molecular basis of the ‘anti-aging’ effect of spermidine and other natural polyamines – a...

7/25/2019 Molecular Basis of the Anti-Aging Effect of Spermidine and Other Natural Polyamines a Mini-Review

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E-Mail [email protected]

Experimental Section / Mini-Review

Gerontology 2014;60:319326

DOI: 10.1159/000356748

Molecular Basis of the Anti-AgingEffect of Spermidine and OtherNatural Polyamines A Mini-Review

Nadge Minois

School of Biology, University of St Andrews, St Andrews, UK

trigger its effects is the MAPK pathway. Conclusions:Given

that polyamines can interact with many molecules, it is not

surprising that they affect aging via several mechanisms.

Many of these mechanisms discovered so far have already

been linked with aging and by acting on all of these mecha-

nisms, polyamines may be strong regulators of aging.

2014 S. Karger AG, Basel

Introduction

Aging is a multifaceted process, probably caused by amyriad of interacting factors and with consequences at alllevels of the organism. Research into the subject has re-

vealed that factors leading to aging are as varied as sus-

tained exposure to cellular stress, chronic inflammation,dysregulation of lipid metabolism, autophagy and cellsurvival and death. These factors will impinge upon eachother in complex interactions. Effective interventionsagainst aging will need to be able to impact as many aspossible of the factors causing aging and their interac-tions. Dietary restriction may be one such interventionwith its wide-ranging effects. Polyamines, especially sper-midine, have also emerged as strong potential candidates

Key Words

Spermidine Polyamines Longevity Aging Autophagy

Inflammation Metabolism Cell survival

Abstract

Background:Spermidine, a naturally occurring polyamine,

has recently emerged as exhibiting anti-aging properties. Its

supplementation increases lifespan and resistance to stress,

and decreases the occurrence of age-related pathology and

loss of locomotor ability. Its mechanisms of action are just

beginning to be understood. Objectives: An up-to-date

overview of the so far identified mechanisms of action of

spermidine and other polyamines on aging is presented.

Methods:Studies of aging and of the molecular effects of

polyamines in general and spermidine in particular are usedto synthesize our knowledge on what molecular mecha-

nisms spermidine and other polyamines trigger to positively

affect aging. Results:Autophagy is the main mechanism of

action of spermidine at the molecular level. However, recent

research shows that spermidine can act via other mecha-

nisms, namely inflammation reduction, lipid metabolism

and regulation of cell growth, proliferation and death. It is

suggested that the main pathway used by spermidine to

Received: July 7, 2013

Accepted: October 15, 2013

Published online: January 28, 2014

Nadge MinoisBiomedical Sciences Research ComplexUniversity of St Andrews, North HaughSt Andrews, Fife KY16 9ST (UK)E-Mail nm61 @ st-andrews.ac.uk

2014 S. Karger AG, Basel0304324X/14/06040319$39.50/0

www.karger.com/ger
http://dx.doi.org/10.1159%2F000356748http://dx.doi.org/10.1159%2F000356748


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and this review will give evidence to support the involve-ment of polyamines in aging.

Spermidine belongs to the family of polyamines. Poly-amines are polycations that will interact readily with neg-atively charged molecules, including DNA, RNA and lip-ids. This ability to bind such different molecules meanspolyamines are involved in many important processessuch as DNA stability, cell growth, proliferation anddeath. To regulate these processes, a set of specific en-zymes tightly regulate polyamine synthesis and catabo-lism (fig. 1) [reviewed in 1]. Polyamine metabolism is

very dynamic and many studies have investigated the roleof all three main polyamines (putrescine, spermidine andspermine) on aging, so this review will discuss all threepolyamines and not only spermidine.

