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Ageing Research Reviews 13 (2014) 38–45
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Ageing Research Reviews
journal homepage: www.elsevier.com/locate/arr
Review
What are the roles of calorie restriction and diet quality in promoting
healthy longevity?
Wanda Rizza a,b , Nicola Veronese a,c , Luigi Fontana a,d,e,∗
a
Division of Geriatrics and Nutritional Science and Center for Human Nutrition, Washington University School of Medicine, St. Louis, MO, USA
Department of Food and Human Nutrition Science, University Campus Bio-Medico, Rome, Italy
Division of Geriatrics, Department of Medicine, University of Padova, Italy
d
Department of Medicine, University of Salerno Medical School, Salerno, Italy
e
CEINGE Biotecnologie Avanzate, Napoli, Italy
b
c
a r t i c l e
i n f o
Article history:
Received 29 August 2013
Received in revised form
12 November 2013
Accepted 19 November 2013
Available online 27 November 2013
Keywords:
Calorie restriction
Diet quality
Health
Lifespan
Vegetarian diet
Disease prevention
a b s t r a c t
Epidemiological and experimental data indicate that diet plays a central role in the pathogenesis of many
age-associated chronic diseases, and in the biology of aging itself. Data from several animal studies suggest that the degree and time of calorie restriction (CR) onset, the timing of food intake as well as diet
composition, play major roles in promoting health and longevity, breaking the old dogma that only calorie intake is important in extending healthy lifespan. Data from human studies indicate that long-term
CR with adequate intake of nutrients results in several metabolic adaptations that reduce the risk of
developing type 2 diabetes, hypertension, cardiovascular disease and cancer. Moreover, CR opposes the
expected age-associated alterations in myocardial stiffness, autonomic function, and gene expression in
the human skeletal muscle. However, it is possible that some of the beneficial effects on metabolic health
are not entirely due to CR, but to the high quality diets consumed by the CR practitioners, as suggested
by data collected in individuals consuming strict vegan diets. More studies are needed to understand
the interactions among single nutrient modifications (e.g. protein/aminoacid, fatty acids, vitamins, phytochemicals, and minerals), the degree of CR and the frequency of food consumption in modulating
anti-aging metabolic and molecular pathways, and in the prevention of age-associated diseases.
© 2013 Elsevier B.V. All rights reserved.
Contents
1.
2.
3.
4.
5.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Roles of calorie intake and diet quality in the prevention of cardiovascular disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Role of nutrients in the primary and secondary prevention of CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
The role of CR in CVD prevention . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
The role of specific nutrients in the pathogenesis of CVD . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Calorie restriction, protein intake and diet quality. What roles in the prevention of cancer? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.1.
Excessive food intake, CR and cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.2.
Role of protein intake on the IGF1 signaling pathway . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
3.3.
Role of micronutrients in the pathogenesis of cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Which is the role of calorie intake and diet composition in slowing aging? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.1.
Dietary restriction and aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.2.
Role of diet quality in modulating the biology of aging . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
4.3.
Role of dietary supplements on lifespan extension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Does calorie restriction slow the aging process in humans? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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∗ Corresponding author at: Washington University School of Medicine, 4566 Scott Avenue, Campus Box 8113, St. Louis, MO 63110, USA. Tel.: +1 314 747 1485; fax: +1 314
362 7657.
E-mail address: [email protected] (L. Fontana).
1568-1637/$ – see front matter © 2013 Elsevier B.V. All rights reserved.
http://dx.doi.org/10.1016/j.arr.2013.11.002
W. Rizza et al. / Ageing Research Reviews 13 (2014) 38–45
6.
Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
That nutrition plays a central role in preventing diseases and
promoting health is well established. Before mechanical refrigerators became available, sailors and soldiers on long voyages eating
diets rich in cured and salted meats and dried grains developed a
life-threatening disease (i.e. scurvy), unless their diets were supplemented with fresh fruits and vegetables, or lemon juice loaded
with vitamin C (Carpenter, 2003). Despite adequate intake of calories and protein, chronic vitamin D and iodine deficiencies causing
rickets, goiter, and sometimes cretinism, were common problems
in Western Europe and United States during the Industrial Revolution (Carpenter, 2003; Heimburger, 2014). Today the likelihood of
developing these and other deficiency diseases (e.g. beriberi, pellagra, Keshan disease, and night blindness) in a developed country
is extremely low. On the other hand, the likelihood of developing
and dying of other chronic diseases (e.g. heart disease, stroke, type
2 diabetes, and certain cancers) is very high. Accumulating data
from epidemiological and experimental studies suggest that calorie intake, the timing of food intake (e.g. fasting cycles), and some
of the nutrients we ingest with foods are fundamentally implicated
in the pathogenesis of these chronic diseases, and also in the biology of aging itself (i.e. they control the rate of aging of our body)
(Fontana et al., 2010; Mattson, 2005; Eyre et al., 2004).
