How increased oxidative stress promotes longevity and metabolic health:
The concept of mitochondrial hormesis (mitohormesis)
Michael Ristowa,b,*, Kim Zarsea
aDept. of Human Nutrition, Institute of Nutrition, University of Jena, 29 Dornburger Str., Jena D-07743, Germany
bDept. of Clinical Nutrition, German Institute of Human Nutrition, 114 Arthur-Scheunert-Allee, Nuthetal D-14558, Germany
a r t i c l e i n f o
Received 1 July 2009
Received in revised form 9 March 2010
Accepted 19 March 2010
Available online 27 March 2010
Reactive oxygen species
a b s t r a c t
Recent evidence suggests that calorie restriction and specifically reduced glucose metabolism induces
mitochondrial metabolism to extend life span in various model organisms, including Saccharomyces cere-
visiae, Drosophila melanogaster, Caenorhabditis elegans and possibly mice. In conflict with Harman’s free
radical theory of aging (FRTA), these effects may be due to increased formation of reactive oxygen species
(ROS) within the mitochondria causing an adaptive response that culminates in subsequently increased
stress resistance assumed to ultimately cause a long-term reduction of oxidative stress. This type of ret-
rograde response has been named mitochondrial hormesis or mitohormesis, and may in addition be
applicable to the health-promoting effects of physical exercise in humans and, hypothetically, impaired
insulin/IGF-1-signaling in model organisms. Consistently, abrogation of this mitochondrial ROS signal by
antioxidants impairs the lifespan-extending and health-promoting capabilities of glucose restriction and
physical exercise, respectively. In summary, the findings discussed in this review indicate that ROS are
essential signaling molecules which are required to promote health and longevity. Hence, the concept
of mitohormesis provides a common mechanistic denominator for the physiological effects of physical
exercise, reduced calorie uptake, glucose restriction, and possibly beyond.
? 2010 Elsevier Inc. All rights reserved.
1. Calorie restriction
A limited reduction of nutritional calorie uptake, so-called calo-
rie restriction (CR), has been shown to extend life span in multiple
species and model organisms, as initially observed by McCay et al.
(1935). It is beyond the scope of this review to summarize the mul-
tiple findings on CR, since excellent reviews on this topic have been
published in the past (Weindruch and Walford, 1988; Masoro,
2000; Speakman et al., 2002; Heilbronn and Ravussin, 2003; In-
gram et al., 2004; Anson et al., 2005; Gredilla and Barja, 2005; Sin-
clair, 2005; Wolff and Dillin, 2006; Bishop and Guarente, 2007;
Piper and Bartke, 2008). It should be emphasized, however, that
unequivocal evidence for the effectiveness of CR in primates and
especially humans is missing. A recent publication on an ongoing
study in Macaca mulatta shows that CR has no statistically signifi-
cant effect on overall mortality (Colman et al., 2009). However,
since about half of the study group was still alive at the time of
manuscript preparation, future findings from this ongoing study
may show whether CR in rhesus monkeys significantly affects mor-
tality. Nevertheless, so-called ‘‘age-related mortality” was signifi-
cantly decreased in M. mulatta. It should be noted, though, that
age-related mortality (as defined in this study) accounted for only
54% of deaths during the study period. In contrast and quite strik-
ingly, age-related gluco-regulatory impairment was completely
abolished in calorically restricted monkeys. Hence and due to addi-
tional findings (Fontana et al., 2004; Heilbronn et al., 2006; Ingram
et al., 2006a; Weindruch, 2006; Fontana and Klein, 2007) it appears
possible that CR extends life span in primates and/or humans.
The initial conceptual background for restricting dietary calo-
ries is based on the assumption that reducing nutritive calorie
availability would reduce the metabolic rate of an organism.
Accordingly, it was proposed more than a century ago that maxi-
mum life span is inversely proportional to the amount of nutritive
energy metabolized (Rubner, 1908). Subsequently, the rate-of-liv-
ing hypothesis evolved, suggesting that an increased metabolic
rate would decrease life span in eukaryotes (Pearl, 1928). Several
decades later it was proposed that increased metabolic rate would
promote increased formation of reactive oxygen species (ROS) to
cause cumulative damage to the cell, and hence the organism (Har-
man, 1956). Notably, respiratory enzymes using oxygen to gener-
ate readily available energy were explicitly proposed to be the
most relevant culprit in this regard (Harman, 1956). This concept
was named free radical theory of aging (FRTA).
