Paths of Convergence:
Sirtuins in Aging and Neurodegeneration
Li Gan1,2,* and Lennart Mucke1,2,*
1Gladstone Institute of Neurological Disease, 1650 Owens Street, San Francisco, CA 94158, USA
2Department of Neurology, University of California, San Francisco, San Francisco, CA 94158, USA
*Correspondence: email@example.com (L.G.), firstname.lastname@example.org (L.M.)
Members of the sirtuin family of protein deacetylases support and promote longevity in diverse organisms
and can extend life span when upregulated. Sirtuin pathways also modulate fundamental mechanisms in
aging-related neurodegenerative diseases, including protein aggregation, stress responses, mitochondrial
the neurobiology of sirtuins is shedding light on the pathogenesis of these devastating conditions. We will
also examine the potential and challenges of targeting sirtuin pathways therapeutically.
ciated neurodegenerative diseases pose major medical and
economic challenges to modern societies. Indeed, the increas-
ing prevalence of these disorders threatens to overwhelm our
healthcare systems. Although significant progress has been
made in deciphering the molecular mechanisms underlying
these conditions, there is an urgent need for better strategies
to stall, reverse, and prevent them.
Although neurodegenerative diseases have distinct clinical
manifestations, mostly due to the impairment of specific neural
networks, they have features in common, including the intra- or
extracellular accumulation of misfolded proteins, compromised
stress responses, mitochondrial dysfunction, and inflammation.
Most of these processes are strongly influenced by aging, the
predominant and unifying risk factor for neurodegenerative
diseases. Thus, activating molecular pathways that slow
aging may provide a broad strategy to treat and prevent these
conditions. This is where sirtuins may come into play.
Sirtuins—A Family of Histone Deacetylases
Sirtuins were first identified in Saccharomyces cerevisiae as si-
its name (Rine and Herskowitz, 1987). These class III histone
deacetylases (HDACs) consume one nicotinamide adenine
dinucleotide (NAD+) for every acetyl group they remove from
a protein substrate (Landry et al., 2000). Their activities produce
deacetylated proteins, nicotinamide, and O-acetyl-ADP-ribose
(OAADPr) (Tanner et al., 2000). Sirtuins are dependent on the rel-
ative levels of NAD+and NADH and are thus uniquely responsive
to the redox and metabolic states of a cell.
Sirtuins are phylogenetically conserved from bacteria to
humans and regulate cell functions by deacetylating both his-
tone and nonhistone targets. Sir2 in S. cerevisiae is the founding
member of the sirtuin gene family, and its deacetylase activity is
required for chromatin silencing at mating-type loci, telomeres,
and the ribosomal DNAlocus (Buck etal., 2004).There areseven
human homologs (SIRT1–7), which are divided into four classes
according tophylogeneticanalysis (Frye,2000) (Table1).SIRT1–
3 are robust deacetylases, whereas SIRT4–6 exhibit weak de-
acetylase activity on substrates that have been tested so far.
The distinct subcellular localizations of the sirtuins also con-
tribute to their diverse functions (Saunders and Verdin, 2007).
SIRT1, SIRT6, and SIRT7 reside predominantly in the nucleus
and have been implicated in genomic stability and cell prolifera-
of its nonhistone substrates have been identified, including p53,
NF-kB, forkhead transcription factor (FOXO), Ku70, peroxisome
proliferator-activated receptor-g coactivator-1a (PGC-1a), and
liver X receptor (LXR) (Li et al., 2007b; Motta et al., 2004; Nemoto
et al., 2005; Rodgers et al., 2005; Vaziri et al., 2001; Yeung et al.,
2004). SIRT2, which resides mostly in the cytoplasm, is involved
in mitosis and differentiation of oligodendrocytes, likely through
deacetylation of tubulins (Li et al., 2007a; North et al., 2003). Be-
cause SIRT3, SIRT4, and SIRT5 are localized in mitochondria,
they may play a role in energy metabolism and responses to
In this review, we will focus on SIRT1 and, to a lesser extent,
SIRT2, because these sirtuins play important roles in aging and
neurodegeneration and because next to nothing is known about
the roles of the other sirtuins in the central nervous system.