In 1935 McCay and associates published the first paper showing that food restriction without malnutrition extends average and
maximal lifespan in rats (McCay et al., 1935). Since then, several
other research groups have consistently shown that restricting food
intake without malnutrition slows aging, and results in a marked
healthspan and lifespan extension in yeasts, fruit flies, nematode
worms, fish, hamsters, and in a wide variety of mice and rat strains
(Fontana et al., 2010; Weindruch and Walford, 1988; Masoro,
2005). The age when calorie restriction is started and the degree of
restriction determine the magnitude of maximal lifespan extension
(Fontana et al., 2010; Weindruch and Walford, 1982; Means et al.,
1993). These “super-lean” animals not only live longer and healthier lives, but at any time they are physiologically younger than
ad libitum fed animals (Weindruch and Walford, 1988; Masoro,
2005). Approximately, 30% of the CR rodents die at old ages without any significant pathological lesion, suggesting that in mammals
aging is not inevitably linked with debilitating, painful and costly
medical conditions (Shimokawa et al., 1993; Ikeno et al., 2013).
Alternate day fasting and methionine restriction have also been
shown to increase lifespan and prevent chronic diseases in certain species of rodents (Carlson and Hoelzel, 1946; Goodrick et al.,
1982; Miller et al., 2005; Orentreich et al., 1993). This research has
been reviewed previously (Mattson, 2005; Varady and Hellerstein,
2007; Cavuoto and Fenech, 2012) and need not be considered here
in detail. Moreover, data from genetic and pharmacological animal
models of longevity indicate that down-regulation of the PI3K/AKT
and mTOR signaling pathways, which are key cellular nutrientsensing pathways controlled by energy and aminoacid availability,
significantly extends both average and maximal lifespan in simple
model organisms and rodents (Fontana et al., 2010).
Nonetheless, because large variations exist in metabolism, life
expectancy and susceptibility to diseases among yeast, worms,
flies, rodents and humans, some key questions remain to be
addressed: “Can human beings live a long life without ever developing chronic disease?”, “Does CR without malnutrition extend
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healthspan and lifespan in humans?” How important are meal
frequency/timing (i.e. cycles of fasting) and dietary composition
(e.g. protein, aminoacid, fat, mineral, vitamin and phytochemical
intake) in mediating health or longevity? This last question is particularly important because accumulating data from non-human
and human primates suggest that both diet quality and calorie
intake are important in modulating the metabolic and molecular
pathways, and physiological processes that promote health and
longevity.
2. Roles of calorie intake and diet quality in the prevention
of cardiovascular disease
Cardiovascular disease (i.e. coronary heart disease, stroke, heart
failure) is the primary cause of morbidity, disability and mortality
in both men and women in the developed countries. Around 2200
people die of CVD each day in USA, an average of 1 death every 39 s
(Roger et al., 2012). Well-established, modifiable cardiometabolic
risk factors are high blood pressure, hypercholesterolemia, type
2 diabetes, smoking, inflammation and excessive adiposity. In
the Framingham Heart Study, men with normal cardiometabolic
profiles (i.e. total cholesterol less than 180 mg/dl, blood pressure
<120/80 mm Hg, fasting glucose <125 mg/dl, BMI < 25 kg/m2 , and
no smoking) at age 50 have a 13 fold lower risk of developing CVD
during their remaining lifetime than individuals with two or more
risk factors (Lloyd-Jones et al., 2006).
