Summary
Voluntary fasting,
whether intermittent or continuous, religious or therapeutic, is becoming
increasingly popular. Despite the scarcity of randomized and controlled studies
in humans, therapeutic fasting is often proposed in specific chronic
pathologies, such as type 2 diabetes, high blood pressure, and cancer. It is
also practiced to lose weight in overweight or obese subjects. Its practice is
not without risks.
Weight loss is often
associated with a loss of lean body mass, which is a poor prognostic factor.
Finally, while the
caloric restriction is associated with longevity in some animal studies, its
effects have been little studied in humans. Good quality clinical studies are
needed better to evaluate the impact of fasting on health and disease.
Introduction
Fasting is a mode of
deprivation of food and energy drinks, voluntary or involuntary.
Physiologically, at the onset of fasting (seven hours after energy intake), the
main metabolic characteristic is the obligation to supply glucose to tissues by
hepatic glycogenolysis initially.
When fasting is
prolonged, glycogen stores are depleted, insulin levels drop, and fatty acids
are released by lipolysis of triglycerides stored in fat tissue; these fatty
acids will be used preferentially as energy substrates by specific tissues
capable of metabolizing them (muscles, heart), while glucose will be
"reserved" for other organs (brain, red blood cells).
After depletion of
glycogen reserves, glucose-dependent tissues will be supplied with glucose by
gluconeogenesis from amino acids, mainly glycerol.
During this period
called "short fasting," the muscle thus becomes an essential producer
of amino acids via increased muscle proteolysis. At the same time, muscle
synthesis is reduced, resulting in rapid muscle wasting. A phase of adaptation
to prolonged fasting occurs after 4-5 days with ketone bodies as energy
substrates, particularly for the brain. Ketone bodies are
metabolites produced by hepatic ketogenesis from fatty acids. The result is a
decrease in gluconeogenesis and, therefore, a reduction in muscle protein
hyper-catabolism.
The mechanisms
allowing this nitrogen saving are not fully elucidated. The practice of
physical activity during fasting could make it possible to limit muscle
wasting, and prayer/meditation could also have beneficial effects by inhibiting
the axis of stress.
Voluntary Religious
Fasting
Voluntary fasting is
becoming increasingly popular in our food-abundant societies and is often aimed
at correcting a continuous excess of caloric intake harmful to health.
Voluntary fasting can be religious; food deprivation is then associated with
spiritual enhancement.
There are many types
of religious fasting, intermittent or continuous, of varying durations (from 1
to 200 days per year), more or less restrictive, associated or not with
physical activity, prayer, and meditation.
In a recent literature
search, the cardiometabolic effects of different types of religious fasts were
evaluated. Although beneficial effects have been reported, including
carbohydrate-lipid metabolism, inflammation, oxidative stress, most currently
available studies are non-randomized, uncontrolled, and trim. Further studies
are needed to understand better the mechanisms involved in the metabolic
effects of religious fasting.
Therapeutic Fasting
Fasting is more and
more considered as a healing path in many pathologies. Many claims are not
supported by reliable scientific data or are based on animal studies.
A distinction must be
made between intermittent fasting (periodic caloric restriction) and continuous
caloric restriction in these studies.
Fasting and
Cardiovascular Risk Factors
Early epidemiological
studies reported that the practice of intermittent fasting was associated with
a lower prevalence of cardiovascular disease and diabetes in a Mormon
population in Utah.
More recently, in
search of the literature, Horne and coll. Reported on the effects of
intermittent fasting on cardiovascular risk factors in humans: weight, lipid
profile, and type 2 diabetes. Only three randomized controlled studies reported
beneficial effects of fasting, including decreases in body fat, LDL-cholesterol,
triglycerides, and CRP.
However, partly due to
the lack of multivariate analyses and evaluation of the adverse effects of
fasting, the low methodological quality does not allow for a conclusion.
Further randomized controlled clinical studies are needed to assess better and
understand the cardiovascular effects of fasting in humans.
Is it Necessary to
Fast to Lose weight?
Caloric restriction
(periodic or continuous) is often practiced to achieve weight loss in
situations of overweight/obesity and also in cases of restrictive eating
disorders. Nevertheless, few well-conducted randomized controlled studies
evaluate the effects of this restriction on weight in the medium and long term.
In the prospective randomized controlled study CALERIE (Comprehensive
Assessment of Long-Term Effects of Reducing Intake of Energy), Marlatt et al.
evaluated the impact of continuous caloric restriction (-12% of daily caloric
intake) for two years in 39 non-obese subjects.
