Better Living Through Polyamines?

Part 1 of two

Could primordial soup, semen, and rotting flesh hold clues to healthy cognitive aging? If the idea sounds a little repulsive, consider this. These three types of complex organic matter are all packed with polyamines—flat strings of amine groups that have been around since life began, are so concentrated in semen spermidine crystals form, and as putrescine, give dying flesh its characteristic smell. They also happen to abound in foods like aged cheese, soybeans, and broccoli. Now, a handful of studies suggest that dietary polyamines, most notably spermidine, stave off age-related cognitive decline in mice, possibly by revving up mitophagy and mitochondrial function. Could people benefit too? A few small studies hint that foods rich in spermidine keep people sharper into old age, and several clinical trials are testing out spermidine supplements as a treatment for cognitive impairment.

  • Spermidine boosts mitochondrial function and memory in old mice.
  • In flies, these benefits depend upon mitophagy.
  • Cognition slips less with age in people on a diet rich in spermidine.  

Made by our own cells, polyamines, which include putrescine, spermidine, and spermine, in order of increasing length, have been implicated in myriad cellular functions, including transcription, translation, and proliferation (Miller-Fleming et al., 2015; Li et al., 2020). The polycations’ ability to boost autophagy and to dampen oxidative stress was previously linked to longevity of yeast, worms, fruit flies, mice, and human immune cells (Eisenberg et al., 2009; Eisenberg et al., 2016). Polyamines have been implicated in memory and cognitive function, and reportedly act as neuromodulators by latching onto NMDA receptors (Soda et al., 2009; Guerra et al., 2016). They have even been spotted near amyloid plaques and in microglia in mouse models of amyloidosis (July 2014 news; Feb 2021 news). One recent study claimed that injection of polyamines staved off age-related cognitive decline in mice by promoting autophagic digestion of misfolded proteins (De Risi  et al., 2020). 

Against this backdrop, researchers led by Frank Madeo and Tobias Eisenberg at the University of Graz, and Stefan Kiechl of the Medical University of Innsbruck, Austria, teamed up to investigate if chronic dietary supplementation with spermidine would influence memory, mitochondrial function, and brain metabolism in aging mice. Previously, the researchers had demonstrated neuroprotective effects of spermidine in fly models of aging and neurodegeneration (Gupta et al., 2013; Büttner et al., 2014). 

For their latest study, co-first authors Sabrina Schroeder, Sebastian Hofer, Andreas Zimmermann, and Raimund Pechlaner fed 18-month-old mice water containing 3 mM deuterated spermidine. They detected the isotope in the brain within one week, and its concentration in brain continued to rise for two months. After six months, they put the now 24-month-old mice through their paces in multiple behavioral tests, and found that mice imbibing spermidine had a slight edge over controls on several tests, including spatial learning.

How did spermidine keep the old mice sharper? The researchers detected no change in NMDA receptor signaling. Instead, they found that spermidine gave mitochondria a boost. Using high-resolution respirometry, which measures oxygen consumption at successive steps in the mitochondrial respiration pathway, the researchers reported flagging respiration in hippocampal extracts from 13-month-old control mice compared to those from young, 5-month-old controls. While treating young mice with spermidine did nothing to improve their already-proficient mitochondria, the treatment enhanced mitochondrial respiration in the old mice.

The scientists found a mitochondrial respiration boost in fruit flies, as well. Teasing apart the pathways involved, they found this boost depended upon the autophagy protein Atg7. More specifically, mitophagy—a type of autophagy that disposes of floundering mitochondria—was required for spermidine’s beneficial effects. Moreover, when the researchers knocked out the mitophagy proteins Pink1 or Parkin, spermidine no longer boosted the flies' mitochondrial health or improved their memory in a smell-based fear-conditioning test.

Hypusi—what?
How did spermidine promote mitophagy? The scientists suspect hypusination could be involved. Yes, hypusination. This little-known post-translational modification transforms a lysine residue into the amino acid hypusine. And, wouldn’t you know, this process requires—spermidine.