The Pleiotropic Antiaging Effects of Sirtuins
and Caloric Restriction
In organisms ranging from protozoa to metazoa, activation of
sirtuins delays the aging process. The replicative life span of
S.cerevisiae isshortened bythedeletion ofSIR2andlengthened
by the overexpression of Sir2 (Kaeberlein et al., 1999). In
Caenorhabditis elegans, life span extension induced by Sir-2.1
(the Sir2 ortholog) is mediated through activation of FOXO tran-
scription factor DAF-16 (Tissenbaum and Guarente, 2001). The
direct interaction of Sir-2.1 with DAF-16 is dependent on
Sir-2.1’s association with 14-3-3 proteins (Berdichevsky et al.,
2006) but is independent of insulin/insulin-like growth factor
(IGF)-1 signaling, which also regulates longevity by activating
DAF-16 (Kenyon, 2001). In Drosophila melanogaster, overex-
Neuron 58, April 10, 2008 ª2008 Elsevier Inc.
extends the life span of mice fed a high-caloric diet (Baur et al.,
2006). However, whether increased SIRT1 activity promotes
longevity also in mammals fed a normal diet has not yet been
The most studied nongenetic strategy to extend life span is
caloric restriction (CR), which activates sirtuin pathways (Kenyon,
2001). However, the link between CR-induced longevity and sir-
tuin activation remains somewhat tenuous. There is evidence
that CR extends life span by increasing the activity of Sir2 in
S. cerevisiae (Lin et al., 2000) or the activities of its orthologs
in C. elegans and D. melanogaster (Wood et al., 2004). However,
under certain conditions, CR can also extend life span in
S. cerevisiae in a Sir2-independent manner (Kaeberlein et al.,
2004). CR increases SIRT1 expression in various rat tissues, but
whether CR-induced life span extension in mammals is mediated
by SIRT1 remains unknown. Notably, SIRT1 was required for se-
rum from calorically restricted rats to inhibit Bax-mediated
apoptosis in cultured human cells (Cohen et al., 2004). Moreover,
type mice, but not in SIRT1 knockout mice (Chen et al., 2005a).
Some of the beneficial effects found in calorically restricted wild-
type mice have also been observed in SIRT1-overexpressing
transgenic mice on a regular diet (Bordone et al., 2007). These
findings raise the possibility that at least some of the beneficial
effects of CR in mammals are mediated by sirtuins.
Sirtuins Regulate the Aggregation and Removal
of Misfolded Proteins
Abnormal accumulation of misfolded proteins appears to play
a pivotal role in diverse neurodegenerative diseases (Figure 1).
Pertinent molecules include Ab peptides and tau in AD, a-synu-
clein in Parkinson’s disease (PD), TDP-43 in frontotemporal
dementia, and mutant huntingtin in Huntington’s disease (HD)
(Muchowski and Wacker, 2005).
life? Recent studies suggest that aging promotes the accumula-
be counteracted by antiaging pathways (Figure 1). In C. elegans,
for instance, the accumulation and toxicity of mutant huntingtin
were markedly delayed in an age-1 mutant that has reduced
IGF-1 signaling and extended life span (Morley et al., 2002). This
effect depended on the FOXO transcription factor DAF-16, the
SIRT1). DAF-16 was also required for reduced insulin/IGF-1 sig-
naling to protect against Ab toxicity in C. elegans, an effect that
may relate to increased formation of larger Ab aggregates, which
are less toxic than smaller Ab assemblies (Cohen et al., 2006).
Interestingly, the formation of large and less toxic a-synuclein
aggregates in a cellular model of PD was enhanced by inhibition
of SIRT2 (Outeiro et al., 2007). Specific SIRT2 inhibitors also re-
duced a-synuclein-dependent neuronal deficits in primary neu-
ronal midbrain cultures expressing a mutant form of a-synuclein
that activation of the SIRT1 pathway and inhibition of the SIRT2
pathway have similar effects on the aggregation of misfolded
proteins may be due to the distinct subcellular localization of
these sirtuins and/or to differences in their substrates.
Sirtuins may also regulate the steady-state levels of misfolded
proteins by blocking their production or facilitating their removal.