It has been known for some time that polyamine levelsdecrease with age [reviewed in 1]. However, it is only re-

cently that the effect of polyamines, especially spermi-dine, on aging has been investigated. Indeed, Pucciarelliet al. [2] recently observed that spermidine levels in hu-mans aged between 60 and 80 were lower than in humansbelow 50 but humans older than 90 have levels similar topeople below 50. These results suggest that maintainingspermidine levels in aging may contribute to longevity.Polyamine levels can be increased in both model organ-isms and humans by supplementation in food or water

[35], so the effect of polyamines on aging can be inves-tigated relatively easily. Examples of food and drinks con-taining high levels of polyamines are rice bran, green pep-per, broccoli, soybeans, mushrooms, oranges, and greentea.

We have shown that yeast cells Saccharomyces cerevi-siae, nematode worms Caenorhabditis elegans, fruit fliesDrosophila melanogaster as well as human peripheralblood mononuclear cells supplemented with spermi-dine had increased lifespans [3]. Yeast cells unable tosynthesize polyamines are short-lived and spermidineaddition rescued this lifespan defect [3]. Soda et al. [5, 6]also reported that a high-polyamine diet decreased mor-tality in mice. However in both cases, mice were sacri-ficed at 88 weeks of age for use in other measurements,precluding a full lifespan measurement. The same au-thors also showed that a high-polyamine diet decreased

the incidence of age-related kidney glomerular atrophy.Aging triggered DNA methylation changes in kidneysand the high-polyamine diet suppressed these changes[6]. Finally, they reported that these mice kept thickercoat and higher activity levels with age, although thesevariables were not quantified [5]. Recently, we foundthat spermidine reduced the age-related decline ofclimbing activity in D. melanogaster [Minois, unpubl.results]. It was also reported that spermidine feeding re-

Spermine

Acetyl spermidine

Putrescine

Spermidine

Spm SynSMO

H2N NH2

HNN

H

H2N NH2N

H

Spd Syn

SSAT

PAOPAO

H2N NH2

PAO

Acetyl spermine

Diacetyl spermine

SSAT

SSAT

ODCAntizyme

Ornithine

Arginase

Arginine

Fig. 1.Polyamine metabolism. ODC = Or-nithine decarboxylase; PAO = polyamineoxidase; SMO = spermine oxidase; SpdSyn = spermidine synthase; Spm Syn =spermine synthase; SSAT = spermidine/spermine N1-acetyltransferase [for moredetails, see 1]. The levels of polyamines in

many mammalian tissues are in the orderspermidine > spermine > putrescine, withthe ratios between them easily varyingfrom 2 to 20.


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duced levels of age-related oxidative damage in mice [3]and age-related overproduction of reactive oxygen spe-cies in yeast [7]. Although not measured as a function ofage, spermidine has positive effects on variables relatedto aging, namely resistance to stress. Yeast cells fed sper-midine were more resistant to heat and hydrogen per-

oxide [3]. We also observed that spermidine-treatedD. melanogasterwas more resistant to paraquat and hy-drogen peroxide [8].

Evidence has accumulated that spermidine in particu-lar and polyamines in general have implications for theaging process [1]. However, it is recently that the mecha-nisms of action of spermidine are being brought to light.This short review will discuss this research and give up-to-date information on the molecular basis of action ofpolyamines in general and spermidine in particular.

Autophagy

Autophagy has been identified so far as the mainmechanism of action of spermidine effects on aging. Au-tophagy is the main recycling mechanism of the cell, al-lowing the destruction and re-use of unneeded or dam-aged molecules or whole organelles. A deficient autoph-agy has been linked to many age-related diseases.

We have shown in all models tested that spermidinequickly induced autophagy [3]. This was observed inyeast, worms, flies and mouse liver cells. Furthermore,yeast cells, worms and flies deficient in autophagy did notexhibit an increased lifespan upon spermidine feeding,showing that autophagy is indispensable for the effect ofspermidine on lifespan [3]. Lack of autophagy also pre-

vented spermidine from increasing resistance to paraquatand reducing locomotor decline induced by paraquat inDrosophila[8].