Based on these assumptions, considerable experimental effort
has been made to elucidate the underlying mechanistic principles.
0531-5565/$ - see front matter ? 2010 Elsevier Inc. All rights reserved.
* Corresponding author at: Dept. of Human Nutrition, Institute of Nutrition,
University of Jena, 29 Dornburger Str., Jena D-07743, Germany. Tel.: +49 3641
949630; fax: +49 3641 949632.
E-mail address: email@example.com (M. Ristow).
Experimental Gerontology 45 (2010) 410–418
Contents lists available at ScienceDirect
journal homepage: www.elsevier.com/locate/expgero
On the one hand, it has repeatedly been shown that CR is capable
of delaying a number of age-related diseases, including obesity,
type 2 diabetes, hypercholesterolemia, atherosclerosis, different
cancers, as well as neurodegeneration and cardiomyopathy. This
has been attributed to specific and diverse effects of CR on the
respective molecular processes assumed to cause these disorders.
According to some of these approaches, delayed aging would sim-
ply reflect a cumulative reduction of age-associated and mortality-
promoting medical conditions as a consequence of CR. On the other
hand, it was shown that CR per se promotes increased stress de-
fense, and specifically induces endogenous defense mechanisms
against ROS (Koizumi et al., 1987; Semsei et al., 1989; Rao et al.,
1990; Pieri et al., 1992; Youngman et al., 1992; Xia et al., 1995;
Masoro, 1998a; Barros et al., 2004). In most cases, this was inter-
preted as a consequence of reduced metabolic rate, and hence re-
duced ROS production. More recently, a different perspective has
emerged, suggesting that CR causes an adaptive response to spe-
cific metabolic alterations in states of reduced food uptake.
2. Reduction of specific macronutrients
Nutritional, i.e. metabolizable calories are derived from carbohy-
ent monosaccharides (including glucose), and significant numbers
of fatty acids and amino acids, respectively. Limited evidence exists
whether the generally accepted effects of calorie restriction can be
attributed to specific macronutrients, i.e. whether restriction of a
single macronutrient may exert the same effects than overall CR
does. This topic has been reviewed in detail elsewhere (Piper and
Bartke, 2008), hence the following paragraphs will focus on specific
aspects of macronutrient choice only.
In invertebrate model organisms, restriction of proteins as well
as carbohydrates, mostly glucose, has been studied with different
and sometimes opposing outcomes, whereas studies on triacylgly-
cerols are lacking for invertebrates. While the effects of glucose
restriction will be discussed below, in Drosophila melanogaster,
restriction of casein extends life span (Min and Tatar, 2006). More-
over, it has been proposed that restriction of both yeast as well as
sugar may extend Drosophila lifespan despite unaltered calorie up-
take (Mair et al., 2005). Very recently, it was shown that increased
abundance of essential amino acids, and particularly methionine
counteracts the lifespan-extending effects of CR in D. melanogaster
(Grandison et al., 2009). Notably, restriction of methionine in ro-
dents similarly delays ageing (Zimmerman et al., 2003; Miller
et al., 2005) and increasing protein content impairs antioxidant de-
fense in rats (De et al., 1983). For Caenorhabditis elegans, impaired
activity of peptide transport similarly extends life span (Meissner
et al., 2004). However, selective depletion of nutritive amino acids
is difficult to achieve in C. elegans, and hence to our best knowledge
has not been studied.
In mammals and especially humans, increasing evidence sug-
gests that a number of health-promoting metabolic effects can by
more easily achieved by a selective reduction of dietary carbohy-
drates: Whereas efficacy of long-term weight reduction appears
to be comparable between low-carbohydrate and low-energy diets
(mainly depleted in triacylglycerols) (Nordmann et al., 2006; Hes-
sion et al., 2009), several serum parameters seem to be favourably
affected by a specific reduction of carbohydrate uptake, whereas
total energy uptake was, in most studies, not significantly affected
by the type of diet (Nordmann et al., 2006; Hession et al., 2009).