In mammalian neurons, increased expression of SIRT1 pre-
vented Ab production by promoting the antiamyloidogenic
cleavage of APP by a-secretase, a process that involved inhibi-
tion of ROCK1 expression (Qin et al., 2006). In cultured human
embryonic kidney cells, the Ab-reducing effect of resveratrol
was mediated by proteasome-dependent intracellular Ab degra-
dation (Marambaud et al., 2005). Recent evidence also suggests
that SIRT1 deacetylates autophagy genes and stimulates basal
rates of autophagy (Lee et al., 2008), which has emerged as an
important route for the removal of toxic misfolded protein aggre-
gates that accumulate in neurodegenerative diseases (Levine
and Kroemer, 2008). Defining the precise roles of sirtuins in the
production, assembly, and degradation of pathogenic proteins
may help elucidate the etiology of neurodegenerative diseases
and open up new avenues for therapeutic intervention.
Sirtuins Regulate Stress Responses and Cell Survival
Aging and neurodegenerative diseases are both associated with
of cell loss differs between the conditions. It has been hypothe-
sized for some time that oxidative stress, DNA damage, and
defects in DNA repair may play a causal role in neuronal loss
(Rass et al., 2007).
In response to DNA damage and oxidative stress, SIRT1 di-
rectly deacetylates p53, repressing p53-dependent apoptosis
(Luo et al., 2001; Vaziri et al., 2001) (Figure 1). Treatment with
resveratrol resulted in deacetylation of p53, reduced neuronal
loss, and improved associative learning in p25 transgenic mice,
and, without treatment, show significant neuronal loss and cog-
nitive impairments (Kim et al., 2007). Similarly, overexpression
of SIRT1 protected against neurodegeneration induced by a
lateral sclerosis (Kim et al., 2007). Whether SIRT1 protects neu-
rons in these models by deacetylating and inactivating p53
remains to be determined. Other cellular substrates in the DNA
repair and stress-response pathway may be involved. For exam-
ple, SIRT1 deacetylates the DNA repair protein Ku70, enabling
Ku70 to interact with Bax, which prevents Bax from interacting
with mitochondria and inducing apoptosis (Cohen et al., 2004)
Table 1. Classification of Mammalian Sirtuins and Their
Mammals D. melanogasterC. elegans S. cerevisiae
SIRT1 dSir2 (D. mel 1) Sir-2.1 Sir2 & Hst1
SIRT2/3 D. mel 2– Hst2
Class IISIRT4D. mel 3 C. ele 2 & 3–
Class IVSIRT6D. mel 4 C. ele 4–
SIRT7D. mel 5––
The seven mammalian sirtuins and their orthologs in other eukaryotes are
classified into four classes according to phylogenetic analysis (Frye,
2000). Genes in bold are discussed in detail in this minireview. Dashes
indicate that no corresponding molecules have been identified.
Neuron 58, April 10, 2008 ª2008 Elsevier Inc.
Forkhead transcription factors of the FOXO subfamily are
transactivators that share functional similarities and participate
in crosstalk with p53 (Pinkston-Gosse and Kenyon, 2007).
FOXOs induce the transcription of a variety of genes involved in
stress responses and survival, including DNA repair (GADD45),
oxidative stress (MnSOD), cell-cycle arrest (p27kip1), and apo-
potsis (BIM). Depending on the promoters, the effects of SIRT1
on FOXO-induced gene expression range from activation to re-
pression (Figure 1). In general, SIRT1 appears to shift FOXO-in-
duced responses away from death by inhibiting apoptotic genes
(BIM) and toward survival by promoting the expression of
GADD45, p27kip1, and MnSOD (Brunet et al., 2004). Interest-
ingly, SIRT2-mediated deacetylation of FOXO3aelevates the ex-
reactive oxygen species but promotes cell death when cells are
ity of sirtuins in the cellular stress response (Figure 1). However,
because some related studies were performed in nonneuronal
transformed cell lines, many aspects of the intricate crosstalk
between sirtuins and FOXO-dependent pathways need to be
re-examined in postmitotic neurons.