Interestingly, hypusine occurs but once in the human proteome. It is found within eukaryotic initiation factor 5a (eIF5a), a translation elongation factor. Studies in human B cells revealed that hypusinated eIF5a mediates translation of the autophagy regulator TFEB, while studies in human macrophages indicated that eIF5a also promotes translation of a cadre of mitochondrial proteins (Zhang et al., 2019; Puleston et al., 2019). 

In support of this idea about lysine modification, Schroeder and colleagues detected an uptick in hypusinated eIF5a within the hippocampi of spermidine-treated mice.

Hello Hypusination. Spermidine helps convert lysine into hypusine within the eIF5a protein. The modification helps eIF5a promote translation of proteins related to mitochondrial respiration and autophagy. [Courtesy of Liang et al., Cell Reports, 2021.]

For their part, a separate groups of researchers led by Stephan Sigrist of Freie University in Berlin employed a menagerie of fly models to explore this mechanism in depth. In the same issue of Cell Reports, they reported that eIF5a hypusination in the fly brain waned as the flies aged, as did the vigor of their mitochondria. The insects also became sluggish. Co-first authors Yong Tian Liang, Chengji Piao, Christine Beuschel, David Toppe, and colleagues reported that spermidine boosted the flies’ mitochondrial function and movement. Using hypusination-deficient flies, the scientists found that spermidine’s salubrious effects hinged upon this particular modification of eIF5a. None of the corresponding authors of the Cell Reports papers responded to Alzforum’s request for an interview.

Beyond their studies in mice and flies, Schroeder and colleagues in Austria searched for connections between dietary spermidine and cognition in people. This was possible thanks to the Bruneck prospective study, which documents health, longevity, and age-related diseases such as atherosclerosis, cardiovascular disease, neurodegeneration, and cancer among a population of 1,000 people in the northeastern Italian Alps near the Austrian border. Starting in 1990, participants filled out extensive, 118-item dietary questionnaires every five years and underwent cognitive tests.

Using the USDA nutrient database to reference spermidine content in different foods, the study estimated each participant’s daily intake of the polyamine. In a previous paper, the researchers had reported that daily intake of spermidine ranged from 9 mg to 11.5 mg per day, and those who consumed more spermidine were less likely to die during a 15-year follow-up (Kiechl et al., 2018). Their current analysis added that people who ate foods high in spermidine were also less susceptible to cognitive decline. For example, the estimated dietary spermidine content correlated with higher scores on the mini-mental state exam at baseline and with less slippage on this brief memory screen over time. People who had more dietary spermidine were less likely to become cognitively impaired during the five-year follow-up. Participants also took a cognitive test battery developed by the Consortium to Establish a Registry for Alzheimer’s Disease (CERAD). There, too, spermidine intake was tied to scores in domains of memory, executive function, and cumulative impairment. 

The authors acknowledged the possibility that other components in the diet could have contributed to the effects. However, when they controlled for diet quality using the Alternate Healthy Eating Index, spermidine levels still correlated with better cognition. The Bruneck study did not measure spermidine levels directly.

Spermidine Across Species. In flies, spermidine was shown to enhance auto- and mitophagy and the memory of smells. In mice, it boosted mitochondrial respiration in hippocampus and spatial navigation (middle). In people, dietary spermidine correlated with better cognition (right). Bottom shows the proposed mechanism, starting with eIF5a hypusination. [Courtesy of Schroeder et al., Cell Reports, 2021.]

Combined, the two papers build a case for a beneficial role of spermidine in preventing age-related brain mitochondrial dysfunction and memory decline, commented Sergio Ferreira of the Federal University of Rio De Janeiro in Brazil. Ferreira noted that for people, it will be crucial to consider how, and by how much, one could safely increase spermidine levels. “Autophagy has been shown to be either beneficial or detrimental to learning and memory in the published literature, suggesting it may not be easy to find the right amount of autophagy needed for optimal memory function,” he wrote.

Polyamine Trials?
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.

Natto. An acquired taste, the Japanese breakfast staple made from fermented soybeans comes loaded with spermidine. [Courtesy of Wikimedia.]

