Sestrins at the crossroad between stress and aging
Abstract
Sestrins are a family of stress-inducible proteins that can function as antioxidants and as inhibitors of target of rapamycin complex 1. In this research perspective, we discuss the possible roles of Sestrins in diverse stress-induced patho-physiological contexts that can result in premature aging and age-related diseases. We suggest that Sestrins provide critical feedback regulation that adjust metabolic and stress responses to different environmental cues and evolutionary constraints.
The
discovery of Sestrins as p53 targets [1,2] suggested that these proteins are
stress-inducible because they protect cells against various insults [2].
Sestrins have dual biochemical functions, as antioxidants that control the
activity of peroxiredoxins which scavenge reactive oxygen species (ROS) [3] and
as inhibitors of target of rapamycin complex 1 (TORC1) signaling [4,5]. Both
ROS accumulation [6] and TORC1 activation [7,8] are associated with accelerated
aging and development of age-associated pathologies in diverse organs and
organisms, implicating Sestrins as anti-aging agents. Conversely, reduction of
ROS accumulation with antioxidants or as a result of TORC1 inhibition [7-12]
causes an extension of life span as well as health span. Indeed, we recently
confirmed Drosophila Sestrin (dSesn) prevents age-associated pathologies
including fat accumulation and cardiac and skeletal muscle degeneration by
providing a feedback loop that prevents excessive TORC1 activation and ROS
accumulation [4]. In this research perspective, we discuss the possible roles
of Sestrins in diverse stress-induced patho-physiological contexts that can
result in premature aging and age-related diseases. We suggest that Sestrins
provide critical feedback regulation that adjust metabolic
and stress responses to different environmental cues and evolutionary
constraints.
DNA
damage
Chronic
exposure to genotoxic stress is known to accelerate aging, and mutations that
disrupt proper DNA damage responses and interfere with DNA damage repair are
associated with premature aging in humans [13]. Many studies have established
that genotoxic stresses can inhibit protein and lipid synthesis, and that these
coordinated responses may be essential for survival because reducing energy
expenditure on macromolecule biosynthesis can divert scarce resources to the
repair of damaged DNA [14]. Sestrins, as DNA damage-inducible proteins, may
play a critical role in this process [15]. Both mammalian Sesn1 and Sesn2 are
induced upon DNA damage in response to activation of p53 [1,2], and dSesn is
also induced upon radiation-induced DNA damage (Figure 1). Increased Sestrin
abundance potentiates the activity of AMP-activated protein kinase (AMPK),
thereby diminishing TORC1 activity [5]. Reduced TORC1 activity inhibits
anabolic pathway including protein and lipid
synthesis [16,17]. Shutdown of TORC1-dependent anabolism upon genotoxic stress
is likely to be important for minimizing new protein and membrane synthesis and
use the energy that was thus saved to promote DNA repair. Therefore, DNA
damage-dependent induction of Sestrins may minimize the detrimental effects of
DNA damage that contribute to accelerated aging and various pathologies that
are associated with premature aging.
Age-dependent
accumulation of DNA damage can lead to cancer [13], one of the leading causes
of mortality worldwide [18]. Therefore, Sestrin induction in response to DNA
damage [1,2] may contribute to the many tumor suppressor functions carried out
by p53 [19]. In addition to inhibiting cell proliferation and promoting the
death of cells with excessive DNA damage, p53 was recently found to inhibit
TORC1 [14] and to suppress cell growth as well as cellular and organismal
senescence [19-21]. We found that Sesn1 and/or Sesn2 are critical mediators of
p53-induced TORC1 inhibition in cultured cells and in mouse liver [5]. In
addition, Sestrins can suppress the growth of some cancer cell lines [2] and
loss of Sesn2 makes immortalized cells more susceptible to oncogenic
transformation [5]. The SESN1 (6q21) and SESN2 (1p35) loci are frequently
deleted in a variety of human cancers [1,22,23], implicating loss of Sestrins
in tumor progression and suggesting that Sestrin-dependent inhibition of TORC1
is critical for suppressing tumorigenesis spurred by age-dependent accumulation
of damaged DNA.
Figure 1. Induction of dSesn after DNA damage. First instar
fly larvae were challenged with 4000 rads (R) of gamma radiation, and RNA
was extracted after 4 hrs. Northern blot analysis revealed that dSesn
mRNA is highly induced upon irradiation. rp49 mRNA was used as a
loading control.
