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.
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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
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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.
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