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).

Others agree that the mitochondrial data bodes well for preventing or even treating AD. “To me, these papers support the argument that bioenergetic metabolism and mitochondrial biology critically contribute to AD, and are justified targets,” commented Russell Swerdlow of Kansas University Medical Center in Kansas City.—Jessica Shugart

Comments

  1. Spermidine and polyamines: What they could do in aging and AD?

    The role of polyamines in the context of aging was elegantly investigated in three recent complementary studies: dysregulation of the polyamine metabolism induced by overexpression of the ornithine decarboxylase antizyme inhibitor 2 (AZIN2) in tau transgenic mice as shown by Sandusky-Beltran et al. (2021) increased anxiety and impaired memory. With an inverse approach, Liang et al. (2021) and Schroeder et al. (2021) accurately demonstrated that supplementation with spermidine improved age-impaired cognitive function in mice and flies, adding to the known neuroprotective and lifespan-expanding effects of spermidine. It is fascinating to see that spermidine-induced hypusination of the translation initiation factor eIF5A—which is involved in the regulation of TFEB, the main regulator for transcription of autophagic genes—seems to be an essential mechanism for spermidine actions on mitochondrial function and functionality in the hippocampus. Translationally, Schroeder et al. revealed a negative correlation between cognitive impairment and dietary spermidine intake in a large, older-aged cohort, aligning well with earlier studies by Wirth et al. (2018), which detected an improvement of short-term memory performance in elderly complaining about subjective cognitive decline upon supplementing spermidine.

    These data raise the question whether spermidine supplementation may be a promising approach in the course of treating Alzheimer's disease (AD). While we were able to provide first in vivo data that spermidine supplementation results in a specific reduction of soluble β-amyloid species in the amyloid-deposition-wise rapid and aggressive AD-like APPPS1 mouse model (Freitag et al., 2020), De Risi and colleagues described spermidine actions in a mouse model of mild cognitive impairment (De Risi et al., 2020). To pinpoint and link the multiple facets of spermidine's action in neuroprotection and their anti-inflammatory effects described by the polyamine community, more detailed analyses, ideally on a single-cell level, are required to shed light onto the various mechanisms induced by polyamines, ultimately aimed at identifying distinct pathways and cell populations involved in responding to spermidine treatment in Alzheimer's disease and aging. As spermidine is well-tolerated and can be applied orally, it is of course an exciting interventional approach in AD, which thus deserves continued research attention, both on the benches as well in translational approaches.

    References:

    De Risi M, Torromino G, Tufano M, Moriceau S, Pignataro A, Rivagorda M, Carrano N, Middei S, Settembre C, Ammassari-Teule M, Gardoni F, Mele A, Oury F, De Leonibus E. Mechanisms by which autophagy regulates memory capacity in ageing. Aging Cell. 2020 Sep;19(9):e13189. Epub 2020 Jul 30 PubMed.

    Liang Y, Piao C, Beuschel CB, Toppe D, Kollipara L, Bogdanow B, Maglione M, Lützkendorf J, See JC, Huang S, Conrad TO, Kintscher U, Madeo F, Liu F, Sickmann A, Sigrist SJ. eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction. Cell Rep. 2021 Apr 13;35(2):108941. PubMed.

    Sandusky-Beltran LA, Kovalenko A, Placides DS, Ratnasamy K, Ma C, Hunt JB Jr, Liang H, Calahatian JI, Michalski C, Fahnestock M, Blair LJ, Darling AL, Baker JD, Fontaine SN, Dickey CA, Gamsby JJ, Nash KR, Abner E, Selenica MB, Lee DC. Aberrant AZIN2 and polyamine metabolism precipitates tau neuropathology. J Clin Invest. 2021 Feb 15;131(4) PubMed.