Oxidative
stress
Oxidative
stress not only can interfere with the proper flow of genomic information by
oxidizing DNA and RNA, but also can damage other macromolecules such as
proteins and lipids [6]. Accumulation of oxidative macromolecular damage causes
cellular senescence, tissue aging and reduced life span [6], as well as
neurodegeneration [24] and metabolic disorders [25], which are diseases
associated with aging. Amongst the organelles that are affected by oxidative
stress, mitochondria appear to be the most sensitive [6,26]. Moreover, damaged
mitochondria are a major source of ROS [6], which escalates oxidative damage in
stressed cells. Extensive mitochondrial dysfunction causes cell death, and in
some cases can lead to neuronal or muscular degeneration [6,24,27]. To prevent
the detrimental consequences of mitochondrial dysfunction, cells eliminate
damaged mitochondria through an autophagic process, called mitophagy [28,29].
Sestrins
are transcriptionally induced upon oxidative stress [2], and are important for
cell survival under oxidative stress [2,3,30,31]. Sestrins can function as
oxidoreductases in vitro and in vivo that lead to the reactivation of
peroxiredoxin [3], and may be involved in reducing oxidative stress [30-32] by
scavenging ROS and/or regenerating reduced peroxiredoxin [3]. Independent of
their oxidoreductase activity, Sestrins induce autophagy by inhibition of TORC1
[5,33,34]. Enhanced autophagy results in more efficient elimination of
ROS-producing damaged mitochondria in stressed cells [28,29]. Sestrin-induced
activation of AMPK and inhibition of TORC1 can also reduce ROS production by
increasing the efficiency of mitochondrial respiration [11,12]. Therefore,
Sestrins have a key role in maintaining cellular integrity and homeostasis
during oxidative insults.
Hypoxia
Hypoxia
is another environmental stimulus that can induce Sestrin gene transcription
[2]. Sestrins protect cells from apoptosis during hypoxic conditions [2], and
Sestrin-induced shutdown of TORC1 signaling can reduce cellular energy
consumption that is likely to improve adaptation to hypoxic conditions.
Sestrin-stimulated autophagy can provide an additional energy source and at the
same time eliminate dysfunctional mitochondria generated by inefficient
respiration under low oxygen tension.
Ischemic
injury to heart muscles and neurons, which is caused by hypoxia, is one of the
major causes of death in elderly individuals [18]. In an experimental model of
acute stroke, Sesn2 was shown to be highly induced upon hypoxic injury [2],
suggesting that Sesn2 may exert its neuroprotective role during stroke. In the
heart, hypoxic injury and re-oxygenation cause bursts of ROS production, which
can cause irreversible damage to the heart muscle, resulting in cardiac
arrhythmia and heart failure [35,36]. In the Drosophila heart, both aging
[37-41] and hypoxia [39,42,43] cause cardiac dysfunction, and activation of
TORC1 pathway aggravates or accelerates age-associated arrhythmicity and heart
failure [44]. Loss of dSesn function results in a similar cardiac arrhythmicity
[4], suggesting a cardio-protective function of Sestrin in restraining TORC1
activity. Thus Sestrin expression retards the appearance of age-associated
cardiac pathologies, as was previously observed in response to genetic
reduction of TORC1 function [10,44].
Hypoxic
preconditioning can protect both heart and neuronal cells from severe ischemic
injury-induced cellular damage [36,45], but the underlying mechanisms were not
elucidated. Induction of autophagy upon preconditioning was suggested to be
required for protection of heart and neuronal cells from hypoxic insults
[36,46]. An intriguing possibility to investigate therefore is whether hypoxic
preconditioning induces Sestrin
to increase the level of autophagy that is required for the prevention of serious heart
attacks and neurological strokes.
Figure 2. FoxO binding sites in the Sestrin locus vary among the species. Genomic
organization and location of FoxO response elements (FRE, GTAAACAA [57]) in the Sesn1
locus of human and mouse [58] and the dSesn
locus of various Drosophila species [59,60] with indicated
genomic span. Gray boxes indicate untranslated exons (UTR), and black boxes
indicate coding exons (CDS). For Drosophila species other than D.
melanogaster, untranslated regions of dSesn mRNAs are currently
unknown. Forward FREs are indicated by red arrows and reverse FREs by blue
arrows.
