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Spermidine delays aging in humans

Authors:
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.agingus.com   AGING2018,Vol.10,No. 8
Spermidinedelaysaginginhumans
FrankMadeo,DidacCarmona-Gutierrez, OliverKepp, GuidoKroemer
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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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Figure1.Possiblemechanismsofspermidinemediated
rejuvenation.Spermidinemaycounteractthegeneralclock
ofaging,byaglobaleffectoncellularfitness(A),ormayexert
specificeffectsonmultipleorgansystemsengagedinfor
examplecardiovascularfunction,anticancerimmunesurveil
lanceorneurodegenerationandtherebyreducingtheinciden
ceofthemajoragerelateddiseases(B).
GuidoKroemer:CentredeRecherchedesCordeliers,
75006ParisFrance
Correspondence:GuidoKroemer
Email:kroemer@orange.fr
Keywords:autophagy,healthspanextension,cancer
Funding:GKissupportedbytheLiguecontreleCancer
(équipelabellisée);AgenceNationaldelaRecherche(ANR)
Projetsblancs;ANRundertheframeofERare2,the
ERANetforResearchonRareDiseases;Associationpour
larecherchesurlecancer(ARC);CancéropôleIlede
France;ChanceleriedesuniversitésdeParis(LegsPoix),
FondationpourlaRechercheMédicale(FRM);adonation
byElior;theEuropeanCommission(ArtForce);European
ResearchAreaNetworkonCardiovascularDiseases(ERA
CVD,MINOTAUR);theEuropeanResearchCouncil(ERC);
FondationCarrefour;InstitutNationalduCancer(INCa);
Inserm(HTE);InstitutUniversitairedeFrance;LeDucq
Foundation;theLabExImmunoOncology;theRHUTorino
Lumière;theSeeraveFoundation;theSIRICStratified
OncologyCellDNARepairandTumorImmuneElimination
(SOCRATE);theSIRICCancerResearchandPersonalized
Medicine(CARPEM);andtheParisAllianceofCancer
ResearchInstitutes(PACRI).F.M.isgratefultothe
AustrianScienceFundFWF(Austria)forgrantsP23490
B20,P29262,P24381,P29203P27893,I1000,“SFB
Lipotox”(F3012),andDKplusMetabolicand
CardiovascularDiseases(W1226),aswellasto
BundesministeriumfürWissenschaft,Forschungund
WirtschaftandtheKarlFranzensUniversityforgrants
“UnkonventionelleForschung”.Weacknowledgesupport
fromNAWIGrazandtheBioTechMedGrazflagship
project“EPIAge.”
Conflictsofinterest: Allauthorsarethescientificfounders
ofSamsaraTherapeutics.DidacCarmonaGutierrezand
FrankMadeohaveequityinterestinTheLongevityLabs.
Copyright:Madeoetal.Thisisanopenaccessarticle
distributedunderthetermsoftheCreativeCommons
AttributionLicense(CCBY3.0),whichpermitsunrestricted
use,distribution,andreproductioninanymedium,
providedtheoriginalauthorandsourcearecredited
Received:July19,2018
Published:August6,2018
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... As such, while our findings inform on the impact of donor chronological age and biological (e.g., sex and BMI) or genetic factors on inter-donor heterogeneity in arginine metabolism, vesiculation, and hemolytic propensity, this information could be leveraged to inform blood inventory management strategies beyond the standard firstin-first-out approach, whereby units from certain categories of donors (e.g., older, carrying SNPs relevant to arginine metabolism, with higher levels of certain arginine metabolites at donation) are preferentially issued on a priority basis. Independently from informing novel precision transfusion medicine strategies, the present findings also expand our understanding of arginine metabolism as a function of biological and genetic factors, which is relevant to aging and agerelated comorbidities in which anomalies in this pathway have been causally implicated and/or identified as potential therapeutic targets (Gad, 2010;He et al., 2024;Hofer et al., 2022;Madeo et al., 2018;Minois et al., 2011;Morselli et al., 2009;Nam et al., 2024;Polis et al., 2021;Viltard et al., 2019;Wang et al., 2020;Xu et al., 2020). ...
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... SAM also serves as a precursor to S-adenosyl-L-homocysteine (SAH), which donates an aminopropyl group for the synthesis of spermidine [171]. Tissue levels of spermidine have been reported to decline with age in both humans and model organisms [172][173][174], and spermidine has been recognized as a significant geroprotective compound found in food [175]. Remarkably, spermidine has been shown to significantly extend the lifespan of worms, yeast, flies, mice, and human immune cells [174,[176][177][178]. ...