    Schroeder S, Hofer SJ, Zimmermann A, Pechlaner R, Dammbrueck C, Pendl T, Marcello GM, Pogatschnigg V, Bergmann M, Müller M, Gschiel V, Ristic S, Tadic J, Iwata K, Richter G, Farzi A, Üçal M, Schäfer U, Poglitsch M, Royer P, Mekis R, Agreiter M, Tölle RC, Sótonyi P, Willeit J, Mairhofer B, Niederkofler H, Pallhuber I, Rungger G, Tilg H, Defrancesco M, Marksteiner J, Sinner F, Magnes C, Pieber TR, Holzer P, Kroemer G, Carmona-Gutierrez D, Scorrano L, Dengjel J, Madl T, Sedej S, Sigrist SJ, Rácz B, Kiechl S, Eisenberg T, Madeo F. Dietary spermidine improves cognitive function. Cell Rep. 2021 Apr 13;35(2):108985. PubMed.

    Wirth M, Benson G, Schwarz C, Köbe T, Grittner U, Schmitz D, Sigrist SJ, Bohlken J, Stekovic S, Madeo F, Flöel A. The effect of spermidine on memory performance in older adults at risk for dementia: A randomized controlled trial. Cortex. 2018 Dec;109:181-188. Epub 2018 Oct 4 PubMed.

    Freitag K, Sterczyk N, Schulz J, Houtman J, Fleck L, Sigrist SJ, Heppner FL, Jendrach M. The autophagy activator Spermidine ameliorates Alzheimer’s disease pathology and neuroinflammation in mice. BioRxiv, December 28, 2020

    View all comments by Marina Jendrach View all comments by Kiara Freitag View all comments by Frank Heppner

  2. In these back-to-back papers in Cell Reports, two European groups have undertaken a careful and very detailed investigation of the beneficial actions of dietary spermidine supplementation on mitochondrial function and aging-related phenotypes, notably learning and memory, in flies and mice. Combined, the two papers represent a real tour de force and make a very interesting case for a beneficial role of spermidine in preventing age-related brain mitochondrial dysfunction and memory decline.

    In mechanistic terms, the results indicate that increased spermidine availability results in increased hypusination of eIF5A, a component of the translation machinery that plays an important role in the translation of certain types of mRNAs (e.g., coding for long polyproline sequences, or including ribosome pausing sequences). Working with Drosophila, Liang et al. found no evidence of transcriptional alterations in the brains of spermidine-fed flies. However, and consistent with a regulation at the level of translation, they found profound changes in brain proteomic profiles when control versus spermidine-treated flies were compared. Notably, mitochondrial proteins were markedly upregulated by treatment with spermidine. Consistent with this change in the translatome, they found improved respiratory function in brain mitochondria from spermidine-treated flies.

    In the second paper, Schroeder et al. reported similar findings in mice: They first confirmed that dietary spermidine reaches the brain, then found that it increases eIF5A hypusination and mitochondrial function. Remarkably, spermidine was found to improve learning and memory in both aged mice and flies.

    The take-home message from both papers is that increasing brain spermidine levels may be able to prolong healthy brain function and delay aging. In support of this notion, Schroeder et al. report that estimated dietary spermidine intake correlates directly with cognitive preservation in a human cohort followed over a few years. In the context of non-pharmacological interventions to allow healthy aging, this is a very interesting avenue for further investigation.

    Nonetheless, there are a few points that the current studies do not seem to fully address. For example, in the studies with Drosophila, Liang et al. show that the main alteration in mitochondrial function in the brains of aged flies is a reduction in maximal respiratory capacity, while little or no reduction in basal respiratory activity and, importantly, ATP production was observed. Spermidine supplementation appeared to selectively target the maximal respiratory capacity, but not ATP production. If ATP production is not affected, it is not readily apparent why an alteration in the maximal respiratory rate (measured under conditions of mitochondrial uncoupling) would be a relevant target for the beneficial actions of spermidine.

    On a similar note, they show that flies genetically deficient in hypusination of eIF5A show considerable reductions in ATP production, which is not observed in aged flies. Thus, from a mechanistic standpoint, there appears to be a disconnect between mitochondrial dysfunction and the anti-aging effect of spermidine.