The induction of autophagy by spermidine is indepen-dent of pathways previously associated with aging involv-ing sirtuins as observed in human colon cancer HCT116cells, yeast and worms [7]. It is also independent of thecanonical mTOR pathway, as spermidine did not alter the

phosphorylation status of mTOR or its substrate, ribo-somal protein S6 kinase [7]. Spermidine affected the acet-ylation profile of many proteins, a significant proportionof them belonging to the human autophagy protein net-work. Spermidine mostly triggered deacetylation in thecytosol and acetylation in the nucleus. The authors re-ported that spermidine can induce short-term autophagywithout transcription of new proteins and that autophagyby spermidine can be regulated by cytoplasmic (de)acety-

lations. Although very important for the effects of sper-midine on aging, autophagy is not the only mechanism ofaction involved, as for instance spermidine still increasedhydrogen peroxide resistance in autophagy-deficientDrosophila[8].

Inflammation

Aging has been characterized by a chronic inflamma-tion profile that leads to chronic damage to cells and isassociated with many age-associated diseases. Polyaminelevels generally increase with inflammation but whetherthey are more pro- or anti-inflammatory has been debat-ed. As a matter of fact, polyamines trigger the productionof anti-inflammatory cytokines while decreasing the pro-duction of pro-inflammatory ones, but at the same time,polyamine metabolism generates cytotoxic products

(such as hydrogen peroxide) that can themselves causeinflammation. It seems that recent research shows thatpolyamines have mostly anti-inflammatory effects, someof them recently reviewed [9].

Spermidine treatment of microglial cells, the prime ef-fector cells in inflammatory responses in the central ner-

vous system, decreased production of pro-inflammatorymediators and cytokines in reaction to lipopolysaccha-ride (LPS) exposure [10]. Spermidine treatment de-creased nitric oxide and prostaglandin E2production in adose-dependent manner, as well as the mRNA expressionof pro-inflammatory cytokines, among them interleu-kin-6 and tumor necrosis factor-. The authors worksuggested that this anti-inflammatory response was trig-gered by the suppression of the translocation in the nu-cleus of NF-B p65 subunit, leading to a decreased phos-phorylation of Akt and MAPK.

Recently, Paul and Kang [11] studied the effect of poly-amines on ear edema in mice. They induced an inflam-matory response in the ear by applying 12-O-tetradec-anoylphorbol-13-acetate (TPA). Prior to TPA applica-tion, mice were topically treated with saline, hydrocortisone(positive anti-inflammatory control) or the main three

polyamines (putrescine, spermidine or spermine). Theauthors showed that application of polyamines reducedear thickness in a dose-dependent manner to levels simi-lar to the positive control. Spermidine and spermine in-duced the highest water content decrease. Polyaminesalso reduced neutrophil infiltration in the ear tissues. Theauthors then induced inflammation in mice macrophageswith LPS. Polyamines decreased nitric oxide productiontriggered by the LPS treatment, spermine having the


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strongest effect. They also inhibited the expression ofinterleukin-1 and tumor necrosis factor-.

It has to be kept in mind that these studies focus onacute inflammation, in contrast with the chronic, silentinflammation observed in aging. Work on the effects ofpolyamines on chronic inflammation is therefore needed.

However, the present research suggests that spermidinein particular and polyamines in general could promotetheir anti-aging properties by reducing inflammation.

Lipid Metabolism

Lipid metabolism has recently emerged as a strongregulator of health and lifespan. A dysfunction in lipidmetabolism can trigger deleterious consequences onhealth and ultimately aging and lifespan. On the otherhand, many mutations increasing lifespan have been as-

sociated with increased levels of stored lipids (TAG)and changes in lipid profiles (composition and satura-tion levels). The involvement of spermidine in adipo-genesis combined with our results showing that spermi-dine alters lipid profile in fruit flies makes lipid regula-tion a likely contributor for the effect of spermidine onaging.