2.1. Role of nutrients in the primary and secondary prevention of
CVD
Data from several epidemiological and interventional studies
have clearly shown that individuals who are eating diets rich in
fish and nutrient-dense minimally processed plant foods have a
lower risk of developing cardiometabolic abnormalities and CVD
than men and women who consume Western diets rich in empty
calories, saturated/trans fatty acids, animal protein and salt. The
Seven Countries and the Ni-Hon-San were the first population studies to suggest an interrelationship between diet and CVD (Keys
et al., 1986; Kato et al., 1973). The Twenty Country and the INTERHEART studies confirmed and expanded the relationship between
CVD risk and the intake of animal foods, and the potential protective
role of fruit and vegetable consumption (Stamler, 1979; Yusuf et al.,
2004). Several well-conducted randomized clinical trials, including
the Oslo Diet Heart Study, the Los Angeles Veterans Administration Study, the Finnish Mental Hospital Study, also confirmed that
replacing diets rich in animal fat with vegetable oil lowers the risk
of developing CVD morbidity and mortality (Hjermann et al., 1981;
Dayton et al., 1968; Turpeinen, 1979). The PRIDIMED randomized
clinical trial on the cardiovascular effects of a Mediterranean diet
(supplemented with extra-virgin olive oil or nuts) was stopped
after a median follow-up of only 4.8 years because this diet significantly reduced the incidence of the combined cardiovascular end
points and stroke (but not for myocardial infarction alone) (Estruch
et al., 2013). This was a primary prevention trial in high-risk men
and women who were initially free of cardiovascular disease, but
the beneficial effects of an energy-unrestricted Mediterranean diet
rich in alpha-linolenic acid (a main ingredient of walnuts) have also
been shown in a secondary prevention trial, the Lyon Diet Heart
Study. De Lorgeril and associates showed a striking reduction in
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W. Rizza et al. / Ageing Research Reviews 13 (2014) 38–45
rates of coronary heart disease events in patients who had already
suffered a first myocardial infarction (de Lorgeril et al., 1999).
The traditional Mediterranean diet is rich in plant foods (grains,
legumes, vegetables, fruits, tree nuts, seeds and olives), with extravergin olive oil and fish as the primary source of fat. Consumption of
other animal products such as red meat, eggs, and dairy products
is limited, and moderate amounts of wine are consumed mainly
during meals. A similar diet, though more extreme is the Ornish
diet. In a classical paper published in JAMA, Ornish and colleagues
have shown that a low-fat vegetarian diet in conjunction with
other lifestyle changes (i.e. smoke cessation, endurance exercise,
and stress management training) is highly effective in reversing
the progression of coronary atherosclerosis and in reducing cardiac
events even in patients with moderate to severe coronary artery
disease (Ornish et al., 1998), reinforcing the importance of diet in
the primary and secondary treatment of atherosclerotic cardiovascular disease, the leading cause of both death and disability in North
America, Europe and many developing countries.
2.2. The role of CR in CVD prevention
Reducing the risk of CVD progression in metabolically abnormal individuals or diseased patients by lowering for example salt
or saturated fat intakes or by taking drugs (e.g. lipid lowering,
antihypertensive or anti-diabetic medications), is not the same as
preventing the development of any clinically relevant CVD by maintaining optimal cardiometabolic health. Accumulating data show
that men and women practicing long-term severe CR with adequate
intake of nutrients are simultaneously protected against abdominal
obesity, type 2 diabetes, hypertension, dyslipidemia, inflammation and atherosclerosis (Fontana et al., 2004). These individuals,
who call themselves CRONIes (i.e. Calorie Restriction with Optimal
Nutrition), are extremely lean with an average body mass index of
19.6 ± 1.9 kg/m2 and total body fat of ∼12%. Total serum cholesterol, LDL cholesterol, total cholesterol/HDL cholesterol ratio, and
triglyceride values all fall in the lowest 10% for people in their
age groups (Fontana et al., 2004). Even in the elderly CRONies,
blood pressure is extremely low with a systolic blood pressure
of ∼110 mm Hg and a diastolic blood pressure of ∼70 mm Hg,
fasting glucose concentration in the 80 mg/dl range and very low
C-reactive protein concentrations. Accordingly, the intima-media
thickness of the common carotid arteries was ∼40% lower in the
CRONies than in age- and sex-matched controls eating Western
diets (Fontana et al., 2004). However, it is possible that some of the
beneficial effects on the cardiometabolic risk factors are not entirely
due to CR, but to the high quality diets consumed by the CR practitioners. All of the CRONies have eliminated from their diets refined
and processed foods containing salt, trans-fatty acids, dietary glycotoxins and high-glycemic-index foods (e.g. refined carbohydrates,
potato, white rice, sucrose- and fructose-enriched foods). They consume, instead, a wide variety of vegetables, low-glycemic-index
fruits, nuts, low-fat dairy products, egg whites, wheat and soy proteins, fish, and lean meat. Interestingly, we found that men and
women consuming energy unrestricted strict vegan diets also have
extremely low blood pressure, LDL cholesterol, triglycerides and
fasting glucose concentrations, suggesting that the quality of the
diet plays a major role in modulating blood pressure, lipid and glucose metabolism (Fontana et al., 2007). Nevertheless, unlike in the
CRONies, serum HDL-cholesterol and adiponectin concentrations
were not significantly increased in these vegetarians and serum
concentration of fasting insulin, TNF-alpha and triiodothyronine
were higher than in age- and sex-matched individuals practicing CR. Short-term alternate day fasting has also been shown to
result in some beneficial cardiometabolic adaptations in obese individuals eating typical Western diets during the no-fasting days,
including a reduction in body weight, blood pressure, and serum
cholesterol and triglycerides concentrations, but high-density
lipoprotein cholesterol (HDL-C), C-reactive protein, and homocysteine concentrations did not change (Varady et al., 2009; Bhutani
et al., 2010).
