Preserving Mitochondrial and Cognitive Function During Aging: The Role of Spermidine-Induced Hypusination

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- Updated by Jody Mullis

  • Dietary spermidine has been attributed with beneficial effects on the heart, brain, life, and health in general.
  • Hypusination of ElF5A controls spermidine-induced autophagy.
  • Dietary spermidine increases the hypusination levels in different areas of the mouse's brain and in brains of spermidine-treated flies.
  • Spermidine feeding influenced the neuronal tissue markedly, changing proteomes and increasing mitochondrial proteins.
  • It was observed that, with age, the levels of spermidine and mitochondrial respiration decrease in brain tissues which can be partially countered with spermidine-feeding.
  • With spermidine supplementation, aged male mice registered better performance in spatial learning tasks, revealing a sex-specific difference.
  • An inverse correlation was observed between spermidine intake levels and cognitive impairment in humans.
  • Further research is required to understand the complete mechanism of how spermidine influences mitochondrial respiration and cognitive function and how spermidine is taken up by different cell types

Spermidine Study 2021


Published online in June 2021, the study suggested the impactful role of dietary spermidine in preserving mitochondrial and cognitive functions during aging.

Over the years, dietary spermidine has been broadly respected for its profound physiological effects laced with cardioprotective, neuroprotective, and life-promoting properties. However, it has been observed that the effects of spermidine supplementation vary with tissue type and experimental model. As of recently, the posttranslational modification Hypusination of ElF5A (eukaryotic translation initiation factor 5A) made headlines for its central role in controlling spermidine-induced autophagy.

In the study, spermidine, when added in drinking water, was found to reach different areas of the mouse's brain. This spermidine supplementation led to a notable increase in hypusination levels in the hippocampi of aged mice and in the brains of spermidine-treated flies. This result brought into play the possibility of other biological players in the spermidine-induced effects, especially concerning brain aging.

Spermidine feeding reflected a sizable molecular impact on the neuronal tissue with major changes in the proteomes of aged mouse brains and increased mitochondrial proteins in the proteomic landscape of spermidine-fed fly brains. The in-depth analysis suggested the hypusination's potential role in synthesizing specific subsets of the mitochondrial proteins.

As one ages, a noticeable decline in spermidine levels is observed along with a dwindling of mitochondrial respiration, an effect seen in both mouse and fly brains. Compellingly, the study found that these age-associated decreases in both hypusination and mitochondrial function can see some reversal with spermidine-feeding.

Further research laid bare the interconnected relationship; dietary spermidine levels enhance eEF5/EIF5A-hypusination, which, in turn, elevates the mitochondrial function. But the chronological sequence of the causative factors, the possible involvement of intermediatory transcription factors, or other mediators are questions yet to be resolved.

Mitochondrial function and abundance play a very significant role in maintaining proper synaptic function and has been known to foster an improvement in the cognitive capacity of aged flies by spermidine-mediated autophagy.

Surprisingly, a sex-specific difference was observed when aged male (but not female) mice supplemented with spermidine displayed better performance in spatial learning tasks. What causes this gender discrepancy in performance suggests a new course for further research, whether it involves testing for different dosing requirements or an inherent performance difference between genders.

A significant inverse correlation between spermidine intake levels and cognitive impairment was observed in humans in the Bruneck study conducted between 1995 and 2000.

Despite all these observations, many steps remain elusive in deciphering the full effect of dietary spermidine. The intricacies how increased mitochondrial respiration influences cognitive function, or what sequence the molecular events take place, and understanding how spermidine feeds into the intracellular polyamine pathway call for further study.

The study can be found here.