    Another important point to consider in terms of the translatability of the findings to aging humans is how, and by how much, one could increase spermidine levels. Evidence provided in both papers connected spermidine treatment to upregulation of components of autophagy, notably of mitophagy. Given the central role of autophagy in proteostasis, improving it in aging cells holds potential to counteract aging-related unbalances in the control of cellular protein levels. For example, in a very recent paper the group of Ana Maria Cuervo described that a compound capable of boosting levels of L2A, a central component of chaperone-mediated autophagy, is able to rescue aging-impaired proteostasis (Bourdenx et al., 2021). 

    Nonetheless, autophagy has been shown to be both beneficial and detrimental to learning and memory in the published literature, suggesting it may not be easy to find the right amount of autophagy needed for optimal memory function. In line with this notion, Schroeder et al. report that treatment of mice with 3 mM spermidine resulted in memory improvement, but 6 mM spermidine was not effective. Given this narrow concentration window, it may prove difficult to determine the right amount of spermidine to improve memory and brain function.

    Nonetheless, and all things considered, these two papers provide compelling evidence that dietary spermidine may be a viable tool to rescue aging-related defects in proteostasis and mitochondrial function.

    References:

    Bourdenx M, Martín-Segura A, Scrivo A, Rodriguez-Navarro JA, Kaushik S, Tasset I, Diaz A, Storm NJ, Xin Q, Juste YR, Stevenson E, Luengo E, Clement CC, Choi SJ, Krogan NJ, Mosharov EV, Santambrogio L, Grueninger F, Collin L, Swaney DL, Sulzer D, Gavathiotis E, Cuervo AM. Chaperone-mediated autophagy prevents collapse of the neuronal metastable proteome. Cell. 2021 May 13;184(10):2696-2714.e25. Epub 2021 Apr 22 PubMed.

    View all comments by Sergio Ferreira

  3. Interestingly, while many studies reveal that pathological changes of Aβ and tau, including their aggregation into oligomers and fibrils, can lead to mitochondrial dysfunction, a similar causality cannot be easily established for mitochondrial dysfunction with regard to Aβ and tau pathology.

    Here, Sandusky-Beltran and colleagues revealed that spermidine sequesters tau in the monomeric state, preventing oligomerization and fibrillization, whereas the two Drosophila studies show that spermidine boosts mitochondrial functions, in part by mediating mitophagy, a mitochondrial control mechanism of getting rid of damaged mitochondria via a Pink1/Parkin-dependent mechanism. We have previously shown that pathological tau traps Parkin, preventing it from translocating to mitochondria to execute its normal function (Cummins et al., 2019). Knowing that pathological tau impairs not only mitophagy, but also mitochondrial transport, mitochondrial dynamics, and oxidative phosphorylation, it would be great to determine which of these aspects spermidine can rescue.

    References:

    Cummins N, Tweedie A, Zuryn S, Bertran-Gonzalez J, Götz J. Disease-associated tau impairs mitophagy by inhibiting Parkin translocation to mitochondria. EMBO J. 2019 Feb 1;38(3) Epub 2018 Dec 11 PubMed.

    View all comments by Jürgen Götz

  4. To someone who sees bioenergetic metabolism, mitochondria, and mitochondria-related biology as sitting at the center of brain aging and Alzheimer’s disease, these are very exciting papers.

    There are pretty solid experimental data from animal studies that claim nuanced differences in mitochondrial function influence cognitive performance, and emerging findings from AD transgenic models establishes that messing with mitophagy rates profoundly influences brain amyloidosis (Roubertoux et al., 2003; Sorrentino et al., 2017; Du et al., 2017). If spermidine promotes these events in experimental models, then it is worth considering what it does in humans.

    One of the spermidine papers noted humans with higher spermidine content in their diets, which is a characteristic of a Mediterranean diet, appeared to have more successful brain aging. To me, these papers support the argument that bioenergetic metabolism, mitochondria, and mitochondrial-biology critically contribute to AD, and that as far as developing drugs or lifestyle interventions that prevent AD goes, these are justified targets. 