Hence, it appears feasible that a depletion of carbohydrates and/
or glucose only exerts specific effects beyond those observed with
general CR. In anticipation of mechanisms outlined below, it
should be noted that metabolism of glucose can yield ATP even
in the absence of mitochondrial organelles or even oxygen, while
conversion of fatty acids and/or (most) amino acids into ATP de-
pends on oxidative phosphorylation (OxPhos) and hence oxygen.
3. Glucose restriction
A specific restriction of nutritive glucose is, with the exception
of yeast and D. melanogaster, difficult to achieve in eukaryotic mod-
el organisms. In Saccharomyces cerevisiae, it was shown that re-
duced glucose availability significantly extends chronological life
span, and this extension depends on induction of respiration (Lin
et al., 2002) as well as sirtuins (Lin et al., 2000). While the depen-
dence on sirtuins is a matter of debate (Kaeberlein et al., 2004;
Agarwal et al., 2005; Guarente, 2006; Smith et al., 2007), alterna-
tive mechanisms independent of sirtuins have been proposed (Bar-
ros et al., 2004; Roux et al., 2009).
In C. elegans and mammals, a specific restriction of intracellular
glucose availability is commonly achieved by application of a com-
petitive inhibitor of glycolysis, 2-deoxy-glucose (DOG) (Wick et al.,
1957). In C. elegans, it was shown that application of DOG induces
respiration and extends life span (Schulz et al., 2007), in this regard
reflecting previous findings in yeast (Lin et al., 2002). However and
in conflict with these aforementioned findings in yeast, this pro-
cess was independent of sirtuins, but rather required activation
of AMP-activated kinase (AMPK) (Schulz et al., 2007). This kinase
was previously established as a sensor of cellular energy depletion
in both mammals (Hardie et al., 2006) and specifically C. elegans
(Apfeld et al., 2004; Greer et al., 2007), and has been found to in-
duce a health-promoting metabolic state particularly by inducing
mitochondrial metabolism (Hardie et al., 2006). Accordingly, appli-
cation of DOG to rodents efficiently mimics features of the meta-
bolic state of CR (Lane, 1998) as well as carbohydrate restriction
(Garriga-Canut et al., 2006), suggesting that DOG acts as a CR mi-
metic (Duan and Mattson, 1999; Sinclair, 2005; Zhu et al., 2005; In-
gram et al., 2006b).
Accordingly and as an alternate route to modulate intracellular
glucose availability, combined disruption of insulin-dependent glu-
cose transporter GLUT4 in adipose and muscle tissues of mice
causes adult hyperglycemia as well as a metabolic switch to in-
creased fatty acid turnover and utilization, while lifespan was stud-
ied up to 18 months of age only, and found to be unaltered (Kotani
et al., 2004). Conversely, transgenic over-expression of GLUT4 in
mice efficiently lowers blood glucose by increasing cellular glucose
uptake, but does not extend life span (McCarter et al., 2007). More-
over, it was shown thatincreased glucose availability reduces C. ele-
gans lifespan (Schulz et al., 2007) while potentially underlying
mechanisms have been subsequently proposed (Lee et al., 2009;
Schlotterer et al., 2009). Altogether, these findings suggest that in-
creased intracellular glucose availability exerts detrimental effects
on longevity, whereas decreased glucose availability promotes oxi-
dative metabolism and extends life span.
4. Impaired insulin/IGF-1 signaling and glucose availability
Insulin and insulin-like growth factor 1 (IGF-1) are peptide hor-
mones. Insulin is produced in and secreted from the pancreatic
beta-cells, while IGF-1 is produced in the liver. IGF-1 production
and release depends on a third hormone named somatotropin
(STH) a.k.a. growth hormone (GH) which stems from the anterior
pituitary gland. Insulin, GH and IGF-1 are hormones that bind to
specific and, at least in mammals, distinct receptors. However,
GH exerts some of its effects indirectly by regulating the abun-
dance of IGF-1. Moreover, it should be noted that most of the
IGF-1-independent, i.e. direct and receptor-mediated effects of
GH commonly counteract insulin action.
