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Intermittent fasting from dawn to sunset for 30 consecutive days is associated with anticancer proteomic signature ...

intermittent fasting

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#1 Engadin

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Posted 23 April 2020 - 06:36 PM


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F U L L   T I T L E :   Intermittent fasting from dawn to sunset for 30 consecutive days is associated with anticancer proteomic signature and upregulates key regulatory proteins of glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system and cognitive function in healthy subjects.

 

 

 

 

 

S O U R C E :   ScienceDirect

 

 

 

 

 

Highlights

 
  •  First human serum proteomics study of 30-day intermittent fasting from dawn to sunset in healthy subjects
 
  •  The 30-day intermittent fasting from dawn to sunset is associated with a serum proteome protective against cancer
 
  •  Intermittent fasting from dawn to sunset for 30 days upregulates proteins protective against obesity, diabetes, and metabolic syndrome
 
  •  Intermittent fasting from dawn to sunset for 30 days induces key regulatory proteins of DNA repair and immune system
 
  •  Intermittent fasting from dawn to sunset for 30 days upregulates proteins protective against Alzheimer’s disease and neuropsychiatric disorders
 
 
 
Abstract
 
Murine studies showed that disruption of circadian clock rhythmicity could lead to cancer and metabolic syndrome. Time-restricted feeding can reset the disrupted clock rhythm, protect against cancer and metabolic syndrome. Based on these observations, we hypothesized that intermittent fasting for several consecutive days without calorie restriction in humans would induce an anticarcinogenic proteome and the key regulatory proteins of glucose and lipid metabolism. Fourteen healthy subjects fasted from dawn to sunset for over 14 h daily. Fasting duration was 30 consecutive days. Serum samples were collected before 30-day intermittent fasting, at the end of 4th week during 30-day intermittent fasting, and one week after 30-day intermittent fasting. An untargeted serum proteomic profiling was performed using ultra high-performance liquid chromatography/tandem mass spectrometry. Our results showed that 30-day intermittent fasting was associated with an anticancer serum proteomic signature, upregulated key regulatory proteins of glucose and lipid metabolism, circadian clock, DNA repair, cytoskeleton remodeling, immune system, and cognitive function, and resulted in a serum proteome protective against cancer, metabolic syndrome, inflammation, Alzheimer's disease, and several neuropsychiatric disorders. These findings suggest that fasting from dawn to sunset for 30 consecutive days can be preventive and adjunct therapy in cancer, metabolic syndrome, and several cognitive and neuropsychiatric diseases.
 
 
Significance
 
Our study has important clinical implications. Our results showed that intermittent fasting from dawn to sunset for over 14 h daily for 30 consecutive days was associated with an anticancer serum proteomic signature and upregulated key regulatory proteins of glucose and lipid metabolism, insulin signaling, circadian clock, DNA repair, cytoskeleton remodeling, immune system, and cognitive function, and resulted in a serum proteome protective against cancer, obesity, diabetes, metabolic syndrome, inflammation, Alzheimer's disease, and several neuropsychiatric disorders. Importantly, these findings occurred in the absence of any calorie restriction and significant weight loss. These findings suggest that intermittent fasting from dawn to sunset can be a preventive and adjunct therapy in cancer, metabolic syndrome and Alzheimer's disease and several neuropsychiatric diseases.
 
 
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1. Introduction
The disruption of circadian rhythm has been associated with alterations in glucose and lipid metabolism and immune system responses, and carcinogenesis [1,2]. Resetting the disrupted rhythm of the circadian clock could be a key strategy in the prevention of metabolic syndrome, immune system dysfunction, and cancer [3,4]. There are two primary mechanisms to reset the circadian clock. The first mechanism functions through the master clock located in the suprachiasmatic nucleus of the anterior hypothalamus that is entrained by dark-light cycles of the day [[5], [6], [7], [8], [9], [10], [11]]. All peripheral clocks are then synchronized by the master clock via neuronal and humoral signals [[5], [6], [7], [8], [9], [10], [11], [12]], and this appears to be the dominant mechanism resetting all peripheral clocks, including hepatic clock during ad libitum food consumption. The second mechanism to reset the circadian clock works in response to mealtime during rhythmic, consecutive, time-restricted feeding-fasting cycles [5,7,10]. Rhythmic consecutive time-restricted feeding-fasting cycles have shown to release peripheral clocks, including the hepatic clock, from the control of the master clock and entrain them independent of the master clock [5,7,10]. Uncoupling of the peripheral clocks from the master clock shifts and resets the phase of the peripheral clocks [5,7,10]. As such, mealtime and duration between meals are critical in resetting and maintaining the circadian rhythmicity of the peripheral clocks [13].
 
