Dietary Energy Intake, Hormesis, and Health
Bronwen Martin, Sunggoan Ji, Caitlin M. White, Stuart Maudsley,
and Mark P. Mattson
Abstract The ability to adapt to varying levels of available energy in the form of
food in the environment has allowed species to propagate and also thrive during
times of energy surplus. However, in times when there is scant food available, simi-
lar evolutionary pressures have ensured that physiological systems can adapt to and
utilize this food scarcity to their advantage. Considerable research has demonstrated
that upon reduction of food intake, there are several beneficial effects upon cardio-
vascular, endocrinological, immune, and neuronal systems. Some of the effects of
caloric restriction, however, tend to be exaggerated in many experimental cases due
to biasing of overweight control subjects, yet reduction of total body weight still
seems to engender beneficial effects for the individual. Some of the beneficial effects
of caloric restriction are believed to arise from a reflexive response to the “stress”
of reduced food intake. In conjunction with this is a similar hypothesis, known as
“hormesis,” which proposes in a similar vein that other forms of stress, such as tox-
icological stress, can also engender a “protective” set of physiological responses
that shields the individual from further stresses. This chapter discusses how these
two theories of protective responses—caloric restriction and hormesis—share many
overlapping properties.
Keywords Caloric restriction · Energy homeostasis · Endocrinological ·
Neuroprotective · Adaptive · Evolutionary
Introduction
It is clear that many organisms have thrived throughout evolutionary history by
developing mechanisms to control their physiology during times of either abundant
or scarce food resources. Both mechanisms to store food as well as to extract the
B. Martin (B)
Laboratory of Clinical Investigation, National Institutes of Health, National Institute on Aging,
Baltimore, MD 21224, USA
e-mail: martinbro@mail.nih.gov
123M.P. Mattson, E.J. Calabrese, Hormesis, DOI 10.1007/978-1-60761-495-1_7,
C© Springer Science+Business Media, LLC 2010
124 B. Martin et al.
greatest amount of energy from available food have been developed. It has recently
been proposed that not only do these mechanisms ensure short-term survival, but
also that they may exert life-long effects by promoting a protective response, espe-
cially during times of stress. Indeed, even in the brief era of Homo sapiens evolution
in multiple areas across the world, cultures have recognized the beneficial effects
on health of limiting food intake for certain periods of time, either for religious
reasons or during times of famine. The first widely recognized scientific study of
the beneficial effects of caloric restriction (CR) was performed by McCay et al
(1935). They demonstrated that rats fed with a diet containing indigestible cellu-
lose possessed an extended mean and maximum lifespan compared to animals fed
with a higher-caloric-density diet (McCay et al., 1935). Many studies since have
confirmed this result and have extended it to other organisms, such as mice and fruit-
flies (Weindruch and Walford, 1988; Sprott, 1997; Chapman and Partridge, 1996;
Houthoofd et al., 2002). It has been postulated that one of the broad mechanisms
by which many of the beneficial effects of CR are created is through the invocation
of cellular protection mechanisms. These general mechanisms are activated by the
stressor and then serve to protect protein structure, energy production, and DNA
stability for a considerable period of time that may even extend beyond the period
of exposure to the stressor. In the specific case of CR, the stressor primarily takes
the form of attenuated energy production. Therefore, it is possible that energetic
processes are modified to utilize resources more efficiently, and critical systems are
selectively protected against damage during this period. The hormetic hypothesis
proposes that organisms can respond in a long-term protective manner to multiple
environmental or physical stressors.
In this chapter, we use the paradigm of CR to explore the implications of the
hormetic hypothesis for our understanding of how physiological mechanisms can
adjust to and utilize factors that have previously been considered to be deleteri-
ous. We provide a comprehensive overview of many of the mechanisms by which
CR can exert beneficial effects upon general physiology and how these may then
be controlled by additional exogenous factors, such as xenobiotics or synthetically
derived chemicals, to improve health and general well-being.
CR as a Hormetic Effector
Hormesis is defined as the beneficial effects that agents previously considered dele-
terious can have upon biological systems. These effects are ascribed to low doses of
xenobiotic agents (e.g., natural defensive chemicals derived from plants or animals),
environmental chemicals, or even ionizing radiation. The hormesis hypothesis pro-
poses that biological and physiological systems can adjust to and thrive in the face
of such insults as they induce a beneficial compensatory response in the organism.
This response then readjusts the organism’s physiology to make it more resistant
to future stressors and utilize its endogenous resources in a more efficient manner.
