Metabolic syndrome is characterized by abdominal obesity, high blood pressure, high triglycerides and low-density lipoprotein (LDL) cholesterol levels, and insulin resistance and is associated with an increased risk of certain cancers such as colorectal cancer, liver cancer, etc. Prevalence in the United States has been steadily increasing to about 1 in 3 adults now having metabolic syndrome. Notably, disruptions in circadian control by the Suprachiasmatic Nuclei (SCN) can lead to cancer induced by metabolic syndrome because cell proliferation is dependent on growth factors which are under the control of the circadian rhythm. One way to restore this circadian clock is time-restricted feeding and ideally, the fasting period aligns with the activity hours of the day to maximize its anti-cancer effects. A study conducted using B6D2F1 osteosarcoma inoculated mice provided evidence for significant improvement in cancer treatment using time restricted feeding. The study found that mice who were allowed to feed only during the 12-hour light period and fasted during the dark, had significantly lower mean tumor weight and prolonged survival compared to mice fed during dark phase or ad-libitum. In contrast, there is little to no change in phase of gene expression when mice were fasted during the inactive phase. It is important to consider that mice are nocturnal animals with peak active phases during the dark, whereas humans are diurnal with the active phase occurring during the daylight hours.
It is well recognized that intermittent fasting and time restricted feeding can improve health incl. treatment of metabolic syndrome, but there had not been many studies done on the mechanism behind the anticancer effect of time restricted feeding or intermittent fasting. Mindikoglu and colleagues hypothesized that fasting from dawn to sunset would lead to anticancer serum proteome response, upregulation of anticancer proteins and regulatory proteins of DNA repair, and downregulation of pro-cancer protein in humans. The results of the study indicate that 4-weeks of intermittent fasting in humans from dawn to sunset was associated with anticancer serum proteome response, upregulation of factors involved in tumor suppression, DNA repair, Insulin signaling, glucose and lipid metabolism, circadian clock, cytoskeletal remodeling, immune system, and cognitive functions.
This study enrolled 14 subjects with metabolic syndrome with an average age of 59 years. All subjects participated in the religious fast Ramadan, and the fast was religious habitual conduct so the study was observational in nature. All subjects fasted for a total of 29 days for more than 14 hours each day from dawn to sunset. Nine subjects were on anti-hypertensive medications and seven subjects were on antidiabetic medications, and six patients were on statins. All subjects tolerated fasting without any complications. There was no calorie restriction or energy controls put in place for the subjects.
Serum proteome analysis was performed before the beginning of the fast, at the end of the 4-week fasting period, and 1 week after the 4-week intermittent fasting period. The study measured a several fold increase in tumor suppressor/ anticancer proteins at the end of the 4 weeks including CALR, CALU, INTS6, KIT, CROCC, IGFBP4, and SEMA4B. CALR encodes for calreticulin which binds to cancerous cells to trigger phagocytosis. CALU gene encodes for calumenin which inhibits metastasis. CROCC also acts as a tumor suppressor gene. Upregulation of IGFBP4 suppresses hepatocellular carcinoma and delays tumor formation in prostate cancer cells.
There was significant fold reduction in tumor promoter/ pro-cancer gene protein products including POLK, NIFK, SRGN, CAMP, CD109 and PLAC1. POLK acts as an oncogene and enhances DNA damage induced mutations and can inactivate wild-type p53 leading to cancer. Other GPs mentioned also are involved in similar pathways and their upregulation is associated with poor cancer prognosis.
Autophagy appears to be one of the mechanisms affecting cancer development in intermittent fasting. This study found that there was downregulation of hepatocystin encoded by PRKCSH which results in increased autophagy via the mTOR dependent pathway. However, 1 week after the 4-week fast, there was a 73-fold increase in PRKCSH GP levels suggesting that intermittent fasting increased autophagy during the 4-week intermittent fasting period.
There was a 6-fold increase in H2B Histone GP levels 1 week after the fasting period compared to before the 4-weeks suggesting that intermittent fasting is associated with prolonged longevity. Histone proteins are lost in aging and an extra supply of them can provide better chromatin packaging. A 74-fold increase was observed in AP5Z1 GP at the end of the 4-week period. AP5Z1 plays an important role in DNA repair so this data suggests that intermittent fasting can be associated with DNA repair as well.
The four-week intermittent fasting induced insulin signaling proteins including VPS8, POLMRT, AND IGFBP 5 at the end of the 4 weeks. This increase in GPs preceded the decrease in insulin resistance observed by the HOMA IR 1 week after the 4-week intermittent fasting.
There was a significant reduction in weight, body mass index, waist circumference, systolic and diastolic blood pressure at the end of the 4 weeks. 1 week after the 4-week intermittent fasting period, blood pressure difference became less significant, but HOMA-IR reduced. Parameters such as insulin, triglyceride levels, leptin, etc. did not reach statistical significance.
The lack of calorie measurement due to the observational nature of the study was one of the limitations of the paper since the improvement in metabolic syndrome could be attributed partially to the weight loss. However, there was no statistical correlation between the BMI and the serum proteome compared before and after the 4-week intermittent fasting period suggesting that the selected protein profile was independent of weight loss.
The 4-week intermittent fasting period followed by the serum proteome results help shed light on understanding the mechanisms that lie behind the anticancer properties of intermittent fasting and other mechanisms such as DNA repair, decreased insulin sensitivity, and improved longevity. The findings in this paper suggest that fasting from dawn to sunset can be an effective treatment for metabolic syndrome and prevention of cancer in humans.
– Aryan Anand, Research Assistant at USC Longevity Institute