M. Ristow, K. Zarse/Experimental Gerontology 45 (2010) 410–418
Impaired availability and/or activity of GH and/or IGF-1 starting
in early life causes reduced growth or dwarfism. Mice with the cor-
responding mutations are called Ames, Snell, and little, and have
been described in more detail elsewhere (Quarrie and Riabowol,
2004). Interestingly, such growth-impaired mice have increased
lifespan (Brown-Borg et al., 1996), while increased GH signaling
impairs lifespan (Pendergrass et al., 1993; Steger et al., 1993).
tor function (Kappeler et al., 2008) extend murine lifespan, and
prevents proteotoxicity and neurodegeneration (Cohen et al., 2009).
Impaired activation of the insulin receptor has been linked to a
state called insulin resistance, defined as an inappropriately re-
duced intracellular response to an extracellular insulin stimulus
(Kahn, 1994). The key intracellular response towards extracellular
activation of the insulin receptor is increased glucose uptake as
mediated by translocation of the glucose transporter GLUT4. Hence
it appears generally accepted that insulin resistance causes type 2
diabetes leading to reduced intracellular glucose availability (Bid-
dinger and Kahn, 2006). This notion is supported by observations
from humans in regards to increased prevalence of hyperglycemia,
insulin resistance and lastly type 2 diabetes with increasing age
Conversely, targeted whole-body disruption of the insulin
receptor in mice causes embryonic lethality, but when disruption
is restrictedto the (in regards to glucose metabolism)most relevant
tissue, skeletal muscle, neither hyperglycemia nor diabetes was ob-
served, but rather a striking increase in fatty acid turnover occurred
(Brüning et al., 1998). Life span analyses in these mice have not
been published. In addition, adipocyte-specific disruption of the
insulin receptor extends murine life span (Blüher et al., 2003) and
so does global heterozygous disruption of the downstream insulin
receptor substrate 1 (IRS-1) (Selman et al., 2008a) which interest-
ingly also is located downstream of the of IGF-1 receptor. Similarly,
neuronal disruption of IRS-2 was shown to promote longevity
(Taguchi et al., 2007), and so did heterozygous global disruption
of IRS-2 (Taguchi et al., 2007) while others could not confirm the
latter evidence using the same model (Selman et al., 2008b). Taken
together, these findings suggest that a limited impairment of insu-
lin and/or IGF-1 signaling may actually extend murine life span due
to widely unresolved reasons. Of note, mutations of insulin/IGF-1
signaling have been shown to be associated with human longevity
(van Heemst et al., 2005; Pawlikowska et al., 2009).
In invertebrates, long-standing evidence exists in this regard: In
both C. elegans and D. melanogaster, mutations in the respective
orthologues of the insulin/IGF-1 receptor or proteins located
downstream of these receptors significantly extend life span
(Friedman and Johnson, 1988; Kenyon et al., 1993; Kimura et al.,
1997; Clancy et al., 2001; Tatar et al., 2001). However, there is little
evidence in invertebrates whether and to which extent impaired
insulin/IGF-1 signaling affects glucose availability.
While some authors propose that impaired insulin/IGF-1/GH
signaling extends life span independently of pathways activated
by CR (Lakowski and Hekimi, 1998; Bartke et al., 2001; Houthoofd
et al., 2003; Min et al., 2008; Bonkowski et al., 2009), others have
suggested that impaired insulin/IGF-1 signaling may share mecha-
nistic features of caloric restriction and hence decreased energy
availability, at least to some extent (Brown-Borg et al., 2002; Clan-
cy et al., 2002; Al-Regaiey et al., 2005; Bonkowski et al., 2006;
Greer et al., 2007; Narasimhan et al., 2009; Yen and Mobbs, in
press). Independently, it appears likely that impaired insulin/IGF-
1 signaling causes an intracellular glucose depletion in most model
organisms, hypothetically mimicking the metabolic state of glu-
cose restriction, hence contributing to lifespan extension by im-
paired insulin/IGF-1 signaling. While experimental evidence for
this hypothesis is missing, some findings from rodents support
the assumption that impaired insulin/IGF-1 signaling induces
mitochondrial metabolism, whereas lifespan in most cases has
not been studied (Yechoor et al., 2004; Brooks et al., 2007; Katic
et al., 2007; Russell and Kahn, 2007; Westbrook et al., 2009).
