ABOVE: A spoon filled with spermidine-rich wheat germ

Feeding the organic compound spermidine to mice and fruit flies boosted mitochondrial activity in the animals’ brains and, with it, their cognitive ability, according to a paper in Cell Reports published April 13. The study also intimates a similar spermidine-linked cognition boost applies to humans.

“Overall, I think that spermidine is probably one of the most promising molecules for aging research in general . . .  and here they focus on cognition,” says gerontologist Valter Longo of the University of Southern California who was not involved in the work. The most convincing data are from flies and mice, he says, because the human data are only correlative. But, he adds, “the good news is that if you have a spermidine-rich diet, it seems to be a good one. It’s certainly not bad for you” in terms of cognition....

Spermidine is a natural compound present in a wide range of foods, such as wheat germ and aged cheese, though it was originally identified in semen. The compound promotes autophagy—a sort of cellular self-cleaning process—and levels of both spermidine and autophagy appear to diminish in the body’s cells as animals, including humans, age.

Prior studies on lab animals have shown all manner of benefits from spermidine, from an increase in longevity to fortification of heart and immune cells to preservation of memory in old age.

“Other groups have investigated the effects of spermidine injections . . . on behavioural and cognitive phenotypes, but we wanted to increase translatability for future applications and therefore concentrated on a dietary approach,” study coauthors Frank Madeo and Stephan Sigrist write in an email to The Scientist. Both Madeo, who studies aging at the University of Graz in Austria, and Sigrist, a neuroscientist at Freie University in Germany, have equity stakes in The Longevity Labs, a company that sells spermidine supplements.

Madeo and Sigrist have already been involved in a pilot clinical study in which dietary spermidine was given daily to 14 older individuals for three months. The results of that placebo-controlled trial indicated a slight improvement in memory in the group taking spermidine. The researchers’ new work lends support to those preliminary trial results and dives into the physiological as well as cognitive effects of the compound.

For example, in addition to showing that old mice given spermidine in their drinking water for six months performed better than control mice did in learning and memory tests (associating a light stimulus with access to a reward, and remembering the location of a platform submerged in water), the team observed that the compound crosses the blood-brain barrier and steadily accumulates in the brain over a period of weeks. In the animals’ hippocampi—a brain region associated with learning and memory—the team found that the compound boosted cellular respiration, essentially increasing the brain cells’ energy levels, and promoted the modification of a protein called eIF5A, a translation factor that drives the production of a master autophagy regulator.

Compared with controls, spermidine-fed flies similarly displayed improved memory and higher brain cell respiration, both of which were dependent on autophagy, the team showed. And the treated insects exhibited the eIF5A modification, which Madeo and Sigrist’s team describe in detail in a second Cell Reports paper, also published this week. The modification, known as hypusination, involves the addition of hypusine, an uncommon amino acid—so uncommon, in fact, that eIF5A is the only known protein to contain it.

“It’s quite convincing that they can show the same thing in mice and flies,” says immunologist Katja Simon of the University of Oxford who was not involved in the study. As for the hypusination of eIF5A, which Simon’s team had previously reported drives immune cell rejuvenation in spermidine-fed mice, she adds, “It was pleasing to see that they could see that in the brain [too].” Simon is a paid consultant for Oxford Healthspan, a company that sells a spermidine dietary supplement, but has no financial stake in the company.

In addition to the mouse and fly studies, the team also examined human epidemiological data. They examined cognitive test scores and dietary records of more than 800 older adults, calculating the participants’ spermidine intake from diet questionnaires. After five years from the study’s baseline (1990), estimated spermidine intake positively correlated with cognitive test scores, with higher intakes also reducing the chance of developing cognitive impairment.

Altogether, the work indicates that dietary spermidine may support improved cognition later in life and, says Longo, points to a need for larger-scale clinical studies to investigate spermidine’s effects on cognitive decline.

Although decisive clinical proof for spermidine’s cognitive benefits are lacking, Oxford Healthspan and The Longevity Labs sell spermidine supplements for around $100 for a month’s supply. High levels of this molecule can also be acquired rather more cheaply by eating wheat germ, mature cheddar, soybeans, mushrooms, and other foods in which it is abundant.

S. Schroeder et al., “Dietary spermidine improves cognitive function,” Cell Rep, doi:10.1016/j.celrep.2021.108985, 2021.

YT. Liang et al., “eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction,” Cell Rep, doi:10.1016/j.celrep.2021.108941, 2021.

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