2.3. The role of specific nutrients in the pathogenesis of CVD
Because classical cardiometabolic risk factors do not fully
explain the risk of developing CVD (i.e. 10–20% of patients with
CVD lack any of the conventional risk factors), more studies are
needed to understand the role of macro- and micronutrients in
modulating alternative metabolic pathways that regulate cardiovascular health and disease (Khot et al., 2003). For example, data
from several experimental studies suggest that excessive intake
of salt and partially hydrogenated trans fatty acids play an independent role in promoting the progression of atherosclerotic CVD
(Dickinson and Havas, 2007; Mozaffarian et al., 2006). In contrast,
consumption of omega-3 fatty acids, and certain phytochemicals such as olecanthal may have protective effects because of
their anti-inflammatory and anti-thrombotic effects (De Caterina,
2011; Beauchamp et al., 2005). Recently, it has been shown
that the intestinal microbiota convert dietary phosphatidylcholine
and l-carnitine (a trimethylamine abundant in red meat) into
a metabolite, trimethylamine-N-oxide (TMAO), which promotes
atherosclerosis and increases the risk of developing major adverse
cardiovascular events independently of traditional cardiovascular
risk factors (Tang et al., 2013; Koeth et al., 2013). Data from metabonomic studies in humans indicate that individuals with high-meat
consumption have elevated concentrations of TMAO, creatine, carnitine, and acetylcarnitine, and a vegetarian or high-fiber diet can
reduces phosphatidylcholine intake (Stella et al., 2006).
3. Calorie restriction, protein intake and diet quality. What
roles in the prevention of cancer?
In both men and women cancer is the second most important
cause of death. It has been estimated that approximately 1600 people die of cancer each day in USA, an average of 1 death every 60 s
(Siegel et al., 2013). The lifetime probability of being diagnosed
with an invasive tumor is high: 38% for women and 45% for men.
Prostate, lung, and colon–rectum are the most common cancers in
men, whereas breast, lung, colon, and uterine corpus are the most
frequent in women (Siegel et al., 2013).
3.1. Excessive food intake, CR and cancer
The importance of a healthy diet in reducing the risk of developing some of the most common types of cancer in the Western
world is supported by several experimental and epidemiological studies (Eyre et al., 2004; Longo and Fontana, 2010). Calorie
restriction without malnutrition is the most potent physiological intervention for protecting against spontaneous, chemicallyand radiation-induced cancers in experimental animals (Longo and
Fontana, 2010; Weindruch and Walford, 1988). Young-onset 30%
CR has, so far, completely prevented cancer in the NIA CR monkey study, while adult-onset 30% CR reduced cancer incidence
by 50% in the Wisconsin monkey study (Mattison et al., 2012;
Colman et al., 2009). In contrast, excessive food intake has been
associated with increased cancer risk (Longo and Fontana, 2010).
Excessive energy and protein intake before puberty, by stimulating the insulin/IGF/mTOR pathway, causes rapid growth rates,
and early menarche, which is a well-established risk factor for
breast cancer (Berkey et al., 2000). Whether or not overstimulation of anabolic/mitogenic pathways by excessive nutrition during
childhood influences the development of other cancer types (e.g.
prostate, colon, and endometrial cancer) remain to be tested.