 
 
Murine studies showed that time-restricted access or no access to food during night time/dark phase resets the phase of the hepatic clock, optimizes the amplitude of hepatic clock oscillations, and results in the upregulation of mRNA and various protein synthetic pathways, including enzymes that play a crucial role in carbohydrate and lipid metabolism [3,5,7,9,10,14]. Mice are nocturnal feeders; most food consumption and activity occur at night [5,7,9,10,14,15]. In contrast, in humans, most activity and meal intake occur during the daytime. Therefore, to reproduce similar optimization in key metabolic regulatory proteins in humans, fasting should occur during the daytime activity for several consecutive days. Preserving daytime activity and timing major food consumption at transition zones of the day with a predawn breakfast and dinner at sunset may be as important as caloric content and composition of the food in the prevention of metabolic syndrome and its complications and cancer [13].
 
Since time-restricted access or no access to food during active phase (night time/dark phase for mice) resets the phase of hepatic circadian rhythm and optimizes the functioning of critical regulatory proteins of metabolism in mice [3,5,7,9,10,14], we formulated and tested the hypothesis that consecutive rhythmic intermittent fasting during active hours (from dawn to sunset for humans) could produce similar optimization in key regulatory proteins protective against cancer, inflammation, metabolic syndrome, and its complications.
 
 
 
 
 
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4. Results
 
4.1. Subjects
 
Fourteen healthy subjects (13 males:1 female) with a mean age of 32 were enrolled in the study. All subjects fasted for over 14 h daily for 30 consecutive days beginning from May 16, 2018, until June 14, 2018, except for one subject who fasted for 26 days. The minimum required duration of daily fasting was 14 h, 23 min for the shortest day (May 16, 2018), and 14 h, 48 min for the longest day (June 14, 2018). All subjects tolerated intermittent fasting (no food or drink) well without any complications. The first blood collection occurred before the initiation of 30-day intermittent fasting. The second blood collection occurred on an average of 28 days after the initiation of 30-day intermittent fasting (at the end of the 4th week during 30-day intermittent fasting). The third blood collection occurred on an average of 8.5 days after the completion of 30-day intermittent fasting (one week after 30-day intermittent fasting).
 
 
4.2. Serum proteomics
 
Several sample preparation methods were tested to find the best method for more in-depth proteome coverage. As shown in Fig. 1A, the top 12 abundant protein depletion provides around 58% proteome increase (257 vs. 405 GPs). Suspension traps (S-Trap) were recently reported as a sensitive and time-saving way of proteome profiling sample preparation [26]. Compared to direct in-solution digest, S-Trap provides a 25% better recovery in proteome coverage (324 vs. 405 GPs). Also, we tested two different ways of pre-sample fractionation before UPLC-MS/MS. Comparing high pH STAGE tip and SDS-PAGE, the STAGE tip provides deeper proteome coverage within shorter MS analysis time (Fig. 1B). So, we decided to use S-Trap aided trypsin digestion, high pH STAGE tip method for the preparation of fasting serum samples. The established workflow is shown in Fig. 1C.
 