To this end, CR has often been considered an interesting paragon of this hypothesis
Dietary Energy Intake, Hormesis, and Health 125
because it involves the most basic stressor—direct inhibition of energetic processes.
The lack of input energy may not be the only stress induced by CR, in that there
may also be additional stresses, such as psychosocial stress and secondary cellular
oxidative damage to proteins, lipids, or nucleic acids due to alterations in cellular
metabolism. We will discuss how CR and hormesis have many overlapping prop-
erties and how the effects of CR on whole-body physiology could be considered
hormetic. An overview of the overlapping properties of CR and hormesis is provided
in Fig. 1.
CRCR
Reduced glucose
Reduced ATP
Altered energy stores
Reduced mass
Hunger
HormeticHormetic
ResponseResponse
to CRto CR
Cellular ProtectionCellular Protection
Heat
Shock protein expression
Glucose-regulated proteins
Trophic factor support
PI3K-Akt activity
JNK activity
Transcriptional ProtectionTranscriptional Protection
Sirtuin activity
PPAR activity
NF-κB activity
PGC1-α regulation
FOXO transcription regulation
Somatic ProtectionSomatic Protection
Ketogenesis
Euglycemia
Immunomodulation
Insulin sensitivity
Fig. 1 Calorie restriction as a hormetic effector of multiple protective mechanisms. The induction
of caloric restriction (CR) imposes a myriad of challenges to the body. To maintain survival and
well-being in the face of the reduced capacity to produce and store energy for growth, reproduction,
or homeostasis, the body responds to the CR state with a “hormetic-style” response. Hence, respon-
sive mechanisms at multiple physiological levels are entrained to ameliorate and even employ the
applied CR stress to the benefit of the body. These mechanisms occur at almost all levels of cellular
and tissue organization—for example, with respect to maintenance of intermediary cell metabolism
(cellular protection), generation of new proteins (transcriptional protection), and maintenance of
whole-body endocrine/neurological axes (somatic protection)
CR and Cellular Stress Factors
In the face of reduced energy production (caused by reduced food intake), it is likely
that highly energetic processes such as transcription and translation may be cur-
tailed to conserve levels of nucleotide (adenosine or guanosine) triphosphates. On
the other hand, stress-regulated proteins will be upregulated to exert cellular pro-
tective actions. For example, several different stress proteins have been measured
126 B. Martin et al.
in the brains from rats maintained on either ad libitum or CR diets for 3 months.
Examples of such stress proteins include heat-shock proteins and glucose-regulated
proteins. Heat-shock proteins comprise a huge family of distinct proteins that act as
molecular chaperone proteins that interact with many different proteins in cells and
function to ensure their proper folding, on one hand, and degradation of damaged
proteins, on the other hand (Frydman, 2001; Gething, 1999). It has been shown that
levels of some of these chaperone proteins are increased during the aging process
as a protective response (Lee et al., 2000). Cell culture and in vivo studies have
demonstrated the ability of heat-shock protein 70 (HSP-70) and glucose-regulated
protein 78 (GRP-78) to be neuroprotective in experimental models of neurodegen-
erative disorders, excitotoxic stress, and oxidative injury (Lowenstein et al., 1991;
Yu and Mattson, 1999; Warrick et al., 1999). Levels of HSP-70 and GRP-78 have
also been found to be increased in the cortical, hippocampal, and striatal neurons of
rats on a CR diet compared to age-matched ad libitum–fed animals (Lee et al., 1999;
Mattson, 1998). It has also been demonstrated that heat-shock proteins can bind to
and modify the activity of proapoptotic factors such as caspases (Beere et al., 2000;
Ravagnan et al., 2001). These data may demonstrate that CR can induce a mild
stress response in cells, presumably due to reduced energy—primarily glucose—
availability. In addition to these cellular stress response mechanisms, it has been
reported that reduced dietary energy results in increased levels of circulating cor-
ticosterone (Martin et al., 2006; 2007). Systemic corticosterone levels are usually
associated positively with the stress state of the organism. In contrast to detrimental
stressors such as chronic, uncontrollable stress (which can endanger cells through
glucocorticoid receptor activation), reduced energy intake downregulates glucocor-
ticoid receptors with maintenance of mineralocorticoid receptors in cells, which can
act to prevent neuronal damage and death (Lee et al., 2000; Masoro, 2007). Thus,
periods of energy scarcity may play a mechanistic role in triggering increases in
cellular stress resistance and the repair of damaged proteins and cells.
