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Spermidine: A novel autophagy inducer and longevity elixir

Article · Literature Review (PDF Available) inAutophagy 6(1):160-2 · January 2010with892 Reads
DOI: 10.4161/auto.6.1.10600 · Source: PubMed
Abstract
Spermidine is a ubiquitous polycation that is synthesized from putrescine and serves as a precursor of spermine. Putrescine, spermidine and spermine all are polyamines that participate in multiple known and unknown biological processes. Exogenous supply of spermidine prolongs the life span of several model organisms including yeast (Saccharomyces cerevisiae), nematodes (Caenorhabditis elegans) and flies (Drosophila melanogaster) and significantly reduces age-related oxidative protein damage in mice, indicating that this agent may act as a universal anti-aging drug. Spermidine induces autophagy in cultured yeast and mammalian cells, as well as in nematodes and flies. Genetic inactivation of genes essential for autophagy abolishes the life span-prolonging effect of spermidine in yeast, nematodes and flies. These findings complement expanding evidence that autophagy mediates cytoprotection against a variety of noxious agents and can confer longevity when induced at the whole-organism level. We hypothesize that increased autophagic turnover of cytoplasmic organelles or long-lived proteins is involved in most if not all life span-prolonging therapies.
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Autophagy 6:1, 160-162; January 1, 2010; © 2010 Landes Bioscience
160 Autophagy Volume 6 Issue 1
AUTOPHAGIC PUNCTUM
Key words: spermidine, autophagy,
aging, ageing, epigenetic, histone, acety-
lation, longevity, polyamine
Submitted: 10/27/09
Revi sed: 11/11/ 09
Accepted: 11/11/09
Previously published online:
www.landesbioscience.com/journals/
autophagy/article/10600
*Correspondence to: Frank Madeo and
Guido Kroemer; Email: frank.madeo@uni-graz.at
and kroemer@orange.fr
Spermidine is a ubiquitous polycation
that is synthesized from putrescine
and serves as a precursor of spermine.
Putrescine, spermidine and spermine all
are polyamines that participate in multi-
ple known and unknown biological pro-
cesses. Exogenous supply of spermidine
prolongs the life span of several model
organisms including yeast (Saccharomyces
cerevisiae), nematodes (Caenorhabditis
elegans) and flies (Drosophila melano-
gaster) and significantly reduces age-
related oxidative protein damage in mice,
indicating that this agent may act as a
universal anti-aging drug. Spermidine
induces autophagy in cultured yeast and
mammalian cells, as well as in nematodes
and flies. Genetic inactivation of genes
essential for autophagy abolishes the life
span-prolonging effect of spermidine in
yeast, nematodes and flies. These find-
ings complement expanding evidence
that autophagy mediates cytoprotection
against a variety of noxious agents and
can confer longevity when induced at
the whole-organism level. We hypoth-
esize that increased autophagic turnover
of cytoplasmic organelles or long-lived
proteins is involved in most if not all life
span-prolonging therapies.
A decrease in cellular polyamine content
has been repeatedly correlated with aging.
Therefore, we tested the effects of exter-
nal spermidine administration on aging,
using yeast as a model. When applied at
millimolar concentrations, spermidine
efficiently increased chronological life
span (that is the time that a yeast culture
remains viable in stationary phase) while
it retarded necrotic cell death. In addi-
tion, spermidine could rejuvenate repli-
catively old yeast cells as their replicative
life span was increased (that is the num-
ber of daughter cells generated from one
single mother cell). Chronological aging
is conceived as a model of aging affecting
postmitotic cells from animals, whereas
replicative aging is thought to reflect the
aging process of proliferating cells such as
stem cells. Driven by the discovery that
spermidine improved both the chronolog-
ical and the replicative life span of yeast
cells, we tested its effect on the aging of
several animal species. We found indeed
that spermidine had a beneficial anti-
aging effect on nematodes and fruit ies
when added to their food, again at milli-
molar concentrations. Moreover, addition
of spermidine could retard the spontane-
ous loss of viability of human peripheral
blood mononuclear cells (PBMC) in vitro.
This effect was obtained at relatively low
concentrations (around 20 nM), and it
is not entirely clear whether this reflects
a similar mode of action as that obtained
in whole organisms. When mice were
supplied with 3 mM spermidine in the
drinking water, they manifested reduced
age-associated protein oxidation, which is
one of the hallmarks of aging. Altogether,
these results illustrate spermidine’s poten-
tial to promote longevity.