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... As such, while our findings inform on the impact of donor chronological age and biological (e.g., sex and BMI) or genetic factors on inter-donor heterogeneity in arginine metabolism, vesiculation, and hemolytic propensity, this information could be leveraged to inform blood inventory management strategies beyond the standard firstin-first-out approach, whereby units from certain categories of donors (e.g., older, carrying SNPs relevant to arginine metabolism, with higher levels of certain arginine metabolites at donation) are preferentially issued on a priority basis. Independently from informing novel precision transfusion medicine strategies, the present findings also expand our understanding of arginine metabolism as a function of biological and genetic factors, which is relevant to aging and agerelated comorbidities in which anomalies in this pathway have been causally implicated and/or identified as potential therapeutic targets (Gad, 2010;He et al., 2024;Hofer et al., 2022;Madeo et al., 2018;Minois et al., 2011;Morselli et al., 2009;Nam et al., 2024;Polis et al., 2021;Viltard et al., 2019;Wang et al., 2020;Xu et al., 2020). ...
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Spermidine acts as an endogenous free radical scavenger and inhibits the action of reactive oxygen species. In this study, we examined the effects of spermidine on retinal ganglion cell (RGC) death in a mouse model of optic nerve injury (ONI). Daily ingestion of spermidine reduced RGC death following ONI and sequential in vivo retinal imaging revealed that spermidine effectively prevented retinal degeneration. Apoptosis signal-regulating kinase-1 (ASK1) is an evolutionarily conserved mitogen-activated protein kinase kinase kinase and has an important role in ONI-induced RGC apoptosis. We demonstrated that spermidine suppresses ONI-induced activation of the ASK1-p38 mitogen-activated protein kinase pathway. Moreover, production of chemokines important for microglia recruitment was decreased with spermidine treatment and, consequently, accumulation of retinal microglia is reduced. In addition, the ONI-induced expression of inducible nitric oxide synthase in the retina was inhibited with spermidine treatment, particularly in microglia. Furthermore, daily spermidine intake enhanced optic nerve regeneration in vivo. Our findings indicate that spermidine stimulates neuroprotection as well as neuroregeneration, and may be useful for treatment of various neurodegenerative diseases including glaucoma.
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Background: Spermidine administration is linked to increased survival in several animal models. Objective: The aim of this study was to test the potential association between spermidine content in diet and mortality in humans. Design: This prospective community-based cohort study included 829 participants aged 45-84 y, 49.9% of whom were male. Diet was assessed by repeated dietitian-administered validated food-frequency questionnaires (2540 assessments) in 1995, 2000, 2005, and 2010. During follow-up between 1995 and 2015, 341 deaths occurred. Results: All-cause mortality (deaths per 1000 person-years) decreased across thirds of increasing spermidine intake from 40.5 (95% CI: 36.1, 44.7) to 23.7 (95% CI: 20.0, 27.0) and 15.1 (95% CI: 12.6, 17.8), corresponding to an age-, sex- and caloric intake-adjusted 20-y cumulative mortality incidence of 0.48 (95% CI: 0.45, 0.51), 0.41 (95% CI: 0.38, 0.45), and 0.38 (95% CI: 0.34, 0.41), respectively. The age-, sex- and caloric ratio-adjusted HR for all-cause death per 1-SD higher spermidine intake was 0.74 (95% CI: 0.66, 0.83; P < 0.001). Further adjustment for lifestyle factors, established predictors of mortality, and other dietary features yielded an HR of 0.76 (95% CI: 0.67, 0.86; P < 0.001). The association was consistent in subgroups, robust against unmeasured confounding, and independently validated in the Salzburg Atherosclerosis Prevention Program in Subjects at High Individual Risk (SAPHIR) Study (age-, sex-, and caloric ratio-adjusted HR per 1-SD higher spermidine intake: 0.71; 95% CI: 0.53, 0.95; P = 0.019). The difference in mortality risk between the top and bottom third of spermidine intakes was similar to that associated with a 5.7-y (95% CI: 3.6, 8.1 y) younger age. Conclusion: Our findings lend epidemiologic support to the concept that nutrition rich in spermidine is linked to increased survival in humans. This trial was registered at http://www.clinicaltrials.gov as NCT03378843.
Article
The capacity of cells and organisms to sustain, and to eventually adapt to, environmental and genetic insults declines with age. Because macroautophagy/autophagy is regarded as one of the major determinants of cellular fitness in vitro and in vivo, maneuvers that aim at promoting autophagy may slow down aging and promote health span. Caloric restriction (CR), a reduction in caloric intake without malnutrition, efficiently counteracts aging-associated features, yet is difficult to be applied to humans. Caloric-restriction mimetics (CRMs) are pharmacological agents that recapitulate the main biochemical properties of CR, namely a global reduction of protein acetylation and the induction of autophagy. We found that the ancient drug aspirin and its active metabolite salicylate stimulate autophagic flux by virtue of their inhibitory action on acetyltransferase EP300. The inhibition of EP300 results from a direct competition between salicylate and acetyl coenzyme A for binding to the catalytic domain of the enzyme. This mode of action appears to be conserved across evolution as it accounts for the induction of autophagy by aspirin in various mouse models and in the nematode Caenorhabditis elegans. In sum, aspirin acts as a CRM.