CR Effects Upon Cytokine Levels
There is increasing evidence demonstrating the role of inflammatory mediators
in the development of chronic, age-related disorders such as Alzheimer’s disease.
Pathophysiological activation of microglia is thought to be a major contribu-
tor to such conditions (Griffin, 2006). Any hormetic responsive mechanism—for
example, to CR—may therefore also be able to promote healthy aging through
effective amelioration of this chronic, uncontrolled immune response. It has been
shown that circulating levels of interferon gamma (IFN-γ) are selectively elevated
in monkeys maintained on a CR diet (Mascarucci et al., 2002). IFN- γ levels can
also be enhanced in the hippocampus, where they can exert a profound excitopro-
tective action (Lee et al., 2006). Cytokine synthesis may also be affected by CR in
peripheral tissue, as well as in the general circulation and in the central nervous sys-
tem (CNS) (Bordone and Guarente, 2005). Tissue necrosis factor alpha (TNF-α) can
Dietary Energy Intake, Hormesis, and Health 127
be readily synthesized by adipose tissue, and upon its release it has been shown to
affect insulin resistance and therefore long-term energy regulation and, potentially,
eventual longevity (Feinstein et al., 1993). Of interest, the genetic removal of TNF-α
receptors can improve insulin sensitivity, thus suggesting a potential mechanism of
CR’s hormetic actions, given that energy restriction can reduce the age-dependent
upregulation of the TNF-α–controlling transcription factor NF-κB (Kim et al., 2000;
Bordone and Guarente, 2005). Consistent with a role for suppression of NF-κB
activity in the hormetic antiaging effect of CR, it was recently shown that genetic
blockade of NF-κB for 2 weeks in the skin of chronologically aged mice restored
the skin tissue characteristics back to those of young mice (Adler et al., 2007).
CR and Alterations in Neurotrophic Factors
A significant degree of attention has recently been paid to the emerging concept that
neurological and endocrinological systems are functionally intertwined to a much
greater extent than previously appreciated (Martin et al., 2008). Therefore, it is now
accepted that alterations in neurological factors often can have dramatic effects upon
peripheral physiology and vice versa. To this end, it has been demonstrated that there
are often considerably strong effects of CR upon levels of neurotrophic agents such
as brain-derived neurotrophic factor (BDNF). Given that CR is thought to induce a
mild stress response in many cells in the periphery and the CNS, this can result in the
activation of trophic hormone compensating mechanisms, for example, the upregu-
lation of neurotrophic factors such as BDNF and glial cell line–derived neurotrophic
factor (GDNF) (Bruce-Keller et al., 1999; Maswood et al., 2004). One of the primary
neuroprotective mechanisms attributed to BDNF appears to be the BDNF-mediated
activation of its cognate TrkB receptor tyrosine kinase. Activation of this receptor
results in the potent stimulation of multiple signaling pathways associated with the
ligand-dimerized TrkB receptor. Prominent among these TrkB signaling pathways
is the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt) pathway that has
been implicated in several of the CR protective mechanisms that will be discussed
at greater length later in this chapter.
CR Effects Upon Glycemic Control
During episodic CR, the primary perturbation to the individual relates to the avail-
ability of glucose for oxidative respiration. The mechanisms by which energy is
derived from alternate sources and how the remaining glucose is handled are cru-
cial to the appreciation of the beneficial effects of CR paradigms. With respect to
the hormetic effects of CR upon health and aging, it has been demonstrated that
CR-induced reductions in glucose levels in the blood, integrated over time, can
attenuate the levels of nonenzymatic glycation (a form of protein damage), as well