W. Rizza et al. / Ageing Research Reviews 13 (2014) 38–45
There is also consensus that a positive energy balance during
adulthood, by increasing adiposity, contributes to an increased
risk of developing several cancer types, including cancer of the
colon, breast, prostate, endometrium, pancreas, liver and kidney,
and weight loss lowers this risk (Longo and Fontana, 2010; Calle
and Kaaks, 2004). In a prospective, controlled study involving 4047
obese patients, bariatric surgery-induced weight loss was associated with a 40% reduction in cancer mortality (Sjöström et al.,
2007). Reductions in growth factors/anabolic hormones (such as
insulin, testosterone, estradiol, leptin), inflammatory cytokines and
oxidative stress are probably responsible in part for the lower risk
of death associated with weight loss (Longo and Fontana, 2010;
Calle and Kaaks, 2004). Data from studies conducted in lean and
weight stable men and women practicing long-term CR also show
a significant reduction in serum levels of insulin, sex hormones,
inflammatory cytokines (Fontana et al., 2010a; Cangemi et al.,
2010).
3.2. Role of protein intake on the IGF1 signaling pathway
Whether or not the quality of diet plays a key role in cancer prevention independently of energy intake in non-obese individuals is
still under debate. For example, what is the role of chronic excessive protein intake in the pathogenesis of cancer? In other words,
what are the biological implications of consuming high-protein
low-carbohydrate diets in lean physically active individuals with a
family history of breast, prostate or colon cancer? It is known that
high concentrations of IGF-1 and essential amino acids stimulate
the PI3K/AKT/mTOR pathway, which promotes cell proliferation
and inhibits apoptosis of mutated cells (Pollak, 2004). Individuals
eating an energy-unrestricted plant-only diet have significantly
lower concentrations of total and free IGF-1 than extremely lean
individuals practicing long-term CR or regular endurance exercise
training (Fontana et al., 2008, 2006). Daily protein intake in the
vegan group was ∼0.75 g/kg of body weight (i.e. 10% calories from
protein), whereas the CRONies and the master athletes consumed
a relatively high protein diet (i.e. ∼1.6 g/kg, 23% calories from protein). A 3-week isocaloric reduction of protein intake from ∼1.6 g/kg
to 1 g/kg in the CRONies resulted in a 25% reduction in serum IGF-1
concentration (from 194 ± 34 to 152 ± 41 ng/ml), suggesting that
in humans, protein intake is more important than calorie intake in
modulating IGF-1 concentrations (Fontana et al., 2008). Interestingly, many patients with prostate and breast cancer have at least
one component of the IGF-1/mTOR signaling pathway activated
(Ma et al., 2011; Dai et al., 2009). Consistently, several epidemiological studies have found a strong association between serum
IGF-1 concentration and the risk of developing colon, breast (in
premenopausal women) and prostate cancer in humans (Renehan
et al., 2004).
Interestingly, the inhabitants of Okinawa, who until 1960 were
eating moderate CR diets with 9% calories from protein, had 80%
lower rates of breast, prostate, and colon cancer mortality than the
average U.S. population, and one of the highest numbers of centenarians in the world (Willcox et al., 2007). More studies are needed
to understand the effects of protein intake and dietary aminoacid
composition (e.g. methionine intake) in regulating IGF/mTOR activity, cancer risk, and aging, independently of other risk factors
modulated by caloric intake/energy expenditure (e.g. insulin, leptin, sex hormones, and inflammation).
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intake. In a population-based, prospective study involving 22,043
Greek adults, increasing adherence to a Mediterranean diet has
been shown to be associated with a significant reduction in cancer mortality (adjusted HR, 0.76 [95% C.I., 0.59 to 0.98]) and total
mortality (adjusted HR, 0.75 [95% C.I., 0.64 to 0.87]), independently of body-mass index, waist-to-hip ratio, level of physical
activity and smoking status (Trichopoulou et al., 2003). Accumulating data suggest that certain food constituents may modulate
DNA repair processes, genome stability, epigenetic regulation of
DNA, metabolic activation of carcinogens, cell proliferation and differentiation, and angiogenesis (Kris-Etherton et al., 2012; de Kok
et al., 2010). For example, data from in vitro studies have shown
that folic acid, vitamin A, vitamin B12, vitamin D, calcium, iron,
zinc, allyl sulphide, n-3 fatty acids, genistein and other phenolic
compounds are important regulators of cell cycle progression and
cell proliferation (Kris-Etherton et al., 2012; de Kok et al., 2010;
Stan et al., 2008). Moreover, several phytochemicals extracted
from plant foods (i.e. isothiocyanates, curcumin, resveratrol, EGCG,
genistein, indole-3-carbinol, lycopene, capsaicin, and organosulphur compounds) have been shown to induce apoptosis of cultured
cancer cells (Kris-Etherton et al., 2012; de Kok et al., 2010; Stan
et al., 2008). Some of these effects can be synergistic, as it has been
shown in an animal model of chemically induced gastric cancer.
