Spermidine delays aging in humans

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Summary: External supply of the natural polyamine
spermidine can extend life span in model organisms
including yeast, nematodes, flies and mice. Recent
epidemiological evidence suggests that increased uptake
of spermidine with food also reduces overall, cardio-
vascular and cancer-related mortality in humans. Here,
we discuss the possible mechanisms of this intriguing
spermidine effect.
Polyamines including spermidine play an essential role
in intermediate metabolism. Since they are synthesized
by higher eukaryotic cells, they are not vitamins. How-
ever, the levels of polyamines are profoundly influenced
by their external supply, either by oral ingestion with
different food items or by the intestinal microbiota that
can synthesize polyamines as well [1].
Our groups have shown over the past decade that
supplementing spermidine by adding it to culture media
(as we did for the yeast Saccharomyces cerevisiae, the
nematode Caenorhabditis elegans and the fruit fly
Drosophila melanogaster) or to the drinking water (as
we did for the rodent Mus musculus) is sufficient to
extend longevity and to improve health span at multiple
levels [2, 3]. Thus, in mice, the supplementation was
able to suppress the age-related decline in cardio-
vascular function (as measured at 24 months of age) and
increased overall longevity by approximately 10%, [3].
Of note nutritional uptake of spermidine and spermine
but not putrescence could be linked to improved
cardiovascular health and autopsies performed at death
did not reveal any significant effect of spermidine on
the incidence of cancer, suggesting that the reduction of
cardiovascular morbidity was not compensated by an
increase in malignancies [3]. Rather, in mice, spermi-
dine postpones the manifestation cancer upon oncogenic
stimuli [4, 5].
Moreover, fragmentary evidence suggests that sper-
midine can also delay neurodegeneration, both in non-
mammalian model organisms [6] and in mouse models
[7, 8].
The molecular and cellular mechanisms through which
spermidine delays age-related disease and death have
been elucidated to some extent. Indeed, spermidine can
act as an inhibitor of the acetyl transferase activity of
E1A-associated protein p300 (where E1A = adenovirus
early region 1A), best known as EP300 [9]. EP300 act
as an endogenous inhibitor of autophagy by acetylating
lysine residues within multiple proteins that are involved
Letter to the Editor
in autophagy-regulatory or autophagy-executing cir-
cuitries [1, 10]. As a result, the inhibition of EP300 by
spermidine (which competes with the acetyl group
donor acetyl coenzyme A) stimulates auto-phagy [9]
Autophagy is required for the anti-aging effect of
spermidine as indicated by the fact that genetic
inhibition of autophagy (by knockout or knockdown of
essential autophagy-relevant genes) abolishes the lon-
gevity-extending effects of spermidine on yeast, worms
and flies [11]. Moreover, in mice, deletion/depletion of
essential autophagy genes in myocardial or cancer cells
reduces the beneficial effects of spermidine on cardio-
vascular disease and cancer, respectively [3, 4]. Auto-
phagy is a major mechanism of cellular adaptation to
stress, as well as the most important pathway for the
turnover of cytoplasmic structures including whole
organelles, thus facilitating the rejuvenation of impor-
tant portions of the cell. For this reason, autophagy has
a vast anti-aging potential to the point that most if not
all behavioural, nutritional, pharmacological or genetic
manipulations that extend longevity require autophagy
to be efficient [12-14].
Until now the literature on the longevity-enhancing
effects of spermidine has been limited to model orga-
nisms. Now, two prospective population-based studies
(summarized in the same paper) report for the first time
that nutritional spermidine uptake is also linked to
reduced overall, cardiovascular and cancer-related
mortality in humans [15]. Both studies were based on
the use of food questionnaires that allowed to calculate
for each individual the nutritional uptake of polyamines
including spermidine. Importantly, high spermidine
uptake constituted an independent favourable prog-
nostic parameter for reduced mortality, meaning that
this variable predicted a reduced incidence of death
even after correction for possible confounding factors
such as age, body mass index, consumption of alcohol
or aspirin, diabetes, metabolic syndrome, physical
activity, sex, socioeconomic status and even dietary
quality, supporting the idea that spermidine might
indeed be causally involved in a reduction of overall
morbidity and mortality [15].
In addition to the aforementioned epidemiological
results, there are further, though admittedly indirect
arguments in favour of a health-improving role for sper-
midine in human health. Thus, spermidine has been
classified as a “caloric restriction mimetic” that has
www.aging‐us.com    AGING2018,Vol.10,No. 8
Spermidinedelaysaginginhumans
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FrankMadeo,DidacCarmona-Gutierrez, OliverKepp, GuidoKroemer
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broad health-promoting effects due to its capacity to
induce similar biochemical changes as does caloric
restriction [16]. Second, the proximal pharmacological
target of spermidine is the same as that of salicylic acid,
the active metabolite or aspirin (both inhibit EP300 by
competing for the binding of acetyl coenzyme 1) [17],
knowing that aspirin is probable the one single drug that
has the broadest positive impact on human mortality
from cardiovascular and malignant disease [18].
The fine mechanism through which spermidine (and
aspirin) have such a broad effect on human health have
not yet been fully elucidated. Based on current know-
ledge, these agents may slow down the general clock of
the aging process, for instance by a global effect on
cellular fitness, thereby mediating a pleiotropic effect
on all aging-related diseases. The health-improving
effects of aspirin have been initially attributed to its
capacity to inhibit thrombocyte aggregation (via
inhibition of cyclooxygenase) and hence to act as an
anti-coagulant. Since spermidine has not been reported
to have similar anti-coagulant activity, we prefer the
hypothesis that aspirin may mediate its broad pro-health
effects via the inhibition of EP300. As an alternative,
yet non-exclusive mechanism, the natural EP300
inhibitor spermidine and its pharmacological equivalent
aspirin may both act on different yet distinct cell types
including stem cell compartments and differentiated
cells engaged in cardiovascular function (cardiac
muscle cells, endothelial cells, pericytes, small vessel
myocytes…), anticancer immune surveillance (cancer
and immune cells) or neuro-degeneration (neuronal and
glial cells) to reduce the incidence of the major age-
related diseases (Figure 1). Future research must
elucidate the molecular pathways on which spermidine
acts to identify actionable targets that may be used for
the treatment and prevention of age-related diseases.
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Figure1.Possiblemechanismsofspermidine‐mediated
rejuvenation.Spermidinemaycounteractthegeneralclock
ofaging,byaglobaleffectoncellularfitness(A),ormayexert
specificeffectsonmultipleorgansystemsengagedinfor
examplecardiovascularfunction,anticancerimmunesurveil‐
lanceorneurodegenerationandtherebyreducingtheinciden‐
ceofthemajorage‐relateddiseases(B).

