https://onlinelibrary.wiley.com/doi/full/10.1111/acel.12685
Sitaatti:
Sirtuins, aging, and stem cells
Sirtuins have long been recognized as regulators of aging –
overexpression of sirtuins has been shown to extend lifespan in
several organisms (Tissenbaum & Guarente,
2001;
Kanfi
et al.,
2012).
Sirtuin function in aging has to date been reported to be related to
their roles
in regulation of energy metabolism, r
esponse to calorie
restriction (CR), control of cell death, and circadian rhythms (Araki
et al.,
2004;
Chang & Guarente,
2013;
Guarente,
2013).
A new mechanism of lifespan modulation by sirtuins has been gaining
attention, related to their potential roles
in cellular and
mitochondrial protein homeostasis networks. Recent developments have
highlighted the close relationship between healthy aging and protein
homeostasis, or
proteostasis (Kaushik & Cuervo,
2015;
Walther
et al.,
2015).
A gradual loss of proteostasis is associated with age (Labbadia &
Morimoto,
2015)
and
the longest living organisms are known to have more stable
proteasomes and active proteostasis networks (Perez
et al.,
2009;
Treaster
et al.,
2014).
Most importantly, enhancing the functionality of proteostasis
networks has been shown to extend both lifespan and healthspan of
certain organisms (Morimoto & Cuervo,
2014;
Vilchez
et al.,
2014a;
Labbadia & Morimoto,
2015).
Given that sirtuins are well‐known lifespan modulators whose
deficiencies have been linked to a higher incidence of age‐related
diseases, the investigation of their roles in proteostasis networks
would appear to be warranted. In fact, a relationship between
sirtuins and ER stress appears to be conserved from C. elegans to
mammals, indicating a crucial link between sirtuins and proteostasis
(Viswanathan
et al.,
2005).
SIRT1 is a known negative regulator of ER stress responses through
deacetylating IRE‐1‐generated active XBP1 and subsequent
inhibition of its transcriptional activity to promote ER
stress‐induced apoptosis (Wang
et al.,
2011).
SIRT1 also suppresses pERK‐eIF2α‐dependent translational
inhibition (Ghosh
et al.,
2011).
In breast cancer cells, the unfolded protein response (UPR) triggered
by the accumulation of misfolded proteins in the mitochondria (UPR
mt)
requires the activation of
SIRT3 together with CHOP and estrogen
receptor alpha (ERα). By orchestrating both the antioxidant
machinery and mitophagy in a CHOP‐ and ERα‐independent manner, SIRT3
contributes to overcoming proteotoxic stress and mitochondrial
stress, which may represent an essential mechanism of adaptation of
cancer cells (Papa & Germain,
2014).
Looking more closely into stem cells, they seem to have increased
mechanisms to protect their proteasomes, and proteostasis networks
impact their function (Vilchez
et al.,
2014b).
This would appear to be related to the stem cell theory of aging,
which suggests that a progressive decline in the self‐renewal of
adult stem cells and their potential to differentiate into specific
cell types in order to replenish the tissues of an organism underlie
the mechanistic basis for aging. Although the age‐dependent loss of
function of different types of adult stem cells has been reported, we
are just now starting to understand the molecular mechanisms involved
in this process.
With the focus on sirtuins,
SIRT7‐mediated
alleviation of mitochondrial protein folding stress plays a critical
role in modulating the aging process by regulating HSC quiescence and
tissue maintenance (Mohrin
et al.,
2015).
SIRT7 functions as a stress sensor in proliferating, metabolically
active HSCs and reduces the expression of the mitochondrial
translation machinery through repressing activity of the master
regulator of mitochondria, nuclear respiratory factor 1 (NRF1), which
is necessary to alleviate mitochondrial protein folding stress. Of
note, rescue of the impaired reconstitution capacity in aged HSCs
upon SIRT7 overexpression or NRF1 inactivation underscores the
significance of sirtuin‐regulated proteostasis in maintaining
stemness.
Interestingly,
decreased Sirt3 expression in aged
HSCs is associated with a concomitant repression of mitochondrial
protective programs (Brown
et al.,
2013),
which might result in compromised function of the previously
described SIRT3‐directed UPR
mt pathway. Certainly,
further studies need to address whether similar mechanisms are
involved in other adult stem cells and tissues. Also, it would be
interesting to see whether these mechanisms are crucial for
self‐renewal and differentiation of CSCs based on the fact that
CSCs resemble a proliferating, metabolically active normal stem cell.
Furthermore, even though SIRT7 and SIRT3 cross at mitochondrial
regulation, they do activate these protective mechanisms through
their function in nucleus and mitochondria, respectively. As similar
protective programs might be orchestrated by other sirtuins, it
remains to be determined whether
SIRT2, which is the main cytoplasmic
sirtuin strongly downregulated in aged HSCs as well (Chambers
et al.,
2007),
is involved in stem cell maintenance, and possibly, new pathways
crucial for stem cell maintenance remain to be identified.
Calorie restriction (CR) and stem cells
CR is one of the most potent dietary interventions for increasing
lifespan and delays the onset of age‐related diseases including
cancer (Wanagat
et al.,
1999;
Longo & Fontana,
2010;
Colman
et al.,
2014).