An
evolvable link to the environment
In
addition to the important role that Sestrins play in mediating essential
environmental inputs into metabolic regulation, these molecules may also play
central roles in responding to other environmental cues such as nutrient
supply, hydration status, temperature, chemical damage, and reproductive
signals. One might speculate that because these various cues would have
different impacts on different organisms, Sestrin genes should have evolved
complex cis-regulatory regions to place them under distinct regulatory controls
that vary from one organism to another. Indeed, our analysis of Sestrin genomic
loci revealed that these sequences are rapidly evolving among the various
Drosophila species. For example, the
disposition and number of FoxO binding sites in the Sestrin locus vary
significantly among species (Figure 2). Comparative studies of cis-regulatory
sequences between Drosophila species by swapping these sequences using
recombineering techniques may shed light on mechanisms by which selective
pressures sculpt the stress response during evolution.
Figure 3. Schematic diagram hypothesizing the role of Sestrin as a brake of stress-accelerated aging processes. Various environmental insults increase
expression of Sestrins to affect Sestrin-mediated regulation of AMPK-TORC1
signaling.
Concluding
remarks
In
this research perspective, we briefly reviewed how Sestrins may act as
suppressors of aging that are responsive to stressful stimuli and insults that
can accelerate the aging process. By activating AMPK and inhibiting TORC1,
Sestrins can reprogram cells to adapt to stressful conditions by attenuating
anabolism and enhancing autophagic catabolism. Sestrins can suppress oxidative
damage by acting as either antioxidants, inducers of autophagy that eliminate
ROS-producing dysfunctioning mitochondria, or suppressors of ROS-producing
mitochondrial metabolism. Therefore, we can view Sestrins as physiological brakes
that can attenuate stress-dependent acceleration of aging (Figure 3).
In
addition, it is worth noting that Sestrins are also expressed under normal
unstressed conditions [1,2,4], and that dSesn knockout mutants show accelerated
aging phenotypes even in the absence of any environmental stress [4].
Therefore, it is possible that Sestrins provide a baseline protective function
that reduces the damage from physiological insults that are unavoidable
consequences of basic life processes such as oxidative respiration and DNA
replication.
Over-nutrition
and obesity can elevate the incidence and frequency of physiological insults by
stimulating TORC1 activity [47], which in turn accelerates anabolic metabolism
[16,17]. Hyperactive TORC1 can enhance the accumulation of unfolded and
aggregated proteins [48] and ROS [4,12,49], leading to stress responses that
increase Sestrin expression, thereby activating negative feedback
loops that readjust AMPK and TORC1 activity [4]. Therefore, Sestrins may also
function as metabolic brakes that attenuate the pathological consequences of
over-nutrition and its associated TORC1 hyperactivity [50]. An interesting
human evolutionary question in this regard is whether regulation of Sestrin
induction has been weakened in populations subject to frequent starvation
conditions since such populations have been shown to be particularly at risk for
obesity, presumably as a result of their altered response to nutrient cues
[51,52].
Although
environmental stress generally accelerates aging, it should be considered that
exposure to a low level of stress or stress adaptation can actually be
beneficial for the organism, increasing life span and preventing age-associated
degenerative diseases [53-56]. The beneficial effect of low-level stress
exposure, referred to as hormesis, was observed in both experimental animal
models and human subjects [53-56], but no decisive molecular explanation has
been provided to explain this paradoxical phenomenon. Given that Sestrins are
upregulated in response to a variety of stresses [1,2], it will be interesting
to investigate whether stress-induced Sestrins are also mediators of the
hormetic effect.
In
summary, we suggest that Sestrins are uniquely poised at the crossroads between
stress and aging to adjust the metabolic timbre of an organism to meet its
needs under normal conditions and to respond to predictable forms of
environmental stress. Future experiments should shed light on the specific
mechanisms by which the various effector functions of the Sestrins are
achieved.
Acknowledgments
The authors thank Charles L. Sanders and Myungjin Kim
for their encouragement and intuitive suggestions. Work was supported by grants
from the National Institutes of Health and the Superfund Research Program
(CA118165, ES006376 and P42-ES010337 to M.K., and NS29870 and AI070654 to
E.B.), National Science Foundation (IOS-0744662 to E.B.), Korea Research
Foundation (KRF-2007-357-C00096 to J.H.L.), and Human Frontier Science Program
Organzation (LT00653/2008-L to J.H.L). M.K. is an American Cancer Society
Professor.
Conflicts of Interest
The authors of this manuscript have no conflict of
interests to declare.
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