GuidoKroemer:CentredeRecherchedesCordeliers,
75006ParisFrance

Correspondence:GuidoKroemer
Email:kroemer@orange.fr
Keywords:autophagy,healthspanextension,cancer
Funding:GKissupportedbytheLiguecontreleCancer
(équipelabellisée);AgenceNationaldelaRecherche(ANR)
–Projetsblancs;ANRundertheframeofE‐Rare‐2,the
ERA‐NetforResearchonRareDiseases;Associationpour
larecherchesurlecancer(ARC);CancéropôleIle‐de‐
France;ChanceleriedesuniversitésdeParis(LegsPoix),
FondationpourlaRechercheMédicale(FRM);adonation
byElior;theEuropeanCommission(ArtForce);European
ResearchAreaNetworkonCardiovascularDiseases(ERA‐
CVD,MINOTAUR);theEuropeanResearchCouncil(ERC);
FondationCarrefour;InstitutNationalduCancer(INCa);
Inserm(HTE);InstitutUniversitairedeFrance;LeDucq
Foundation;theLabExImmuno‐Oncology;theRHUTorino
Lumière;theSeeraveFoundation;theSIRICStratified
OncologyCellDNARepairandTumorImmuneElimination
(SOCRATE);theSIRICCancerResearchandPersonalized
Medicine(CARPEM);andtheParisAllianceofCancer
ResearchInstitutes(PACRI).F.M.isgratefultothe
AustrianScienceFundFWF(Austria)forgrantsP23490‐
B20,P29262,P24381,P29203P27893,I1000,“SFB
Lipotox”(F3012),andDKplusMetabolicand
CardiovascularDiseases(W1226),aswellasto
BundesministeriumfürWissenschaft,Forschungund
WirtschaftandtheKarl‐FranzensUniversityforgrants
“UnkonventionelleForschung”.Weacknowledgesupport
fromNAWIGrazandtheBioTechMed‐Grazflagship
project“EPIAge.”
Conflictsofinterest: Allauthorsarethescientificfounders
ofSamsaraTherapeutics.DidacCarmona‐Gutierrezand
FrankMadeohaveequityinterestinTheLongevityLabs.
Copyright:Madeoetal.Thisisanopen‐accessarticle
distributedunderthetermsoftheCreativeCommons
AttributionLicense(CCBY3.0),whichpermitsunrestricted
use,distribution,andreproductioninanymedium,
providedtheoriginalauthorandsourcearecredited

Received:July19,2018
Published:August6,2018
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