 mg spermidine. Wheat germ itself is available in most health food stores, and a few slices of aged cheddar cheese (10 g) or an extra helping of broccoli (60 g) each contain about 2 mg spermidine (Atiya Ali et al., 2011). Though dietary sources of polyamines differ markedly by region, many choices exist, as polyamine-rich foods include soybeans, mushrooms, green peas, eggplant, and citrus fruits.

Even if this new data suggest that enhancing mitochondrial function with spermidine could stave off age-related cognitive decline, what about neurodegenerative disease? “These data raise the question whether spermidine supplementation may be a promising approach in the course of treating Alzheimer's disease (AD),” wrote Marina Jendrach, Kiara Freitag, and Frank Heppner of Charité University in Berlin in a joint comment to Alzforum. They have uploaded a manuscript on bioRxiv that suggests spermidine promoted clearance of neurotoxic Aβ species and dampened neuroinflammation in a mouse model of amyloidosis (see Part 2 of this series).