Gupta et al. report in this issue that, in Drosophila melanogaster, a dietary supplement of spermidine—a polyamine originally isolated from semen—protects against cognitive aging by acting through the autophagic pathway.
In many species of animals—invertebrates and vertebrates alike—memory performance declines with age1. So-called age-related memory impairment of aversive olfactory memory is seen in Drosophila melanogaster, and this has been used as a model system to study molecular mechanisms of cognitive decline. Previously, polyamines such as spermidine and putrescine have been found to promote lifespan by augmenting autophagy2. Autophagy is a cellular process in which organelles, cellular debris and proteins are degraded3. Gupta et al.4 now link polyamine function to age-related memory function independent of organismal age, and report in this issue of Nature Neuroscience that, in Drosophila, a dietary supplement of spermidine protects against cognitive aging. This observation is remarkable, should future research support the conclusion, in light of studies showing that spermidine administration increases longevity in yeast, flies and worms3, promotes stress resistance5, and even promotes the growth of human hair6. Could spermidine be the magical elixir we all want for a graceful, long life with robust cognitive abilities and a full head of hair?
The investigators used Drosophila because of the experimental rigor they offer for studying aging and memory and because the genes required for most biological processes, including memory formation, are highly conserved between flies and mammals7,8,9. It is fair to say that many discoveries made with fruit flies translate quite well to humans. In their initial assay of polyamines in the heads of young and aged flies, Gupta et al.4 discovered that putrescine and spermidine levels both decreased with age, replicating parallel studies performed in rats and humans10,11. Lacing the flies' food with spermidine restored endogenous levels of these polyamines in aged flies to approximately the levels found in young flies.
This led to the central observation of the report: young flies reared on spermidine-laced food showed the same memory performance as those given normal food when tested in an olfactory classical conditioning assay, but aged flies fed spermidine performed about 30% better than unsupplemented controls when tested immediately after conditioning and nearly twice as well 3 h after conditioning. Although initial experiments used flies that were reared continuously on spermidine-laced food, subsequent experiments revealed that a 10-d feeding period before training of old flies at 30 d of age was sufficient to restore memory performance to near youthful levels. The finding that spermidine administration had no effect on the memory of young flies indicates that the molecular and cellular processes affected by spermidine are functioning at near maximal in young flies. These processes become less efficient with age and, in some ways, spermidine potentiates them.
However, if spermidine simply retards aging and cognitive abilities decline as a result of age, might the effects of spermidine supplements on memory simply be a byproduct of retarding the aging process as a whole? The authors provide several arguments that spermidine has independent effects on cognition and aging, but more research is needed to clarify this issue. One argument Gupta et al.4 make is that spermidine supplementation did not seem to affect all of the behavioral performance measures that one might expect to be compromised with age. For instance, old flies do not climb walls or avoid noxious odors as well as young flies. Spermidine supplementation had no effect on these performance measures, consistent with spermidine affecting cognitive processes independently of general health. A weaker argument that the authors do not explicitly make comes from experiments designed to map where in the nervous system spermidine acts to produce its cognitive effects. The authors transgenically overexpressed the enzyme ornithine decarboxylase, the rate-limiting step for spermidine biosynthesis, in neurons of the mushroom body, an area of the insect brain that is known to mediate the formation of olfactory memories7,8, and found that the memory impairment observed with aging was suppressed. This result maps the cognitive effects of spermidine to the neurons of the mushroom bodies, but with two caveats. First, the promoter used to overexpress ornithine decarboxylase was not specific to the neurons of the mushroom bodies, although it was strongest in these neurons. Second, although spermidine likely acts autonomously in the mushroom body neurons, one cannot rule out a non-autonomous effect of this increased biosynthesis. Nevertheless, if one assumes an autonomous action, then the general anti-aging and anti–cognitive aging effects of spermidine would necessarily map to the same set of cells in which the promoter is active. Overall, however, the data point to the provisional conclusion that spermidine has independent effects on cognition and aging.
How does spermidine act at the level of cells and molecules to promote the retention of cognitive functioning in aged flies? A leading model is that spermidine promotes autophagy, the catabolic process of degrading and recycling dysfunctional macromolecules and organelles to keep the cell healthy and functioning optimally (Fig. 1). This makes some sense. Spermidine has been shown to stimulate autophagy in yeast, flies and worms and to promote longevity3,12. One can easily imagine that cellular debris that accumulates during aging might overwhelm this cellular recycling system and that adding a few more sanitation trucks and recycling centers might keep neurons healthier and better able to serve memory processes.
The authors tested this possibility by assessing the state of autophagy in heads of flies and found that several markers of the autophagy pathway, including the autophagy-related protein Atg8a, decline with age. They then asked whether spermidine would have its normal memory-enhancing effects in aged flies if autophagy were blocked using mutations in genes that encode some of the autophagy machinery, Atg7 and Atg8a. The memory-enhancing effects of spermidine were lost in the mutant flies, consistent with spermidine having effects on memory through this process. Furthermore, the decline in autophagy-related protein levels in normal flies was suppressed by spermidine administration. This suppression could be a consequence of spermidine's effects on chromatin and gene expression, as spermidine has been reported to inhibit histone acetyltransferase activity, which can lead to the upregulation of autophagy-related genes3. Gupta et al.'s findings4 are consistent with spermidine affecting gene expression. Transcriptome analyses of flies grown with and without spermidine supplementation revealed that the expression of several thousand transcripts was altered by spermidine supplementation.
Is the real story this simple, with dietary spermidine altering gene expression by inhibiting histone acetyltransferase activity, leading to upregulation of autophagy-related genes, which neutralizes the age-dependent decrease in autophagy, thereby promoting better health of neurons and memory in aged animals? It seems unlikely. Solid evidence has demonstrated that inhibitors of histone deacetylases enhance cognition13, making it somewhat difficult to reconcile evidence that broad inhibitors of both histone acetyltransferases and histone deacetylases act as cognitive enhancers.
Moreover, spermidine does have biological effects other than its inhibition of histone acetyltransferase activity (Fig. 1). Most of the spermidine in the cell is complexed with mRNA and regulates translation, but polyamines have also been reported to modulate the function of potassium channels, calcium channels and NMDA-type glutamate receptors14,15. Moreover, polyamines interact with acidic phospholipids in membranes and may influence membrane function15.
Is spermidine the magical health elixir we all want to maintain brain health as we age? The cognitive effect of dietary spermidine on aged flies reported by Gupta et al.4 is striking. It provides hope that there is something about spermidine's biological actions that can be beneficial. More studies, however, are needed to clarify spermidine's biological roles before one should feel comfortable purchasing it as an over-the-counter supplement for cognitive aging.