    References:

    Roubertoux PL, Sluyter F, Carlier M, Marcet B, Maarouf-Veray F, Chérif C, Marican C, Arrechi P, Godin F, Jamon M, Verrier B, Cohen-Salmon C. Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nat Genet. 2003 Sep;35(1):65-9. PubMed.

    Sorrentino V, Romani M, Mouchiroud L, Beck JS, Zhang H, D'Amico D, Moullan N, Potenza F, Schmid AW, Rietsch S, Counts SE, Auwerx J. Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature. 2017 Dec 14;552(7684):187-193. Epub 2017 Dec 6 PubMed.

    Du F, Yu Q, Yan S, Hu G, Lue LF, Walker DG, Wu L, Yan SF, Tieu K, Yan SS. PINK1 signalling rescues amyloid pathology and mitochondrial dysfunction in Alzheimer's disease. Brain. 2017 Dec 1;140(12):3233-3251. PubMed.

    View all comments by Russell Swerdlow

  5. Polyamines are physiologically present in our cells, where they regulate many physiological functions. Their beneficial effects have been observed on the cardiovascular system and longevity. As we age, polyamine levels drop, and this is thought to have a negative effect on cellular aging. Just as for the cardiovascular system, data demonstrating the benefits of a diet rich in polyamines, particularly spermidine, on aging-related neurodegenerative diseases are becoming more consistent. This has led to the investigation of the mechanisms that mediate the beneficial effects of spermidine.

    Of particular note, among these are studies reporting the effects of spermidine on autophagy and on genes involved in autophagy and lysosomal activity. The autophagy/lysosomal system is a cellular waste degradation system—a kind of incinerator. This system is very relevant to aging and neurodegenerative diseases where the accumulation of misfolded proteins requires an increase in the capacity to degrade them in order to avoid flooding the same system, which will ultimately result in the death of neurons. We have shown administering spermidine for one month to middle-aged mice showing a cognitive defect recovers the defect by stimulating autophagy and degradation of amyloid fibrils accumulating in the brain (De Risi et al., 2020). This study is in line with early clinical evidence, which, although including a limited number of subjects, suggests that spermidine rescues cognitive deficits in subjects with mild cognitive impairment (Wirth et al., 2019; Chatterjee et al., 2021;  Pekar et al., 2021). 

    Other studies show that spermidine is also effective in genetic animal models of Alzheimer's disease, making this drug very promising (Vemula et al., 2020). This set of studies has opened two important lines of research on polyamines:

    1. The biological mechanisms that mediate the beneficial effects of polyamines in neurodegenerative diseases. Schroeder et al. confirm our finding on autophagy and highlight a role for spermidine in regulating the expression of inflammatory factors, which we know from previous research to be crucial in neurodegeneration. In addition to this, Puleston et al. found that spermidine also influences mitochondrial respiratory capacity. These data suggest that spermidine may have beneficial effects on several types of neurodegenerative diseases, a hypothesis that we are exploring in our laboratory.
    2. The other very important line of research involves the measurement of polyamine levels as biomarkers of neurodegenerative diseases. Indeed, polyamine levels change not only during aging, but have been shown to correlate with disease progression in Parkinson's disease and more recently in AD patients (Akyol et al., 2020). 

    There is still a lot to understand, for example, if and which tissue (blood, CSF, tissues, etc.) should be analyzed to quantify polyamines in order to use them as biomarkers. Lee and colleagues reported an increase of enzymes involved in the synthesis (SMS, ODC1) and degradation (SAT1, SMOX, and PAOX) of polyamines in the hippocampi of AD patients, indicating an alteration in all steps of synthesis and degradation (Sandusky-Beltran et al., 2021). The same study highlights that AZIN2 is a protein that co-localizes with phospho-tau (the pathological form of tau protein). In animal models they show that an overexpression of the AZIN2 gene, while insufficient per se to induce proteinopathy, worsens it in genetic models of AD. Since AZIN2 favors the synthesis of polyamines, one might expect to find them increased in AD, which is in apparent contrast to what we have considered. In fact, the authors observe that overexpression of AZIN2 does not lead to an increase in spermidine in the brain, but an increase of an acetylated form of it, which might be responsible for the damage. This study confirms the causal link between polyamine metabolism and neuropathy in AD and reinforces the importance of thoroughly studying all the mechanisms involved in synthesis and degradation and how they can be manipulated in order to use them as drugs for AD and other neurodegenerative diseases.