At two years, the mean
weight loss was nine ± 0.6 kg, associated with decreased body fat, improved
lipid profile, and insulin sensitivity. Two years after the end of the study,
about 50% of the subjects showed weight loss maintenance, probably reinforced
by restrictive eating behavior.
Furthermore, in a
meta-analysis published in 2018, Harris and coll. Reported significantly higher
weight loss in obese subjects with intermittent fasting than a control group of
obese subjects without therapeutic intervention (- 4.14 kg; 95% CI: - 6.30 kg
to - 1.99 kg; p ≤ 0.001; 2 studies). In addition, no significant difference was
observed in the effects of intermittent fasting and continuous caloric
restriction on weight loss in obese subjects (- 1.03 kg; 95% CI: - 2.46 kg to
0.40 kg; p = 0.156; 4 studies). Decreases in body fat, abdominal circumference,
and insulin levels were significantly greater during intermittent fasting than
continuous caloric restriction.
However, these results
must be interpreted with caution given the small number of studies included, their
low methodological quality (2 randomized studies; 10 men in the analysis), and
their short evaluation period, on average five months (3 to 12 months). It
should also be kept in mind that in these studies, weight loss is associated
with a loss of fat mass, but also of lean body mass, a poor prognostic
factor.
Furthermore, the lower
the bodyweight of the fasting subject initially, the greater the adverse effect
of fasting on lean body mass and the greater the risk of fat expansion when
fasting is stopped.
Metabolically, in a
recent Geneva study by Mirko Trajkovski and coll. Mice subjected to daily
caloric restriction (60% of usual caloric intake) showed browning of
subcutaneous and visceral adipose tissue and decreased the volume of white
adipose tissue and the size of adipocytes.
Since browning fat
plays a significant role in thermogenesis by increasing energy expenditure,
some researchers would consider fasting, or more precisely continuous caloric
restriction, as an attractive therapeutic avenue in the management of obesity.
Further studies in humans are needed to understand better the mechanisms
involved.
Fasting and Cancer
Intermittent fasting
is believed to be beneficial in the prevention and treatment of cancer.
Throughout life, free radicals' accumulation causes cellular dysfunction and
DNA mutations that lead to aging and certain diseases, including cancer.
Fasting is known to
trigger cellular protective mechanisms, including cell cycle arrest and
autophagy, which reduces free radical capital and recycles organelles,
proteins, and other metabolites through autolysosomes.
The molecular
mechanism for activating autophagy during fasting is through inhibition of the
insulin pathway (Ras, Akt, and mTOR), a path targeted by novel anti-cancer
molecules. Experimental evidence suggests that fasting can be considered in
prevention and adjunct to chemotherapy to improve therapeutic efficacy while
protecting healthy tissues from excessive chemotoxicity.
In healthy cells with
functional cell cycle regulatory mechanisms, fasting would induce cell cycle
arrest and autophagy, allowing the elimination of metabolites and free radicals
produced by chemotherapy.
In cancer cells, on
the other hand, the presence of mutations, translocations, and oncogenic
amplifications would prevent their passage into stress-resistant mode and
promote the induction of apoptosis or necrosis following cellular damage caused
by chemotherapy.
Although the
scientific rationale for fasting in oncology is convincing, evidence of
improved therapeutic efficacy is still awaited. The lack of usable clinical
data may be explained by certain methodological constraints facing clinical
studies on fasting, such as biased recruitment of participants already
convinced of its effectiveness, the impossibility of a double-blind protocol,
the heterogeneity of cancers and treatments, or even a holistic approach with
multiple interventions (enema, physiotherapy or hydrotherapy).
Besides, treating physicians
may be reluctant to offer intermittent fasting to their patients for fear of
compromising their nutritional status and promoting cancer cachexia.
This last point is
particularly relevant in light of the recent recommendations issued by the European
Society for Clinical Nutrition and Metabolism (ESPEN) to combat the high rate
of undernutrition observed in cancer patients. Experts from the French NACRe
network (Réseau national alimentation cancer recherche) recommend proposing and
implementing a dietary and nutritional evaluation before any glucidocaloric
restriction diet.
In case of
undernutrition or significant risk of undernutrition, the practice of a
glucidocaloric restriction diet is then not recommended. For this reason,
intermittent fasting is only clinically evaluated in the treatment of cancers
where weight loss is not a limiting factor.