Sirtuins may also play a role in axonal degeneration, although
this area is quite controversial. For example, it has been debated
whether SIRT1 is responsible for the delay in injury-induced
axonal degeneration in Wldsmutant mice (Fainzilber and Twiss,
2006). The Wldsmutant protein consists of the N-terminal 70
amino acids of the Ube4b ubiquitination assembly factor fused
with full-length nicotinamide mononucleotide adenyltransfer-
ase-1 (Nmnat1). Opinions are divided as to whether the protec-
tion is mediated by (1) a dominant-negative effect of Ube4b, (2)
an increase in Nmnat, an essential enzyme in the biosynthesis
pathway leading to NAD, which in turn is required for SIRT1 ac-
tivation, or (3) the effects of regulatory regions outside the two
open reading frames (Fainzilber and Twiss, 2006). Even among
the studies supporting a protective role of increased Nmnat
activity, the involvement of SIRT1 is controversial. For example,
NAD was applied locally (Wang et al., 2005). This discrepancy
might be explained by the different time frames studied (12–72 hr
in the former study and 4–12 hr in the latter). Intriguingly, in
Wldsmice, tubulin is hyperacetylated, and overexpression of
SIRT2 led to tubulin deacetylation and reversed the delay in in-
jury-induced axonal degeneration in Wldsgranule cells,suggest-
ing that inhibition of SIRT2 is protective by regulating microtu-
bule acetylation and stability (Suzuki and Koike, 2007). Sorting
out the complex roles of sirtuins in axonal degeneration remains
a challenging objective.
Sirtuins Modulate Mitochondrial Functions
Various factors contribute to mitochondrial dysfunction in neuro-
degenerative diseases (Lin and Beal, 2006). Remarkably, in
a proteomic survey of proteins acetylated on lysine residues,
more than 20% of them were mitochondrial proteins involved
in longevity regulators and metabolism (Kim et al., 2006). This
study supports the importance of sirtuin-mediated deacetylation
in the maintenance of mitochondrial functions during aging. Par-
ticularly interesting in this regard is PGC-1a, a master regulator
of mitochondrial number and function, which is directly deacety-
lated and activated by SIRT1 (Rodgers et al., 2005) (Figure 1).
It exerts robust protection against neuronal injury induced by
hydrogen peroxide, the excitotoxin kainic acid, and the PD-re-
lated neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydro-pyridine
(St-Pierre et al., 2006). Mutant huntingtin inhibits expression of
PGC-1a, leading to impairment of mitochondrial function (Cui
et al., 2006). In transgenic mouse models of HD, genetic deletion
of PGC-1a exacerbates the degeneration of striatal neurons and
motor abnormalities (Cui et al., 2006). In contrast, overexpres-
tin in these models and in cell culture (Cui et al., 2006). Further-
more, activation of SIRT1 prevented polyglutamine-induced cell
Figure 1. Potential Roles of Sirtuins in Aging and
Shown are major pathways and downstream mediators by
which SIRT1 and SIRT2 may regulate aging and neurodegen-
erative processes, including protein aggregation (DAF-16),
stress responses (FOXO, p53, Ku70), mitochondrial dysfunc-
tion (PGC-1a), and inflammation (NF-kB and LXR). Some of
the downstream mediators are involved in multiple pathways.
For example, FOXO transcription factors regulate genes in-
volved in stress responses (GADD45, MnSOD, p27kip),
survival (Bim), and the aggregation and degradation of pro-
teins. In a similar vein, the processes that sirtuins affect are
highly interconnected. For example, abnormal protein aggre-
gates may injure neurons directly or indirectly by activating
inflammatory processes, which can further enhance protein
aggregation. By intervening at one or more critical steps,
sirtuins could block vicious cycles and exert broad protective
effects. Arrows indicate activation; blunt arrows indicate
Neuron 58, April 10, 2008 ª2008 Elsevier Inc.
death in striatal neurons derived from HdhQ111 knockin mice
(Parker et al., 2005). These findings suggest that SIRT1 counter-
acts HD-related mitochondrial impairments by activating
Sirtuins as Anti-inflammatory Mediators
Aging is associated with an upregulation of genes involved in
inflammatory responses in the human brain (Lu et al., 2004).