It is accepted that its beneficial effects might relate, at least in
some significant part, to
epigenetically reprogramming stemness
while prolonging the capacity of stem‐like cell states to
proliferate, differentiate, and replace mature cells in adult aging
tissues. This is based on studies showing that CR may maintain stem
cell function of HSCs (Ertl
et al.,
2008),
enhance stem cell availability and activity in the muscle of young
and old animals (Cerletti
et al.,
2012),
and increase hippocampal neural stem and progenitor cell
proliferation in aging mice (Park
et al.,
2013b).
Considering that sirtuins are NAD‐dependent protein deacetylases
directly activated by CR, it could be proposed that they may mediate
some of the beneficial effects of CR on normal stem cells in adult
somatic tissues. However, this is a
relatively unexplored area of
research and there is lack of experimental evidence to either
support or counter this hypothesis.
Only very recently, it was
reported that SIRT1 is necessary for the expansion of intestinal
stem cells (ISCs) upon CR. More specifically, CR results in
deacetylation of p70 ribosomal S6 kinase due to
SIRT1 activation,
which consequently promotes its phosphorylation by mammalian target
of rapamycin complex 1 (mTORC1).
This signal‐response mechanism
mediates the increase in both protein synthesis and number of ISCs,
even as mTOR signaling is turned down by CR in more differentiated
cells (Igarashi & Guarente,
2016).
Similarly, little is known about the role of sirtuins as mediators
of the CR‐induced effect on tumorigenesis. As previously
mentioned, cancer was among the age‐related diseases which
exhibited a delayed onset in response to CR in several early studies
(Hursting
et al.,
1994;
Berrigan
et al.,
2002;
Mai
et al.,
2003).
Thus, it is rather surprising that there is a lack of experimental
data to address the contribution of sirtuins in the inhibitory
effect of CR on tumorigenesis. Regarding
SIRT1, which is the only
sirtuin studied so far, its overexpression failed to influence the
anticancer effects of
every‐other‐day fasting (a variation in
CR), suggesting that SIRT1 may play a limited role in the effects of
CR on cancer (Herranz
et al.,
2011).
Undoubtedly,
future studies are necessary to check more thoroughly
the role of sirtuins under this setting. However, it seems a very
intriguing question to ask whether sirtuin‐directed functions may
regulate either CSCs or non‐CSCs, given tha
t cancer is now viewed
as a stem cell disease. This is further supported by recent evidence
highlighting the effect of CR on unique characteristics of CSCs such
as EMT (Dunlap
et al.,
2012),
protein synthesis (Lamb
et al.,
2015),
metabolic plasticity (Peiris‐Pages
et al.,
2016),
as well as the importance of the HIF pathway in regulating
metabolism, cellular responses to hypoxia and stemness (Lim
et al.,
2010;
Zhong
et al.,
2010;
Yun & Lin,
2014),
which are all processes previously shown to be regulated by
sirtuins. It is hoped that future research will shed light on
mechanisms underlying the interplay between CR, sirtuins, and stem
cells.
Conclusion/Future
directions
Emerging evidence suggests that
sirtuins could be placed at the
crossroads of stemness,
and
cancer. This is based on the
plethora of functions they regulate both in normal stem cells and in
CSCs. However, it is clear that we are just starting to appreciate
the importance of identifying specific processes regulated by the
different members of the sirtuin family in a tissue‐, cell type‐,
and genetic‐specific context. This might be necessary in order to
gain a better understanding of their role and fill current knowledge
gaps in the field. With this in mind, it is worth mentioning that
most of the previous studies, including the published papers
presented in this review article, have followed a targeted approach
regarding elucidation of mechanisms regulated by sirtuins. To do so,
they were focused on either unraveling how sirtuins regulate
signaling pathways/processes already implicated in stemness or
exploring whether previously well‐established functions of sirtuins
play a significant role in stem cells. Toward this direction, it
could be proposed that implementation of unbiased high‐throughput
experimental approaches would provide more mechanistic insights.
Proteomics have been employed in the past to identify
sirtuin‐specific interacting proteins and substrates. The
regulatory role of
SIRT2 on anaphase‐promoting complex (APC/C)
during mitosis was identified based on a proteomics approach that
revealed its interaction with proteins of the complex including the
APC activator proteins Cdc20 and Cdh1 (Kim
et al.,
2011).
Recently, proteomics were used to elucidate the mitochondrial sirtuin
protein interaction landscape showing that this experimental approach
can uncover novel functions and/or substrates (Yang
et al.,
2016).
Thus, it could be suggested that similar approaches on stem and
progenitor cells or CSCs would identify novel functions of sirtuins.
Furthermore, recent advances in high‐resolution mass
spectrometry‐based proteomics have enabled the study of the
acetylome under different experimental conditions establishing
acetylation as an equally widespread PTM as phosphorylation (Kim
et al.,
2006;
Choudhary
et al.,
2009,
2014).
Given that similar approaches have enabled the identification of
sirtuin‐specific deacetylation targets (Hebert
et al.,
2013;
Vassilopoulos
et al.,
2014),
it would be reasonable to suggest that studying the acetylome in the
context of stem cells/progenitors or CSCs would reveal novel
functions/substrates regulated at the post‐translational level. In
a similar way, a detailed characterization of target genes
epigenetically regulated by sirtuins in specific subcellular
populations could help shape new directions in this field and
complement previous comprehensive studies focused on the analysis of
the transcriptome, DNA methylome, and histone modifications (Sun
et al.,
2014)
in stem cells. Collectively, such studies will provide novel insights
into both aging and cancer.