Proteome coverage and its dynamic order of average iFOT values from the end of 4th week during 30-day intermittent fasting samples are shown in Fig. 2A. A total of 3181 GPs were recovered with over eight orders of magnitude of dynamic range. There was significant fold change in the levels of multiple GPs at the end of 4th week during 30-day intermittent fasting compared with the levels before 30-day intermittent fasting (Fig. 2B, Supplementary Table S1). Fig. 2A, B, and Table 1A display selected GPs of interest that are associated with immune system regulation, DNA repair, carcinogenesis, tumor suppression, circadian clock, Alzheimer's disease, and neuropsychiatric disorders. There was an average 40 fold increase in asialoglycoprotein receptor 2 (ASGR2) (log2 fold = 5.315, P = .0058), 45 fold increase in the centrosomal protein 164 (CEP164) (log2 fold = 5.499, P = .0157), 160 fold increase in complement factor H related 1 (CFHR1) (log2 fold = 7.320, P = .0199), 14 fold increase in collectin subfamily member 10 (COLEC10) (log2 fold = 3.781, P = .0383), 9 fold increase in large tumor suppressor kinase 1 (LATS1) (log2 = 3.243, P = .0415), 11 fold increase in NR1D1 nuclear receptor subfamily 1 group D member 1 (NR1D1) (log2 = 3.455, P = .0417), and 25 fold increase in homer scaffold protein 1 (HOMER1) (log2 fold = 4.664, P = .0443) GP levels at the end of 4th week during 30-day intermittent fasting compared with the levels before 30-day intermittent fasting. The amount of these GPs of interest was relatively high, located in the top 50% rank order (Fig. 2A). We found a significant reduction in the amyloid beta precursor protein (APP) (log2 fold = −7.147, P = .0026), beta-1,4-galactosyltransferase 1 (B4GALT1) (log2 fold = −3.194, P = .0192), ArfGAP with SH3 domain, ankyrin repeat and PH domain 1 (ASAP1) (log2 fold = −3.715, P = .0219), tankyrase 2 (TNKS2) (log2 fold = −3.416, P = .0402), flavin containing dimethylaniline monoxygenase 5 (FMO5) (log2 fold = −4.031, P = .0406), ribosome binding protein 1 (RRBP1) (log2 fold = −3.403, P = .0408), cAMP regulated phosphoprotein 21 (ARPP21) (log2 fold = −4.977, P = .0410) and HECT, UBA and WWE domain containing E3 ubiquitin protein ligase 1 (HUWE1) (log2 fold = −2.931, P = .0411) GP levels at the end of 4th week during 30-day intermittent fasting compared with the levels before 30-day intermittent fasting.
 
The proteome coverage and its dynamic order from triplicate of samples collected one week after 30-day intermittent fasting are shown in Fig. 2C. A total of 3416 GPs were recovered with over seven orders of magnitude of dynamic range. There was a significant fold change in the levels of multiple GPs one week after 30-day intermittent fasting compared with the levels before 30-day intermittent fasting (Fig. 2D, Supplementary Table S2). Fig. 2C, D and Table 1B display selected GPs of interest that are associated with insulin signaling, cytoskeleton remodeling, glucose and lipid metabolism, carcinogenesis, Alzheimer's disease and neuropsychiatric disorders. There was an average 127-fold increase in the tropomyosin 3 (TPM3), (log2 fold = 6.988, P = .0007), 95-fold increase in profilin 1 (PFN1) (log2 fold = 6.566, P = .0060), 21-fold increase in cofilin 1 (CFL1) (log2 fold = 4.375, P = .0162), 13-fold increase in pyruvate kinase M1/2 (PKM) (log2 fold = 3.743, P = .0287), 32-fold increase in perilipin 4 (PLIN4) (log2 fold = 4.997, P = .0383), and 15-fold increase in tropomyosin 4 (TPM4) (log2 fold = 3.938, P = .0446) GP levels one week after 30-day intermittent fasting compared with the levels before 30-day intermittent fasting (Table 1B). The amount of these GPs was relatively high, rank order between 479 and 879 out of 3416 GPs (Fig. 2C). We found a significant reduction in the Rho guanine nucleotide exchange factor 28 (ARHGEF28) (log2 fold = −4.510, P = .0111), partner and localizer of BRCA2 (PALB2) (log2 fold = −3.715, P = .0147), SPARC related modular calcium binding 1 (SMOC1) (log2 fold = −4.776, P = .0264), spectrin repeat containing nuclear envelope protein 1 (SYNE1) (log2 fold = −2.576, P = .0274), interleukin 1 receptor associated kinase 3 (IRAK3) (log2 fold = −3.097, P = .0357), TNKS2 (log2 fold = −3.416, P = .0402), mucin 20, cell surface associated (MUC20) (log2 fold = −3.149, P = .0404), ARPP21 (log2 fold = −4.977, P = .0410) and HUWE1 (log2 fold = −2.931, P = .0411) GP levels one week after 30-day intermittent fasting compared with the levels before 30-day intermittent fasting.
 
Fig. 3 shows the change (logiFOT X 105) in the levels of 13 selected GPs that significantly increased at the end of 4th week during 30-day intermittent fasting or one week after 30-day intermittent fasting compared with the levels before 30-day intermittent fasting.
 
 
 
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