CR, which activates sirtuin pathways, attenuates this upregula-
tion (Cao et al., 2001), suggesting an intriguing connection be-
tween the anti-inflammatory function of sirtuins and their potent
The molecular mechanisms of age-related inflammation are
unclear. Potential mechanisms include the activation of redox-
sensitive transcription factors by the cumulative effects of oxida-
tive damage during aging. For example, increased production of
reactive oxygen species during aging is associated with upregu-
lation of NF-kB (Kabe et al., 2005). Activation of NF-kB, in turn,
induces the expression of proinflammatory genes, including cy-
tokines, growth factors, and chemokines (Mattson and Meffert,
2006). Because some of the NF-kB-induced proteins are also
potent NF-kB activators, the resulting vicious cycle may contrib-
ute to the establishment of a chronic inflammatory state and
Prolonged innate immune responses, including prominent
generative diseases (Figure 1). In primary rat glial-neuronal cul-
tures, Ab1-42 dimers elicit the death of primary neurons only in
the presence of microglia (Roher etal., 1996). Constitutive inhibi-
tion of NF-kB signaling in microglia by expression of a non-
degradable IkBa superrepressor blocked this neurotoxicity,
indicating a critical role for microglial NF-kB signaling in Ab-de-
pendent neurodegeneration (Chen et al., 2005b). Notably, NF-
kB-dependent transcription can be repressed by SIRT1, which
deacetylates RelA/p65 at lysine 310 (Yeung et al., 2004). In-
creased expression of SIRT1 or treatment with resveratrol mark-
edly reduced Ab-dependent NF-kB activation in microglia and
neuronal loss, suggesting that sirtuins block neuropathogenic
inflammatory loops (Chen et al., 2005b) (Figure 1).
LXRs further highlights the anti-inflammatory function of sirtuins
(Li et al., 2007b) (Figure 1). Originally identified as key regulators
glia (Joseph et al., 2003), and LXR signaling lowers Ab levels in
of the direct transcriptional target of the LXR, ATP-binding
cassette transporter A1, in neuronal cells (Sun et al., 2003).
More recent data suggest that LXR activation may also lower Ab
levels by promoting the phagocytic ability of microglia (Zelcer
et al., 2007). Because of the prominence of microglial activation
in diverse neurodegenerative conditions, these effects of sirtuins
and LXRs could have important therapeutic implications.
Conclusions and Perspectives
Activation of sirtuin signaling pathways has diverse antiaging ef-
delaying aging-related ailments, including neurodegenerative
diseases. By identifying downstream effectors of sirtuins, recent
studies have unraveled some of the mysteries underlying the
pleiotropic antiaging effects of sirtuin activation (Figure 1).
Sirtuins can block several processes that may contribute to
aging-dependent neuronal injury, including the abnormal aggre-
gation and accumulation of misfolded proteins, the engagement
of cell-death pathways, and mitochondrial dysfunction. By en-
hancing stress resistance and promoting repair processes, sir-
tuins can counteract the results of increasing oxidative damage.
Besides protecting neurons directly, sirtuin activators also re-
press pathogenic inflammatory responses of glial cells.
From a therapeutic perspective, it is promising that the activity
of some sirtuins and of some of their downstream mediators,
such as LXR receptors (Joseph et al., 2003), can be enhanced
by small-compound activators. Activation of SIRT1 by the non-
specific sirtuin activator resveratrol reduces insulin resistance,
increases mitochondrial function, and prolongs survival in mice
fed a high-fat diet (Baur et al., 2006; Lagouge et al., 2006). Highly
potent and much more specific SIRT1 activators that are struc-
turally unrelated to resveratrol improve whole-body glucose
homeostasis and insulin sensitivity in mouse models related
to type-2 diabetes (Milne et al., 2007). However, it remains to
be determined whether these SIRT1 activators can pass the
blood-brain barrier and how they may affect brain functions in
It isalso important to notethat the effects and regulation of sir-
tuins areextremely complex.Broad activation ofsirtuins willlead
to deacetylation of histones and various nonhistone proteins,
which may affect diverse cellular functions. For example,
SIRT1 and SIRT2 appear to have opposite effects on the aggre-
gation of misfolded proteins. Moreover, depending on the cell
sirtuin may have divergent outcomes. For example, in primary
cells that have DNA damage, wild-type p53, and FOXO, SIRTI
activation leads to cell-cycle arrest and promotes survival by in-
hibiting apoptosis. Intumor cells thathave DNAdamage butlack
wild-type p53 or FOXO, SIRTI activation does not lead to cell-
cycle arrest, which promotes tumorigenesis by allowing cells
with damaged DNA to proliferate (Saunders and Verdin, 2007).
It is likely that much more information will need to be gathered
about this intriguing network of antiaging molecules before it
can be harnessed pharmacologically and effectively engaged
in the fight against neurodegenerative disorders.
We gratefully acknowledge support for research on related topics from
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