    These two aspects must be studied in parallel so that we end up with a “polyamines profile” upon which to decide if spermidine treatment can prevent dementia or at least delay its onset. Of note, spermidine is present in many foods, some of which are peculiar to the Mediterranean diet, which is known to lower risk of dementia. There are many other foods, such as seasoned cheese, that contain high levels of spermidine and that are omitted from the diets of aging people in the attempt to control cholesterol; the cost/benefit analysis of these nutritional choices should take into account the protective role of polyamine in aging and neurodegenerative disorders.

    References:

    De Risi M, Torromino G, Tufano M, Moriceau S, Pignataro A, Rivagorda M, Carrano N, Middei S, Settembre C, Ammassari-Teule M, Gardoni F, Mele A, Oury F, De Leonibus E. Mechanisms by which autophagy regulates memory capacity in ageing. Aging Cell. 2020 Sep;19(9):e13189. Epub 2020 Jul 30 PubMed.

    Wirth M, Schwarz C, Benson G, Horn N, Buchert R, Lange C, Köbe T, Hetzer S, Maglione M, Michael E, Märschenz S, Mai K, Kopp U, Schmitz D, Grittner U, Sigrist SJ, Stekovic S, Madeo F, Flöel A. Effects of spermidine supplementation on cognition and biomarkers in older adults with subjective cognitive decline (SmartAge)-study protocol for a randomized controlled trial. Alzheimers Res Ther. 2019 May 1;11(1):36. PubMed. Correction.

    Chatterjee P, Fagan AM, Xiong C, McKay M, Bhatnagar A, Wu Y, Singh AK, Taddei K, Martins I, Gardener SL, Molloy MP, Multhaup G, Masters CL, Schofield PR, Benzinger TL, Morris JC, Bateman RJ, Greenberg SM, Wermer MJ, van Buchem MA, Sohrabi HR, Martins RN, Dominantly Inherited Alzheimer Network. Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations. J Alzheimers Dis. 2021;79(2):895-903. PubMed.

    Pekar T, Bruckner K, Pauschenwein-Frantsich S, Gschaider A, Oppliger M, Willesberger J, Ungersbäck P, Wendzel A, Kremer A, Flak W, Wantke F, Jarisch R. The positive effect of spermidine in older adults suffering from dementia : First results of a 3-month trial. Wien Klin Wochenschr. 2021 May;133(9-10):484-491. Epub 2020 Nov 19 PubMed.

    Vemula PK, Jing Y, Cicolini J, Zhang H, Mockett BG, Abraham WC, Liu P. Altered brain arginine metabolism with age in the APPswe/PSEN1dE9 mouse model of Alzheimer's disease. Neurochem Int. 2020 Nov;140:104798. Epub 2020 Jul 23 PubMed.

    Akyol S, Yilmaz A, Oh KJ, Ugur Z, Aydas B, McGuinness B, Passmore P, Kehoe PG, Maddens M, Green BD, Graham SF. Evidence that the Kennedy and polyamine pathways are dysregulated in human brain in cases of dementia with Lewy bodies. Brain Res. 2020 Sep 15;1743:146897. Epub 2020 May 22 PubMed.

    Sandusky-Beltran LA, Kovalenko A, Placides DS, Ratnasamy K, Ma C, Hunt JB Jr, Liang H, Calahatian JI, Michalski C, Fahnestock M, Blair LJ, Darling AL, Baker JD, Fontaine SN, Dickey CA, Gamsby JJ, Nash KR, Abner E, Selenica MB, Lee DC. Aberrant AZIN2 and polyamine metabolism precipitates tau neuropathology. J Clin Invest. 2021 Feb 15;131(4) PubMed.