Encouraged by the aforementioned
observations, we decided to determine the
mechanisms through which spermidine
might exert its anti-aging effect. Driven
by the knowledge that sirtuins may pro-
mote longevity by catalyzing the deacety-
lation of histones, we investigated whether
Spermidine
A novel autophagy inducer and longevity elixir
Frank Madeo,1,* Tobias Eisenberg,1 Sabrina Büttner,1 Christoph Ruckenstuhl1 and Guido Kroemer2- 4,*
1Institute of Molecular Biosciences; University of Graz ; Graz, Austria; 2INSERM, U848; Villejuif, France; 3Institut Gustave Roussy; Villejuif, France ;
4University Paris Sud; Villejuif, France
Punctum to: Eisenberg T, Knauer H, Schauer A,
Büttner S, Ruckenstuhl C, Carmona- Gutierrez D,
Ring J, Schroeder S, Magnes C, Antonacci L, Fussi
H, Deszcz L, Har tl R, Schraml E, Criollo A, Megalou
E, Weiskopf D, Laun P, Heeren G, Breitenbach M,
Grubeck-Loebenstein B, Herker E, Fahrenkrog B,
Fröhlich KU, Sinner F, Tavernarakis N, Minois N,
Kroemer G, Madeo F. Induction of autophagy
by spermidine promotes longevity. Nat Cell Biol
2009; 11:1305-14; PMID: 19801973; DOI: 10.1038/
nc b1975.
www.landesbioscience.com Autophagy 161
AUTOPHAGIC PUNCTUM
ARTICLE ADDENDUM
remained selectively acetylated, allowing
for its transcription in a state of general
gene silencing. The spermidine-driven
transactivation of autophagy-related genes
indeed induced signs of macroautophagy
(Fig. 1). In this context it should be noted
that Sirtuin-1-induced autophagy has
been correlated with the deacetylation of
essential autophagy-related proteins such
as Atg5 and Atg7. Therefore, it remains
to be investigated whether spermidine
might induce autophagy by a combina-
tion of transcriptional and cytoplasmic
(transcription-independent) mechanisms
(Fig. 1).
Spermidine induced signs of macroau-
tophagy in all systems that we investi-
gated including yeast cells, C. elegans,
Drosophila and human tumor cells. Thus,
the microtubule-associated light chain 3
(LC3), also called Atg8 protein, redistrib-
uted from a diffuse location to a punctate
cytoplasmic location, at the surface of
autophagosomes. Moreover, LC3/Atg8
underwent lipidation (which increases its
electrophoretic mobility), a post-trans-
lational modification that is required for
its association with autophagosome mem-
branes. Ultrastructural analyses confirmed
the formation of characteristic two-mem-
braned vesicles indicative of autophagy in
spermidine-treated cells. Since autophagy
is impaired in innumerous pathological
conditions, medical application of sper-
midine as a natural autophagy-inducing
treatment is of most interest for future
research. Hence, its applicability to other
cell types and conditions—associated
with a variety of pathological conditions
that differ from aging—should be tested.
Finally, we found that inhibition
of autophagy by knockout of essential
autophagy-related genes (such as ATG5,
ATG6 (bec-1 in C. elegans) or ATG7) abro-
gated the life span-prolonging effect of
spermidine in yeast, nematodes and ies,
indicating that induction of autophagy is
indeed essential for the anti-aging activity
of spermidine. In this respect, it should be
mentioned that pharmacological induc-
tion of autophagy using rapamycin also
has life span-prolonging effects in yeast,
flies and in mice. Moreover, caloric restric-
tion can only prolong the life span of C.
elegans that harbor an intact autophagic
machinery. These results suggest that
transferases (HAT) in an in vitro HAT
activity assay. Importantly, spermidine also
reduced the acetylation of histone H3 in
human PBMC cultured in its presence and
changed the acetylation pattern of tissues
from mice that received oral spermidine.
This suggests that histone H3 deacetyla-
tion is a general correlate of the life span-
extending action of spermidine. In yeast
cells, spermidine causes hypoacetylation
of histone H3 associated with several
promotor regions (adjacent to ATG7 ),
while the promotor region of ATG7 itself
spermidine may affect the acetylation of
histones as well. We observed that spermi-
dine-treated yeast cells exhibited a marked
hypoacetylation of histone H3 at all acety-
lation sites located at the amino terminal
tail (Lys 9, 14 and 18). Given that spermi-
dine exerted its life-span extension also in
yeast cells that lack the ortholog of sirtuin
1 (SIR 2), we postulated that spermidine
must affect another enzyme that catalyzes
histone (de)acetylation. Accordingly, we
found that spermidine directly inhibited
the enzymatic activity of histone acetyl
Figure 1. Mechanism of spermidine-enhanced longevity in yeast. Spermidine inhibits histone
acetyl transferases (such as Iki3p and Sas3p), thereby reducing the acetylation of histone H3 (and
perhaps that of other proteins). This leads to epigenetic reprogramming of the transcriptome,
resulting in an enhanced expression of autophagy-related genes in the context of a general
silencing of many other genes. Autophagy, in turn, causes an increase in chronological life span.
In addition, spermidine might have yet elusive transcription-independent eects that stimulate
autophagy and confer longevit y.
162 Autophagy Volume 6 Issue 1
autophagy might be a common pathway
of several (if not all) life span-prolonging
measures. This hypothesis requires urgent
exploration.
Acknowledgements
G.K. is supported by grants from Ligue
contre le Cancer, Agence Nationale pour
la Recherche, Institut National du Cancer,
Fondation pour la Recherche Médicale,
and European Union (active p53, Apo-
Sys, Apop-Train, ChemoRes). We are
grateful to the European Union for grant
Apo-Sys (FP7) to F.M. and T.E. and to
the Austrian Science Fund (FWF) for
grant S-9304-B05 and “Lipotox” to F.M.
and for grant T-414-B09 to S.B. (Hertha-
Firnberg fellowship).
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