5. Induction of mitochondrial metabolism by calorie/glucose
While some papers suggest that the net uptake of calories is not
reduced over life time in states of CR (Masoro et al., 1982; Mair
et al., 2005), it is by definition agreed upon that during the actual
CR intervention a relative depletion of available energy occurs.
Mitochondria convert nutritional energy more effectively into
readily available energy, i.e. ATP, than non-oxidative metabolism
of carbohydrates and some amino acids does. E.g., while glycolytic
metabolism of one mol of glucose generates 4 mols of ATP only, its
oxidative metabolism generates 30 mols of ATP. Hence, and as indi-
cated by findings in yeast (Lin et al., 2002) and C. elegans (Schulz
et al., 2007), decreased glucoseavailability wouldinducemitochon-
drialmetabolismto increase OxPhos,aiming to maintainintracellu-
lar ATP supply. Similarly, however analyzing global CR (and not
specifically glucose restriction), it was shown that food deprivation
promotes mitochondrial biogenesis and OxPhos in rodents (Nisoli
et al., 2005). Additionally, it has been suggested that mass-specific
energy expenditure in CR rats is higher than expected (Selman
mitochondrial metabolism in rodents (Yechoor et al., 2004; Katic
tion, induction of mitochondrial metabolism by various pharmaco-
logical measures (Ames, 2005) and specifically physical exercise
(Warburtonetal., 2006;Lanzaet al., 2008)has beenproposedto ex-
tend lifespan. In contrast, mitochondrial dysfunction has been pro-
posed as a key cause of aging (Trifunovic and Larsson, 2008; Bratic
and Trifunovic, 2010), diabetes (Wiederkehr and Wollheim, 2006),
cancer (Ristow, 2006), as well as neurodegeneration (Fukui and
Moraes, 2008; Tatsuta and Langer, 2008). Moreover, impaired mito-
chondrial capacity decreases life span in yeast (Bonawitz et al.,
2006), C. elegans (Zarse et al., 2007) and rodents (Thierbach et al.,
2005). Mechanistically, sirtuins (see above) as well as AMPK signal-
ing(seeabove) maybe involved. Moreover,disruptionof the target-
of-rapamycin protein mTOR (Wullschleger et al., 2006) has been
shown to extend S. cerevisae lifespan (Powers et al., 2006) interest-
ingly by inducing mitochondrial metabolism (Bonawitz et al.,
2007). Consistently and as to be anticipated from states of glucose
restriction (Schulz et al., 2007) as well as TOR disruption (Bonawitz
et al., 2007), the TOR target and translational repressor 4E-BP has
subsequently been shown to modulate mitochondria metabolism
in states of CR (Zid et al., 2009). Moreover, TOR/TORC1 activity ap-
pears to be controlled by AMPK (Gwinn et al., 2008), altogether sug-
gesting that both TOR and AMPK may be upstream regulators of
mitochondrial metabolism and OxPhos.
While all these aforementioned findings suggest that increased
mitochondrial metabolism is instrumental and possibly required
for the extension of lifespan, it should be noted that, in conflict
with the findings mentioned above, CR has been shown to increase
life span in the absence of increased respiration (Houthoofd et al.,
2002; Kaeberlein et al., 2004), or even in the absence of respiration
at all (Kaeberlein et al., 2005).
6. Oxidative stress and mitochondrial hormesis (mitohormesis)
About five decades ago and as stated above, increased forma-
tion of ROS as a consequence of increased metabolic rate was pro-
M. Ristow, K. Zarse/Experimental Gerontology 45 (2010) 410–418
posed to be the major culprit for the ageing process and decreased
life span (Harman, 1956). Mitochondria are the main source of
ROS. For a long time, these were considered exclusively unwanted
by-products of OxPhos. In support of this view, a significant num-
ber of studies in various model organisms suggests that ameliora-
tion of oxidative stress contributes to an increase of lifespan
(Harrington and Harley, 1988; Phillips et al., 1989; Orr and Sohal,
1994; Parkes et al., 1998; Melov et al., 1999; Adachi and Ishii,
2000; Melov et al., 2000; Moskovitz et al., 2001; Bakaev and Lyud-
mila, 2002; Ruan et al., 2002; Ishii et al., 2004; Huang et al., 2006;
Zou et al., 2007; Kim et al., 2008; Quick et al., 2008; Dai et al.,
2009; Shibamura et al., 2009). Consistently, significant effort has
been made to reduce ROS formation due to the assumption that
such interventions may block or at least ameliorate aging pro-
cesses in humans.