Supplementation with lycopene and S-allylcysteine from garlic in
combination was more effective in inhibiting N-methyl-N’-nitroN-nitroso-guanidine induced stomach cancer than when these
bioactive compounds were administered in isolation (Velmurugan
et al., 2005). Similarly, administration of calcitriol with dietary soy
resulted in substantially greater inhibition of tumor growth in a
human xenograft model of prostate cancer (Wang et al., 2012).
However, because these are the result of cell culture and animal
studies using xenograft models in immunosuppresed or transgenic mice, well performed randomized clinical trials are needed to
assess the independent effects of these compounds in the primary
and secondary prevention of cancer in humans.
So far despite the promising data obtained from cell culture and
animal studies, randomized clinical trials have failed to show a
beneficial effect of vitamin C, vitamin E, beta-carotene, selenium
and fiber supplementation on cancer morbidity or mortality, and
2 large randomized clinical trials have shown an increased lung
cancer mortality in smokers that received beta-carotene supplementation (Lippman et al., 2009; Omenn et al., 1994, 1996; The
Alpha-Tocopherol, Beta Carotene Cancer Prevention Study Group,
1994; Alberts et al., 2000). Furthermore, data from a meta-analysis
suggests that supplementation with a high-dose of vitamin E may
increase all-cause mortality in men and women living in developed
countries (Miller 3rd et al., 2005). On the other hand, supplementation with beta carotene, vitamin E, and selenium has been shown
to reduce deaths due to esophageal or stomach cancer in a Chinese
rural population with a micronutrient-poor diet (Blot et al., 1993).
Finally, data from both the Women’s Healthy Eating and Living and
the Women’s Health Initiative studies suggest that a reduction of
fat intake does not reduce breast cancer risk, but it may reduce the
incidence of ovarian cancer among postmenopausal women (Pierce
et al., 2007; Prentice et al., 2006, 2007).
4. Which is the role of calorie intake and diet composition
in slowing aging?
3.3. Role of micronutrients in the pathogenesis of cancer
4.1. Dietary restriction and aging
Data from epidemiological and experimental cell and animal
studies suggest that other nutrients (e.g. fat, vitamins, phytochemicals, and minerals) may play a role in modulating cancer
initiation and progression independently of calorie and protein
The importance of diet (i.e. CR, intermittent fasting and methionine restriction) in slowing aging and extending lifespan in simple
model organisms and rodents is well established (Fontana et al.,
2010; Weindruch and Walford, 1988; Masoro, 2005; Goodrick et al.,
42
W. Rizza et al. / Ageing Research Reviews 13 (2014) 38–45
Poor health
Decreased survival
Good health
Increased survival
Poor health
Decreased survival
Fat and muscle wasting
Metabolic dysfunction:
Insulin resistance
Amenorrhea
Infertility
Immune dysfunction
Cardiac dysfunction
Optimal tissue & organ
function
Decreased risk of chronic
disease
Excess adipose tissue
Metabolic dysfunction:
Insulin resistance
Amenorrhea
Infertility
Immune dysfunction
Cardiac dysfunction
Cancer
Potential lifespan/
Life expectancy
Activation of PI3K/AKT/mTOR pathway
Calorie & Protein intake/Adiposity
Fig. 1. Relationship between healthy longevity and calorie-protein intake and adiposity.
1982; Mattson, 2005; Miller et al., 2005; Arum et al., 2009). In
many strains of rats and mice a monotonic linear relationship
between CR and lifespan extension exists. A 10–50% reduction in
calorie intake below usual ad libitum intake causes a proportionate
increase in maximum life span, whereas CR exceeding 50% typically causes starvation and increases mortality (Fontana et al., 2010;
Weindruch and Walford, 1988; Masoro, 2005). However, this relationship between CR and life extension seems not to be universal.