At the cellular level, the level of lipids is regulated bythe differentiation of preadipocytes into mature adipo-cytes. Spermidine is a key factor in this process of adipo-genesis. An irreversible inhibitor of polyamine synthesis,-difluoromethylornithine (DFMO) that depletes thecells of polyamines, completely blocked adipogenesis in3T3-L1 cells: the cells kept a fibroblast-like appearance[12, 13]. Treatment of the cells with natural spermidineor stable methylated analogues triggered differentiationin the presence of DFMO. These cells accumulated fat aswell as control cells. Spermidine analogues could also res-cue the growth arrest induced by longer exposure toDFMO, although some of them not to the level of the con-trol cells. DFMO blocked the expression of transcriptionfactors key in preadipocytes differentiation as well as lateadipocyte markers. Supplementation with natural sper-

midine and some of the analogues rescued the expressionof these genes to allow the differentiation of preadipo-cytes into mature adipocytes. The molecular mechanismsof spermidine allowing adipogenesis are summarized infigure 2.

Although these last studies showed an important in-volvement of spermidine in adipogenesis, other studiespointed to more complex interactions between poly-amines and adipogenesis. For instance, in 3T3-L1 pre-

adipocytes, inhibiting spermidine synthase or sperminesynthase respectively decreased and increased TAG ac-cumulation. These inhibitions had opposite effects in ma-ture adipocytes. Polyamine catabolism also regulates adi-pogenesis in these cells [14].

We have recently discovered that spermidine altered

lipid metabolism in whole D. melanogaster[Minois, un-publ. results]. Spermidine supplementation increasedTAG levels and altered lipid profile. We observed thatspermidine supplementation changed the relative abun-dance of fatty acids (for instance a decline in C14: 1, C14: 0,C20: 3 and C20: 2 and an increase in C18: 2 in females) andphospholipids (for instance an increase with spermidinein ethanolamine phosphate ceramide EPCd38: 1, phos-phatidylcholine PC32: 2 and phosphatidylethanolaminePE38 in males). Spermidine also triggered changes in theratio of saturated over unsaturated fatty acids and someceramide phosphoethanolamine species, the main sphin-

golipid in invertebrates. Most of these changes are au-tophagy-dependent. The changes in lipids profile willmodulate membrane fluidity and proneness to oxidativedamage as well as signalling. How this can affect agingwill need to be further studied.

Cell Growth and Death

It is undoubted that cells senesce and lose with timeappropriate responses to growth and death signals. Un-regulated cell growth or death will lead to tissue or organdysfunction. However, how cellular senescence impactswhole organism aging is not fully understood and stilldebated. Polyamines regulate cell growth and death. Thedecrease in polyamine levels with age could play a partin this cellular aging phenotype and polyamine supple-mentation may help lessen the effects of cellular aging.Polyamines are necessary for cell growth as chemicallyblocking polyamine synthesis, leading to their depletiontriggers growth arrest in mammalian cells, predomi-nantly at the G0/G1 phase of the cell cycle [15, 16].Growth arrest was achieved by blocking translation ini-

tiation and elongation. Initiation was stopped via the in-creased phosphorylation of the initiation factors eIF2and 4E-BP. Elongation was inhibited as a lack of sper-midine stopped the synthesis of hypusine, a peculiaramino acid synthesized exclusively from spermidineand essential for the activation of the eukaryotic initia-tion factor eIF5A. A genomic profiling of cells depletedof polyamines and then allowed to grow by addition ofspermidine showed that not surprisingly, growth arrest


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and resumption was accompanied by changes in the ex-pression of genes linked to transcription, DNA replica-tion and cell cycle [16]. Of the genes involved in cellcycle control Cdk7, Cdknla, Gadd45a, Mdm2 and Rb1were upregulated and Cdk2, E2F1, PCNA, Rbl1 and

Uhrf1 were downregulated. Note that some genes acti-vated later in the resumption of growth are associatedwith lipid biosynthesis. Furthermore, the authors ob-served that polyamine-depleted cells exhibited a changein the expression of genes known to be activated during

ANP32

Nucleus

HUR:

HURSpermidine

Preadipocyte Adipocyte

Adipogenesis

2SREBP-1c

X PP2Ac

FASHSL

Lipids

GLUT4

Fig. 2.