as attenuate damaging oxyradical production (Weindruch and Sohal, 1997; Cefalu
128 B. Martin et al.
et al., 1995). Dietary energy restriction typically has the predictable effects upon
somatic glycemic physiology with respect to levels of insulin and glucose, that is,
CR causes a reduction in both. A longitudinal study on male rats (Masoro et al.,
1992) showed that CR decreases the mean 24-hour plasma glucose concentration by
about 15 mg/dL and the insulin concentration by about 50%. Of interest, however,
CR animals utilized glucose at the same rate as ad libitum–fed animals despite the
lower plasma glucose and markedly lower plasma insulin levels, indicating that their
energy system was more efficient. CR has also been found to reduce plasma glucose
and insulin concentrations and insulin sensitivity in fasting rhesus and cynomolgus
monkeys (Kemnitz et al., 1994; Lane et al., 1996; Cefalu et al., 1997). The poten-
tial importance of modulating energy regulation by CR is the demonstration that
loss-of-function mutations of the insulin signaling system result in life extension
in three species: nematode worms (Kenyon et al., 1993), fruitflies (Clancy et al.,
2001), and mice (Bluher et al., 2003). Therefore, it is highly likely that CR engen-
ders complex physiological states that can result in enhanced glucose effectiveness,
insulin responsiveness, or both, and that the maintenance of low levels of glucose
and insulin may in part mediate the beneficial and life-extending hormetic actions of
CR. It is likely that other hormetic agents could induce similar alterations in energy
control and insulin sensitivity.
CR and Satiety/Adipose-Generated Hormones
Traditionally, the circulating hormones that control the desire and responsiveness of
an organism towards food intake have largely been thought to serve only one func-
tion in the body. However, in recent years, our appreciation of hormones such as
leptin and adiponectin has changed how we perceive the activities of these pluripo-
tent hormones (Martin et al., 2007). Because CR can potently affect adiposity in
most animals, it has significant effects upon the levels of satiety-related hormones
synthesized by fat, for example, leptin and adiponectin (Meier and Gressner, 2004).
As we have described, the primary hormetic action of CR could be mediated through
its ability to subtly elevate an animal’s stress response in a manner that engenders
improved tolerance rather than excessive trauma. For example, CR regimens can
effectively downregulate potentially damaging thyroid hormones via attenuation of
circulating leptin levels (Barzilai and Gupta, 1999).
Adiponectin, on the other hand, has been shown to trigger increased insulin sen-
sitivity (Meier and Gressner, 2004; Pajvani and Scherer, 2003) via upregulation
of AMP-activated protein kinase (Wu et al., 2003). This kinase regulates glu-
cose and fat metabolism in muscle in response to energy limitation (Musi et al.,
2001) and has been shown to protect cells against metabolic stress (Culmsee et al.,
2001). Adiponectin levels rise during CR, which suggests that this adipose-derived
hormone might also have an important contributory role in the physiological shift
to an enhanced insulin sensitivity and general protective responsivity in these
animals (Combs et al., 2003). These data suggest that visceral adipose might
Dietary Energy Intake, Hormesis, and Health 129
be especially important in driving insulin sensitivity and potential pathogenesis
(Bjorntorp, 1991), and, thus, alteration of this via CR may again impart a hormetic
action upon whole-body energy regulation.
CR and Ketone Body Synthesis
Part of the beneficial response to CR appears to be a necessitated increase in the
diversity of pathways by which the body can generate usable energy. CR and related
paradigms have been shown to cause an increase in the somatic production of
ketone bodies, for example, β-hydroxybutyrate. This simple ketone can be utilized
by the body as an additional or alternative source of energy generation during peri-
ods of limited glucose availability (Vazquez et al., 1985; Mitchell et al., 1995). A
CR-induced diversification to ketogenic energy generation not only may facilitate
additional energy resources, but also may mediate a strong cytoprotective action. For
example, rats fed a diet that favors the switch to in vivo production of ketones exhibit
increased resistance to seizures (Bough et al., 1999). In addition, β-hydroxybutyrate
can protect neurons in rodent models of neurodegenerative diseases and also reduces
neurological damage incurred due to excitotoxicity during epileptic seizure activity
(Kashiwaya et al., 2000; Gilbert et al., 2000).
CR and Sirtuin Activity
Genetic studies in yeast identified an important factor that seemed to control
longevity—the silent information regulator 2 (SIR2), so denoted because it mediates
a specific gene silencing action (Rine and Herskowitz, 1987). Mutagenesis of SIR2
that results in its inactivation shortens lifespan, and increased gene dose of SIR2
can conversely extend it (Kaeberlein et al., 1999). Given that dietary regulation has
also shown to be a powerful modulator of both health and lifespan, it is reasonable
to speculate that CR and SIR2 gene programs may converge to play an important
role in these multiple and complex physiological pathways. The family of proteins
encoded for by the mammalian SIR2 homolog (SIRT1) is collectively termed sirtu-
ins. Several recent reports have shown increases in SIRT1 protein levels in response
to food deprivation (Nemoto et al., 2004; Cohen et al., 2004).
Sirtuins act as NAD-dependent histone deacetylases (Imai et al., 2000; Landry
et al., 2000). The mammalia
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