. 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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  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:

    . Mechanisms by which autophagy regulates memory capacity in ageing. Aging Cell. 2020 Sep;19(9):e13189. Epub 2020 Jul 30 PubMed.

    . eIF5A hypusination, boosted by dietary spermidine, protects from premature brain aging and mitochondrial dysfunction. Cell Rep. 2021 Apr 13;35(2):108941. PubMed.

    . Aberrant AZIN2 and polyamine metabolism precipitates tau neuropathology. J Clin Invest. 2021 Feb 15;131(4) PubMed.

    . Dietary spermidine improves cognitive function. Cell Rep. 2021 Apr 13;35(2):108985. PubMed.

    . 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.

    . The autophagy activator Spermidine ameliorates Alzheimer’s disease pathology and neuroinflammation in mice. BioRxiv, December 28, 2020

    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:

    . 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:

    . 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., 2017Du 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:

    . Mitochondrial DNA modifies cognition in interaction with the nuclear genome and age in mice. Nat Genet. 2003 Sep;35(1):65-9. PubMed.

    . Enhancing mitochondrial proteostasis reduces amyloid-β proteotoxicity. Nature. 2017 Dec 14;552(7684):187-193. Epub 2017 Dec 6 PubMed.

    . 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., 2021Pekar 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:

    . Mechanisms by which autophagy regulates memory capacity in ageing. Aging Cell. 2020 Sep;19(9):e13189. Epub 2020 Jul 30 PubMed.

    . 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.

    . Presymptomatic Dutch-Type Hereditary Cerebral Amyloid Angiopathy-Related Blood Metabolite Alterations. J Alzheimers Dis. 2021;79(2):895-903. PubMed.

    . 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.

    . 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.

    . 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.

    . 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:

    . 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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