Some mice strains undergoing 40% CR do not live longer, or even
live shorter, than ad libitum fed control mice (Harper et al., 1987;
Harrison and Archer, 1987; Forster et al., 2003; Liao et al., 2010).
A possible explanation for these experimental findings is that 40%
CR in these mice strains is excessive, and that lower degree of CR
would be beneficial. In fact, in both wild-caught and C57BL/6J mice
40% CR shortened lifespan when started early in life, but increased
lifespan when started later in life, suggesting that 40% CR was too
extreme in these growing animals (Harper et al., 1987; Harrison
and Archer, 1987). The same may be true for humans. A certain
degree of CR that may be optimal for some individuals, may be
excessive and cause harm in others (Fig. 1). Biomarkers of optimal
calorie intake that define the threshold between optimal health and
starvation/malnutrition are needed to guide dietary prescriptions.
4.2. Role of diet quality in modulating the biology of aging
The apparently contradictory data from the two ongoing CR
monkey studies suggest that diet quality plays a major role in modulating longevity independently of caloric intake. One study, the
Wisconsin National Primate Research Center (WNPRC), has found
that long-term 30% CR results in a significant increase in lifespan
(when considering only age-associated deaths), in a 50% reduction
of cancer and cardiovascular disease morbidity, and in the prevention of sarcopenia and neurodegeneration of some brain regions
(Colman et al., 2009, 2012). In contrast, data from the National Institute of Aging (NIA) monkey study suggest that long-term CR does
not increase lifespan in Rhesus monkeys, even though CR markedly
reduces cancer, obesity and type 2 diabetes incidences (Mattison
et al., 2012). A potential problem is that the WNPRC diet is a semipurified diet rich in dairy proteins, corn oil, and refined and processed
carbohydrates such as sucrose and cornstarch, which resembles
the typical Western diet (Colman et al., 2009). Conversely, the NIA
study is a healthier diet rich in fish and minimally processed plant
foods (i.e. ground wheat and corn, soy, and alfalfa meal) (Mattison
et al., 2012). Fat intake is 10% (mainly from corn oil) in the WNPRC,
and only 5% (mainly from soy oil, fish, and alfalfa) in the NIA study.
Sucrose intake is 28.5% and 3.9% respectively in the WNCRP and NIA
study. Furthermore, unlike in the WNPRC study, the NIA natural
ingredient-based diets are rich in phytochemicals and fish omega3 fatty acids. Therefore, it is possible that the slightly restricted (i.e.
control monkeys were not freely fed, but received a controlled allotment of food each day to avoid obesity) pesco-vegetarian diet of the
NIA control monkeys, that resembles the traditional Mediterranean
diet, exerts a sub-maximal effect in extending lifespan, reducing
the statistical power of the NIA study in detecting statistical differences in survival between groups. Accordingly, in both the NIA
control and CR male monkeys average lifespan was ∼45% longer
than in Rhesus monkeys kept in captivity (Mattison et al., 2012).
Moreover, 4 CR and 1 control NIA monkeys have lived more than
40 years, which is an extraordinary long life for a Rhesus monkey
(Mattison et al., 2012).
4.3. Role of dietary supplements on lifespan extension
Several studies were performed to understand the effects of
supplementation with supposedly anti-aging dietary additives (e.g.
resveratrol, green tea extract, curcumin, oxaloacetic acid, mediumchain triglyceride oil) on lifespan and healthspan extension in
genetically heterogeneous mice. None of the compounds tested so
far in the National Institute on Aging Interventions Testing Program (ITP), with the exception of rapamycin, have resulted in a
statistically significant effect on maximal lifespan of male or female
mice (Strong et al., 2013; Miller et al., 2011). However, supplementation with nordihydroguaiaretic acid and aspirin increased
average but not maximal lifespan in the ITP genetically heterogeneous male mice (Strong et al., 2008). Smaller studies suggest
that treatment with metformin and beta-blockers, but not with
a range of phytonutrients which have been reported to extend
lifespan in Caenorhabditis elegans and Drosophila (e.g. blueberry,
pomegranate, green and black tea, cinnamon, sesame, French maritime pine bark, curcumin, morin, and quercetin), may increase
average but not maximal lifespan in some selected strains of male
mice (Spindler et al., 2013, 2013a; Martin-Montalvo et al., 2013).