The close relationship
between insulin, obesity, and breast cancer makes these patients particularly
suitable candidates for this type of treatment strategy. Our experience has
shown that a 54-year-old patient with grade 3 invasive ductal carcinoma (lymph
nodes+, estrogen+, progesterone+, HER2+) can fully recover her fat and lean
body mass between cycles of fasting adapted to the biological half-life of the
chemotherapeutic agent (3 FEC [5-Fluorouracil, Epirubicin, Cyclophosphamide] +
3 Taxotere [docetaxel] + Herceptin [trastuzumab]). The patient did not
experience any sensation of discomfort or cravings, despite blood glucose
levels between 2.2 and 2.8 mmol/l during the fasting cycles. She tolerated
moderate physical activity during fasting episodes better and was able to
maintain 50% activity.
The resumption of
intestinal transit took place the day after the cessation of fasting. Our
observations are similar to the results of published clinical studies.23 They
show that fasting is well tolerated during chemotherapy and does not carry a
risk of long-term weight loss. It appears to reduce asthenia, gastrointestinal
problems, and hematological chemotoxicity.
Patients report a
positive effect on their sense of psychological and physical well-being.
However, a better therapeutic efficacy has yet to be demonstrated.
Aging and Longevity
The effect of
continuous caloric restriction on longevity has been studied in animal
experiments, particularly in rodents. A 40% reduction in daily caloric intake
increased their lifespan by 30-50%.
Work published in
Nature Communications reported that the beneficial effect of intermittent
fasting on male C57/BL6 mice's longevity was to delay the onset of neoplastic
processes, not to slow aging. Several metabolic mechanisms are believed to be
involved. In humans, studies are rare and epidemiological. Centenarians on the
Japanese island of Okinawa consumed 17% and 40% fewer calories daily than the
average Japanese and American adult, respectively.
Conclusion
Due to the scarcity of
studies in humans, it is challenging to establish recommendations in favor of
therapeutic fasting in the context of chronic cardiovascular pathologies,
diabetes, and obesity. Preliminary clinical results suggest that fasting
decreases asthenia, gastrointestinal problems, and chemotoxicity for
cancer.
Patients report an improvement in their mental and physical well-being. However, it remains to be demonstrated that fasting has no detrimental effect on lean body mass and can potentiate chemotherapy.
References
+ BD Horne JB Muhlestein JL. Anderson Health effects of intermittent fasting: hormesis or harm? A systematic review. Am J Clin Nutr 2015
+ J *Most LA Gilmore SR Smith Significant improvement in cardiometabolic health in healthy non-obese individuals during caloric restriction-induced weight loss and weight loss maintenance. Am J Physiol Endocrinol Metab 2017
+ KL *Marlatt LM Redman JH Burton Persistence of weight loss and acquired behaviors two y after stopping a 2-y calorie restriction intervention. Am J Clin Nutr 2017
+ L Harris S Hamilton LB Azevedo Intermittent fasting interventions for the treatment of overweight and obesity in adults: a systematic review and meta-analysis. JBI Database System Rev Implement Rep 2018
+ M Headland PM Clifton S Carter Weight-loss outcomes: a systematic review and meta-analysis of intermittent energy restriction trials lasting a minimum of 6 months. Nutrients 2016
+ S **Fabbiano N Suárez-Zamorano D Rigo Caloric restriction leads to browning of white adipose tissue through type 2 immune signaling. Cell Metab 2016
+ CH * O'Flanagan LA Smith SB McDonell When less may be more: calorie restriction and response to cancer therapy. BMC Med 2017
+ R Buono VD. Longo Starvation, stress resistance, and cancer. Trends Endocrinol Metab 2018
+ J *Arends V Baracos H Bertz ESPEN expert group recommendations for action against cancer-related malnutrition. Clin Nutr 2017
+ NACRe, RNACRe. Jeûne, régimes restrictifs et cancer: revue systématique des données scientifiques et analyse socio-anthropologique sur la place du jeûne en France, 2017
+ K Xie F Neff A Markert every-other-day feeding extends lifespan but fails to delay many symptoms of aging in mice. Nat Commun 2017
+ J **Most V Tosti LM Redman Calorie restriction in humans: an update. Ageing Res Rev 2017
+ RD Angeliki Persinaki S Karras C. Pichard Unraveling the metabolic health benefits of fasting related to religious beliefs: a narrative review. Nutrition 2017
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