Article
The age-associated deterioration in cellular and organismal functions associates with dysregulation of nutrient-sensing pathways and disabled autophagy. The reactivation of autophagic flux may prevent or ameliorate age-related metabolic dysfunctions. Non-toxic compounds endowed with the capacity to reduce the overall levels of protein acetylation and to induce autophagy have been categorized as caloric restriction mimetics (CRMs). Here, we show that aspirin or its active metabolite salicylate induce autophagy by virtue of their capacity to inhibit the acetyltransferase activity of EP300. While salicylate readily stimulates autophagic flux in control cells, it fails to further increase autophagy levels in EP300-deficient cells, as well as in cells in which endogenous EP300 has been replaced by salicylate-resistant EP300 mutants. Accordingly, the pro-autophagic activity of aspirin and salicylate on the nematode Caenorhabditis elegans is lost when the expression of the EP300 ortholog cpb-1 is reduced. Altogether, these findings identify aspirin as an evolutionary conserved CRM.
Article
Having your longevity and eating too Although caloric restriction has clear benefits for maximizing health span and life span, it is sufficiently unpleasant that few humans stick to it. Madeo et al. review evidence that increased intake of the polyamine spermidine appears to reproduce many of the healthful effects of caloric restriction, and they explain its cellular actions, which include enhancement of autophagy and protein deacetylation. Spermidine is found in foods such as wheat germ, soybeans, nuts, and some fruits and vegetables and produced by the microbiota. Increased uptake of spermidine has protective effects against cancer, metabolic disease, heart disease, and neurodegeneration. Science , this issue p. eaan2788
Article
Liver fibrosis and hepatocellular carcinoma (HCC) have worldwide impact but continue to lack safe, low cost and effective treatments. In this study, we show how the simple polyamine spermidine can relieve cancer cell defects in autophagy which trigger oxidative stress-induced cell death and promote liver fibrosis and HCC. We found that the autophagic marker protein LC3 interacted with the microtubule-associated protein MAP1S which positively regulated autophagy flux in cells. MAP1S stability was regulated in turn by its interaction with the histone deacetylase HDAC4. Notably, MAP1S-deficient mice exhibited a 20% reduction in median survival and developed severe liver fibrosis and HCC under stress. Wild-type mice or cells treated with spermidine exhibited a relative increase in MAP1S stability and autophagy signaling via depletion of cytosolic HDAC4. Extending recent evidence that orally administered spermidine can extend lifespan in mice, we determined that life extension of up to 25% can be produced by lifelong administration which also reduced liver fibrosis and HCC foci as induced by chemical insults. Genetic investigations established that these observed impacts of oral spermidine administration relied upon MAP1S-mediated autophagy. Our findings offer a preclinical proof of concept for the administration of oral spermidine to prevent liver fibrosis and HCC and potentially extend lifespan.
Article
Several metabolic alterations accumulate over time along with a reduction in biological fitness, suggesting the existence of a “metabolic clock” that controls aging. Multiple inborn defects in metabolic circuitries accelerate aging, whereas genetic loci linked to exceptional longevity influence metabolism. Each of the nine hallmarks of aging is connected to undesirable metabolic alterations. The main features of the “westernized” lifestyle, including hypercaloric nutrition and sedentariness, can accelerate aging as they have detrimental metabolic consequences. Conversely, lifespan-extending maneuvers including caloric restriction impose beneficial pleiotropic effects on metabolism. The introduction of strategies that promote metabolic fitness may extend healthspan in humans.
Article
Caloric restriction mimetics (CRMs) mimic the biochemical effects of nutrient deprivation by reducing lysine acetylation of cellular proteins, thus triggering autophagy. Treatment with the CRM hydroxycitrate, an inhibitor of ATP citrate lyase, induced the depletion of regulatory T cells (which dampen anticancer immunity) from autophagy-competent, but not autophagy-deficient, mutant KRAS-induced lung cancers in mice, thereby improving anticancer immunosurveillance and reducing tumor mass. Short-term fasting or treatment with several chemically unrelated autophagy-inducing CRMs, including hydroxycitrate and spermidine, improved the inhibition of tumor growth by chemotherapy in vivo. This effect was only observed for autophagy-competent tumors, depended on the presence of T lymphocytes, and was accompanied by the depletion of regulatory T cells from the tumor bed.