Accordingly, both synthetic as well as naturally occurring com-
pounds that physically interact with ROS to inactivate the latter,
so-called antioxidants, have been extensively been investigated.
Unexpectedly, many prospective clinical trials aiming to find any
health-promoting effects of antioxidants failed, in the best case
showing no health-promoting effects of these compounds (Green-
berg et al., 1994; Liu et al., 1999; Rautalahti et al., 1999; Virtamo
et al., 2000; Heart Protection Study Collaborative Group, 2002;
Sacco et al., 2003; Zureik et al., 2004; Czernichow et al., 2005,
2006; Cook et al., 2007; Kataja-Tuomola et al., 2008; Sesso et al.,
2008; Katsiki and Manes, 2009; Lin et al., 2009; Song et al.,
2009). More importantly, a number of studies suggests that antiox-
idants may promote cancer in humans (Bjelakovic et al., 2004;
Bairati et al., 2005; Hercberg et al., 2007; Bardia et al., 2008;
Lawenda et al., 2008; Myung et al., 2010). Accordingly, other stud-
ies show that antioxidant supplements may be disease-promoting
and/or may even reduce lifespan in humans (Albanes et al., 1996;
Omenn et al., 1996; Vivekananthan et al., 2003; Lonn et al., 2005;
Bjelakovic et al., 2007; Ward et al., 2007; Lippman et al., 2009).
Consistently and in conflict with Harman’s hypothesis, evidence
has emerged in recent years that ROS may actually work as essen-
tial, and potentially lifespan-promoting, signaling molecules which
transduce signals from the mitochondrial compartment to other
compartments of the cell (Barja, 1993; Rhee et al., 2003; Kaelin,
2005; Connor et al., 2005; Guzy et al., 2005; Guzy and Schumacker,
2006; Chandel and Budinger, 2007; Schulz et al., 2007; Veal et al.,
2007; Owusu-Ansah et al., 2008; Finley and Haigis, 2009; Ristow
et al., 2009; Loh et al., 2009). Independently, it has been suggested
that CR acts by inducing low-level stress that culminates in in-
creased stress resistance and ultimately longevity (Masoro,
1998b,a). This would reflect an adaptive response commonly de-
fined as hormesis (Southam and Ehrlich, 1943) (for a current defi-
nition see (Calabrese et al., 2007)), and was later named
mitochondrial hormesis or mitohormesis, referring to ROS-related
stress emanating from the mitochondria (Tapia, 2006).
Consistent with these hypotheses, it was shown in rodents that
calorie restriction induces antioxidant defense capacities (Koizumi
et al., 1987; Semsei et al., 1989; Rao et al., 1990; Pieri et al., 1992;
Youngman et al., 1992; Xia et al., 1995; Sreekumar et al., 2002). In
yeast, glucose restriction decreases ROS production despite in in-
creased respiratory activity (Barros et al., 2004). In contrast and
while using the same model organism, others showed that glucose
restriction increases ROS production (Agarwal et al., 2005; Kharade
et al., 2005; Piper et al., 2006). Interestingly, an induction of ROS
defense enzymes was also observed (Agarwal et al., 2005; Kharade
et al., 2005; Piper et al., 2006), tentatively suggesting a mechanistic
link between increased respiration, elevated ROS production and
adaptive induction of ROS defense.