Data from a recent randomized clinical trial indicate that supplementation with combinations of supplements (i.e. resveratrol,
green, black, and white tea extract, pomegranate extract, quercetin,
acetyl-l-carnitine, lipoic acid, curcumin, sesamin, cinnamon bark
W. Rizza et al. / Ageing Research Reviews 13 (2014) 38–45
43
extract, and fish oil), each of which has been shown to have antioxidant and/or anti-inflammatory effects in cell culture or animal
studies, do not exert any cardiovascular or metabolic effect in nonobese men and women (Soare et al., 2013). Rapamycin, is a powerful
immunosuppressive drug, that inhibits the activity of mTOR, which
controls key cellular responses to energy and aminoacid availability
(Sengupta et al., 2010). Data from dietary and genetic animal models of longevity indicate that inhibition of the IGF/mTOR pathway
plays a crucial role in slowing down aging and increasing lifespan,
whereas increased activity of the IGF pathway markedly accelerates aging and shortens life expectancy (Fontana et al., 2010; Bartke
et al., 2002).
5. Does calorie restriction slow the aging process in
humans?
Whether or not CR slows aging and extends maximal lifespan in
humans is not known yet. However, data collected on humans practicing long-term CR without malnutrition (i.e. CRONies) indicate
that CR opposes the expected age-associated changes in myocardial stiffness and autonomic function. Both left ventricular diastolic
function and heart rate variability indexes, two well accepted markers of cardiovascular aging, are significantly improved by CR, and
resemble those of individuals 20 years younger on a typical Western
diet (Meyer et al., 2006; Stein et al., 2012). Recent data also suggest that CR counters the typical age-dependent gene expression
derangements in the human skeletal muscle. Indeed, the skeletal
muscle transcriptional profile of the CR practitioners resembles
that of much younger individuals (Mercken et al., 2013). Despite
their genetic heterogeneity, CR resulted in a dramatic transcriptional reprogramming of molecular pathways in skeletal muscle,
which shifts cellular metabolism from growth to maintenance and
repair functions. In particular, several inflammatory genes, a number of transcripts along the IGF-1/insulin/FOXO pathway, and akt
phosphorylation were down-regulated by CR in skeletal muscle
(Mercken et al., 2013). However, the independent or additive role
of protein/aminoacid, vitamin and phytochemical intakes in modulating these and other anti-aging molecular pathways is not known
yet. Finally, long term CR in humans is associated with significant
reductions in serum levels of triiodothyronine and core body temperature independently of adiposity (Fontana et al., 2006a; Soare
et al., 2011). The importance of a low body temperature in extending lifespan has been supported by data obtained from CR mice,
dwarf and growth hormone receptor knock-out mice, the HcrtUCP2 mice and the Baltimore Longitudinal Study of Aging (Rikke
et al., 2003; Schonholz and Osborn, 1949; Hauck et al., 2001; Conti
et al., 2006; Roth et al., 2002). Indeed, in the Baltimore Longitudinal Study of Aging men with a lower core body temperature lived
significantly longer (Roth et al., 2002).
6. Conclusions
Several factors have been hypothesized to play a key role in
mediating healthy longevity (Fig. 2). However, more studies are
needed to understand the interactions among single nutrient modifications, CR and regular exercise in the prevention of CVD, cancer,
cognitive impairment/dementia, inflammatory diseases, sarcopenia and immune senescence, in both experimental animals and
humans. The discovery of early predictive biomarkers of cancer,
dementia, sarcopenia/osteoporosis, and biological aging is essential to design new clinical trials and accelerate the acquisition of
the knowledge required to prescribe personalized dietary/life style
modifications based on the individual’s genetic profile. The discovery of biomarkers of optimal caloric and protein intake are also
Fig. 2. The longevity puzzle: determinants of healthy longevity.
essential to define the line that separates optimal health from starvation and malnutrition.
Conflicts of interest
We declare that we have no conflicts of interest.
Acknowledgements
This work was supported by grants from the Bakewell Foundation, AFAR, Glenn Foundation, the Longer Life Foundation (an
RGA/Washington University Partnership), the Scott and Annie
Appleby Charitable Trust, the National Center for Research
Resources (UL1 RR024992), the National Institute of Diabetes And
Digestive And Kidney Diseases (P30DK056341), and the European
Union’s Seventh Framework Programme MOPACT (“Mobilizing the
potential of active ageing in Europe”; FP7-SSH-2012-1 grant agreement no. 320333).
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