Spermidine is indispensable for adipogenesis. Spermidine in-teracts with ANP32, blocking ANP32 interaction with HUR andPP2Ac. This decreases the phosphatase activity of PP2Ac which al-lows the nuclear translocation of HUR. In the nucleus, HUR bindsto C/EBP-, leading to the expression of transcription factors suchas PPAR-2and SREBP-1c. Upon expression of these transcriptionfactors, the preadipocyte differentiates into a mature adipocyte

showing increased lipid levels and expression of key markers suchas FAS, HSL and GLUT4. ANP32 = Acidic nuclear phosphoproteins32; C/EBP- = CCAAT/enhancer binding protein ; FAS = fattyacid synthase; GLUT4 = glucose transporter 4; HSL = hormone-sensitive lipase; HUR = human antigen R; PP2Ac = protein phos-phatase 2Ac; PPAR-2= peroxisome proliferator-activated receptor2; SREBP-1c = sterol-regulatory element binding protein 1c.

eIF2

c

Inflammation Autophagy Cell growth

Spermidine

Lipid metabolism

AgingFig. 3. Synthesis of the possible mecha-nisms of action of spermidine.


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cellular stress response. This stress response was rapidlystopped upon spermidine addition and cell growth re-sumption.

Polyamines also regulate cell death by regulating apop-tosis and necrosis. The relation between polyamines andapoptosis is far from straightforward with polyamines

having been reported to both induce and prevent apop-tosis [reviewed in 1]. Landau et al. [16] reported that de-pleting NIH3T3 cells from polyamines protected themfrom apoptotic death. Polyamines increased Ca2+accu-mulation in mitochondria, modulating the mitochondri-al permeability transition and triggering apoptosis [17].Polyamines can also directly promote cytochrome cre-lease, a prelude to apoptosis [18, 19]. Polyamine catabo-lism produces some toxic by-products (such as hydrogenperoxide) that can themselves trigger uncoupling and cy-tochrome crelease [19].

Finally, polyamines can regulate the other type of cell

death, necrosis. We observed that spermidine feeding in-creased yeast cells chronological lifespan by reducing ne-crotic death and that cells unable to synthesize poly-amines exhibited higher levels of necrosis [3]. A recentreport by Carmona-Gutierrez et al. [20] suggested thatthe regulation of necrosis by polyamines may work viacathepsin D (CatD). The overexpression of PEP4, theyeast orthologue of CatD, increased chronological lifes-pan by reducing necrosis. This anti-necrotic effect wasdependent on putrescine and spermidine synthesis, butnot on spermine synthesis. Furthermore, PEP4 overex-pression prevented the age-related decline of putrescineand spermidine levels.

Signalling Pathways through Which Spermidine

May Act

Eventually, polyamines have to trigger their effectsby activating or repressing signalling pathways at thecellular level. What can be the signalling pathway(s) bywhich spermidine triggers its anti-aging effects? Sper-midine triggered a general hypoacetylation, which will

likely induce gene expression changes [3]. Spermidinetreatment changed the phosphorylation status of manykinases [7] and activated several phosphatases [21] inhuman colon carcinoma HCT116 cells, potentially reg-ulating many signalling pathways. A lot of the anti-ag-ing effects of spermidine seem to involve autophagy andpathways that will lead to the induction of autophagyare likely targets for the mechanisms of action of sper-midine. Among the candidates, SIRT1, the mTOR path-

way as well as AMPK are unlikely to play a role: SIRT1is not necessary for autophagy induction by spermidine,and spermidine does not alter the phosphorylation sta-tus of mTOR, AMPK and their substrates [7]. Autoph-agy is also controlled by other pathways. Autophagygenes have been shown to be targets for Foxo [22], the