Accordingly, in D. melanogaster CR was unable to primarily de-
crease ROS production, and genetically decreased ROS production
was unable to extend life span (Miwa et al., 2004). Consistently,
altering ROS production or antioxidant defense in various model
organisms has similarly failed to reciprocally modulate life span
(Huang et al., 2000; Bayne and Sohal, 2002; Keaney and Gems,
2003; Andziak et al., 2006; Selman et al., 2006; Ran et al., 2007;
Doonan et al., 2008; Heidler et al., 2009; Jang and van Remmen,
2009; Jang et al., 2009; Lapointe et al., 2009; Van Raamsdonk
and Hekimi, 2009; Yen et al., 2009; Zhang et al., 2009; Pun et al.,
2010). Moreover, long-lived mutants of C. elegans unambiguously
show increased stress resistance which in some studies is paral-
leled by increased metabolic activity (Lithgow et al., 1995; Vanflet-
eren and De Vreese, 1995; Honda and Honda, 1999; Murphy et al.,
2003; Houthoofd et al., 2005; Dong et al., 2007). Of note, similar re-
sults in regards to neuroprotective mechanisms of CR and specifi-
cally DOG application have been described in rodents (Arumugam
et al., 2006). Lastly, humans on a ketogenic, i.e. carbohydrate-de-
pleted diet show increased antioxidant defense presumably fol-
lowing increased oxidative metabolism due to increased rates of
beta-oxidation (Nazarewicz et al., 2007).
While all these aforementioned publications support the possi-
bility that ROS itself induce ROS defense and ultimately increase
life span, it remained to be shown that prevention of ROS forma-
tion would reduce the life-extending capabilities of CR. These
experiments were undertaken by showing that DOG reduces glu-
cose availability, increases respiration and ROS formation, pro-
motes activity of ROS defense enzymes, and extends life span in
C. elegans (Schulz et al., 2007). Notably, co-treatment of nematodes
with several different antioxidants which inactivate ROS fully abol-
ished the life-extending effects of CR and DOG, providing direct
evidence for an essential role of increased ROS formation in exten-
sion of life span (Schulz et al., 2007).
7. Physical exercise
As summarized above, CR and specifically glucose restriction in-
duce mitochondrial respiration and ROS formation in various mod-
el organisms. The ROS signal appears to induce ROS defense
mechanisms, culminating in extended lifespan, which reflects a
typical adaptive response, consistent with the mitohormesis
hypothesis. Antioxidants prevent this adaptive response, and
extension of lifespan is abolished. It remains to be resolved, in
which time-resolved order these processes occur, and specifically
whether increased ROS defense counteracts respiration-derived
Moreover, these findings indicate that approaches to induce
mitochondrial metabolism are likely to promote metabolic health
and may potentially extended lifespan. This notion is supported
by the fact that not only calorie and/or glucose (and possibly amino
acid) restriction, but also longevity-promoting physical exercise in-
duces mitochondrial metabolism and ROS formation (Davies et al.,
1982; Chevion et al., 2003; Powers and Jackson, 2008). Notably,
supplementation with ROS-reducing antioxidants inhibits (Go-
mez-Cabrera et al., 2008; Ristow et al., 2009) the health-promoting
effects (Higuchi et al., 1985; Lindsted et al., 1991; Manini et al.,
2006; Warburton et al., 2006; Lanza et al., 2008) of physical exer-
cise. This suggests that CR, glucose restriction and physical exercise
share, at least in part, a common metabolic denominator (Fig. 1),
i.e. increased mitochondrial metabolism and ROS formation induc-
ing a adaptive response that culminates in increased stress resis-
tance, antioxidant defense and extended life span.
Studies in the authors’ laboratory have been or are supported by
the German Research Association (DFG), the German Ministry of
Education and Research (BMBF), the European Foundation for the
M. Ristow, K. Zarse/Experimental Gerontology 45 (2010) 410–418
Study of Diabetes (EFSD), the Leibniz Association (WGL), the Fritz-
Thyssen-Stiftung and the Wilhelm-Sander-Stiftung. We apologize
to those whose work relevant for the topic has not been cited so-
lely due to limitations of space.
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Fig. 1. Mitohormesis and lifespan extension: For both calorie restriction as well as
physical exercise, experimental evidence suggests that induction of mitochondrial
metabolism is required for the lifespan-extending and/or health-promoting effects
of these interventions. This increase in mitochondrial metabolism generates a ROS
signal that is required to induce an adaptive response to culminate in increased
lifespan. For impaired insulin-IGF-1 signaling however, this links remains to be
M. Ristow, K. Zarse/Experimental Gerontology 45 (2010) 410–418