    View all comments by Elvira De Leonibus

  6. In Drosophila, the polyamine spermidine protects against “brain-aging” related phenotypes and this correlates with improved mitochondrial function as shown by Liang et al. This is dependent on a post-translational modification (hypusination) of the translation factor eIF5A, and the new data are consistent with previous work, which showed that hypusination of eIF5A enhances the translation of mitochondrial proteins involved in the TCA cycle of oxidative phosphorylation (Puleston et al., 2019). 

    In the partner study by Schroeder et al., spermidine increased cognitive performances in aged mice (an effect that may be confined to males in the study) and this was associated with increased eIFA hypusination, too. Interestingly, this study suggested that the effects of spermidine in Drosophila were dependent on autophagic removal of mitochondria (mitophagy). Schroder et al. also provide exciting data from a retrospective analysis of a human cohort that shows a correlation between increased spermidine intake (after analysis of dietary records) and protection against age-related cognitive decline.

    It would be interesting to see further studies to understand the extent to which these spermidine effects are related to age-related cognitive decline across all ages over 50 years, versus mild cognitive impairment and dementia risk. This will be important in view of a third study by Sandusky-Beltran and colleagues suggesting that spermidine has additional benefits because it reduces tau fibrillization, oligomerization, and seeding/propagation. This last study also makes the interesting point that different polyamines have differing benefits or risks in the context of tau biology.

    References:

    Puleston DJ, Buck MD, Klein Geltink RI, Kyle RL, Caputa G, O'Sullivan D, Cameron AM, Castoldi A, Musa Y, Kabat AM, Zhang Y, Flachsmann LJ, Field CS, Patterson AE, Scherer S, Alfei F, Baixauli F, Austin SK, Kelly B, Matsushita M, Curtis JD, Grzes KM, Villa M, Corrado M, Sanin DE, Qiu J, Pällman N, Paz K, Maccari ME, Blazar BR, Mittler G, Buescher JM, Zehn D, Rospert S, Pearce EJ, Balabanov S, Pearce EL. Polyamines and eIF5A Hypusination Modulate Mitochondrial Respiration and Macrophage Activation. Cell Metab. 2019 Aug 6;30(2):352-363.e8. Epub 2019 May 23 PubMed.

    View all comments by David Rubinsztein

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References

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External Citations

  1. clinical trials.gov
  2. clinical trials.gov
  3. ;

Further Reading

Papers

  1. Muñoz-Esparza NC, Latorre-Moratalla ML, Comas-Basté O, Toro-Funes N, Veciana-Nogués MT, Vidal-Carou MC. Polyamines in Food. Front Nutr. 2019;6:108. Epub 2019 Jul 11 PubMed.

Primary Papers

  1. Schroeder S, Hofer SJ, Zimmermann A, Pechlaner R, Dammbrueck C, Pendl T, Marcello GM, Pogatschnigg V, Bergmann M, Müller M, Gschiel V, Ristic S, Tadic J, Iwata K, Richter G, Farzi A, Üçal M, Schäfer U, Poglitsch M, Royer P, Mekis R, Agreiter M, Tölle RC, Sótonyi P, Willeit J, Mairhofer B, Niederkofler H, Pallhuber I, Rungger G, Tilg H, Defrancesco M, Marksteiner J, Sinner F, Magnes C, Pieber TR, Holzer P, Kroemer G, Carmona-Gutierrez D, Scorrano L, Dengjel J, Madl T, Sedej S, Sigrist SJ, Rácz B, Kiechl S, Eisenberg T, Madeo F. Dietary spermidine improves cognitive function. Cell Rep. 2021 Apr 13;35(2):108985. PubMed.
  2. Liang Y, Piao C, Beuschel CB, Toppe D, Kollipara L, Bogdanow B, Maglione M, Lützkendorf J, See JC, Huang S, Conrad TO, Kintscher U, Madeo F, Liu F, Sickmann A, Sigrist SJ. eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction. Cell Rep. 2021 Apr 13;35(2):108941. PubMed.

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