downstream effector of the insulin-like signalling (IIS)pathway, indisputably involved in aging and lifespanregulation. Furthermore, spermidine decreases thephosphorylation status of PKB/Akt in HCT116 cells[21] and of Akt in LPS-activated BV2 microglial cells[10]. It will be interesting to study whether the effect ofspermidine on lifespan overlaps with the IIS pathway. Alikely candidate for regulating the anti-aging effects ofspermidine is the MAPK pathway, another pathway in-volved in autophagy modulation [23]. In addition toregulating autophagy, it is known that the MAPK path-way interacts with polyamines [24]. CK2, a ubiquitous

kinase, phosphorylates KSR (kinase suppressor of rasthat serves as scaffold and can act as raf activator) andalso directly raf. Polyamines change the phosphoryla-tion of raf by CK2, either acting as inhibitor (spermine)or activator (spermine plus spermidine or putrescine)of raf. CK2 could act as a sensor for polyamine levelsand translate the information to the MAPK pathway.Furthermore, some MAPKs show altered phosphoryla-tion status upon spermidine treatment in HTC116 cells[21] and MAPKs phosphorylation is reduced by sper-midine in LPS-activated BV2 microglial cells [10]. Intomato green fruits exposed to spermidine (1 mMfor 30min) at high temperature, spermidine upregulatesMAPK family genes [25] suggesting more involvementof polyamines with the MAPK pathway. Finally, the ex-pression of transcription factors targets of MAPKs havebeen shown to be altered upon polyamines depletionand then re-addition of spermidine in NIH3T3 mousefibroblasts [16].

Conclusions and Perspectives

It is herein reviewed that spermidine and related poly-amines play a role in many molecular mechanisms in-volved in aging. These mechanisms are linked and theirregulation by spermidine slows aging (fig. 3). Spermidineinduces autophagy [3, 7], which dysfunction is linked toaging and age-related diseases. In turn, autophagy allowsthe modulation of lipid profile. The changes in lipid com-position will alter membrane fluidity, its proneness todamage, especially lipid peroxidation, as well as signalling


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in which lipids are important messengers. Spermidine di-rectly regulates cell growth by its action on initiation fac-tors and translation. Spermidine also indirectly regulatescell growth via lipid metabolism, during adipogenesis forinstance. Finally, spermidine and other polyamines candirectly reduce inflammation by their action on the ex-

pression of pro- and anti-inflammatory cytokines. Sper-midine also indirectly modulates inflammation via thechanges it induces in lipid composition. Finally, spermi-dine may indirectly alter inflammation and cell growth

via autophagy.Although our knowledge on how polyamines bring

about their anti-aging effects at the molecular level isexpanding, a lot is still to be investigated. Spermidinealters the phosphorylation status of Akt and of someMAPKs [21]. It would be interesting to study the effectsof spermidine in mutants in the IIS and MAPK path-ways as well as the effect of spermidine on the expression

of genes involved in these pathways. Likewise, othermechanisms have not been investigated yet. Spermidinealters acetylation levels [3]. Could it also modify meth-

ylation status, especially DNA methylation, and triggerepigenetic changes?

Spermidine has been the most studied polyamine sofar for its effects on aging. However, polyamine metabo-lism is very dynamic and a better understanding of thespecific roles of each polyamine on aging is needed. For

instance, spermidine feeding in flies increases endoge-nous levels of spermidine, but also of its precursor putres-cine [3]. We should study the effects of all polyamines, ontheir own and in combination, as well as for instancemethylated analogues. These analogues are metabolicallymore stable, some of them cannot be converted into oth-er polyamines and each has different biochemical proper-ties that could help us tease out the exact roles of poly-amines in aging [26, 27].

Acknowledgement

The author wishes to acknowledge the important work of manyauthors that could not be cited due to space restriction.

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