Cancer

De Groot et al.'s 2020 DIRECT trial, published in Nature Communications, randomised 131 women with HER2-negative breast cancer to either a fasting-mimicking diet (FMD, three days before and on the day of chemotherapy) or their regular diet. The FMD group showed a statistically significant reduction in DNA damage to healthy lymphocytes (gamma-H2AX foci) compared with controls, indicating that fasting selectively protected normal cells from chemotherapy toxicity. Clinically, the FMD group reported approximately forty per cent fewer grade III/IV adverse events.

The mechanism is "differential stress resistance": when glucose and growth factors (insulin, IGF-1) drop during fasting, healthy cells enter a protected quiescent state, reducing their vulnerability to chemotherapy. Cancer cells, with their constitutively active growth signalling (oncogenes), cannot enter this protective state and remain vulnerable. Longo's earlier work in mice (2008, PNAS) demonstrated that fasting protected normal cells while sensitising cancer cells to chemotherapy, resulting in improved tumour control with reduced host toxicity. The concept inverts the current oncological model: rather than maximising drug dose at the cost of side effects, fasting creates a metabolic window where lower doses may achieve equivalent cancer kill with less collateral damage.

De Groot et al. (2015, BMC Cancer) conducted a randomised controlled trial in which breast cancer patients undergoing neoadjuvant chemotherapy either fasted for 48 hours before treatment or ate normally. Fasting patients experienced a 75 per cent reduction in grade III and IV toxicity (severe nausea, vomiting, diarrhoea, mucositis). Red blood cell and platelet counts recovered faster in the fasting group. Tumour response to chemotherapy was equal or slightly better in the fasting arm.

The mechanism is differential stress resistance: when deprived of nutrients, normal cells activate protective stress response pathways (AMPK, SIRT1, autophagy) that make them more resistant to damage. Cancer cells, driven by oncogenes that lock them into growth mode, cannot activate these protective pathways and remain vulnerable. Fasting creates a window in which the therapeutic index of chemotherapy widens: normal cells become more resistant while cancer cells remain equally or more sensitive. Longo (2012, Science Translational Medicine) demonstrated this in mice, showing that 48-hour fasting protected normal cells from high-dose chemotherapy that was otherwise lethal while maintaining anti-tumour efficacy.

Night shift work, red meat and glyphosate share an identical IARC Group 2A "probably carcinogenic" classification, yet the three agents occupy entirely different positions in UK public health policy. Red meat has a dedicated NHS page with gram-level guidance and multi-organisation campaigns. Night shift work, affecting 3.2 million UK workers, receives no cancer-specific public health messaging from any UK institution.

Group 2A classification indicates the same strength of evidence for all three agents: limited human evidence supported by animal data and strong mechanistic evidence. The decision to create public health messaging for one and ignore the other is not a scientific distinction. It reflects economic utility. Night shift work is an industrial necessity, and policymakers have treated it as such.

IARC reaffirmed the Group 2A classification for night shift work in 2019 after reviewing the UK cohort studies that had found no significant association, concluding that the international evidence as a whole warranted continued concern. The UK government and NHS have not updated their messaging to reflect this reaffirmation.

Kervezee et al. (2020, Anaesthesia) demonstrated that simulated night-shift conditions (bright light exposure at night, sleep during the day) reduced DNA repair efficiency by 15 per cent within a single 24-hour cycle. The comet assay showed that leukocytes from circadian-disrupted participants had significantly more unrepaired DNA strand breaks than time-matched controls. Concurrent work by Shostak (2017, Genes & Development) showed that nucleotide excision repair, the primary pathway for removing UV-induced and chemically induced DNA lesions, is under direct circadian clock control.

DNA repair enzymes (XPA, XPC, ERCC1 and others) follow circadian expression patterns, with peak activity during the biological night (sleep phase). When the circadian clock is misaligned, as in shift work, jet lag or late-night screen exposure, repair enzyme expression is suppressed precisely when repair activity is most needed. Accumulated unrepaired DNA damage increases mutation rate, the fundamental driver of carcinogenesis. The International Agency for Research on Cancer classified night-shift work as a Group 2A probable carcinogen in 2019, based on the consistent epidemiological association between long-term shift work and cancers of the breast, prostate, colon and lung.

The IARC classified glyphosate, the active ingredient in Roundup and the world's most widely used agricultural herbicide, as a Group 2A probable human carcinogen in 2015, based on sufficient evidence from animal studies and limited evidence from epidemiological studies.

The IARC classification contradicted assessments by the US EPA and European EFSA, both of which concluded glyphosate was unlikely to be carcinogenic at dietary exposure levels. The methodological differences between the assessments are substantial and contested.

Glyphosate is applied as a pre-harvest desiccant to wheat, oats and other UK crops, meaning residues are routinely present in flour, oats and the grain supply at detectable concentrations. The compound is also used in urban parks, roadsides and school grounds.

The IARC classified processed meat (including bacon, sausages, ham and salami) as a Group 1 known human carcinogen in 2015, based on sufficient epidemiological evidence that consumption increases colorectal cancer risk by eighteen per cent per fifty-gram daily serving.

The carcinogenic mechanisms include N-nitrosamines formed from nitrite preservatives reacting with haem iron, polycyclic aromatic hydrocarbons from smoking and high-temperature cooking and haem-catalysed lipid peroxidation in the colon.

The absolute risk increase is modest: colorectal cancer affects about five per cent of the population, and daily processed meat consumption raises this to approximately six per cent. The epidemiological association is real, but the magnitude of individual risk is smaller than media coverage suggested.

Keum and Giovannucci's 2014 meta-analysis in the British Journal of Cancer pooled four randomised controlled trials with 44,492 participants and found that vitamin D supplementation reduced total cancer mortality by thirteen per cent (RR 0.87, 95% CI 0.78 to 0.96). The effect was statistically significant and robust across sensitivity analyses. Notably, the reduction was in cancer death, not merely incidence, suggesting that vitamin D status affects tumour progression and survival after diagnosis, not just initial cancer development.

Vitamin D's anti-cancer mechanisms include promotion of cellular differentiation, inhibition of proliferation, induction of apoptosis in cancer cells and suppression of angiogenesis (tumour blood vessel growth). These operate through the vitamin D receptor (VDR), which is expressed in virtually all human cell types. An estimated one billion people worldwide are vitamin D deficient (25-hydroxyvitamin D below 50 nmol/L), with prevalence highest in northern latitudes, among dark-skinned individuals and in indoor workers. A thirteen per cent reduction in cancer mortality from a cheap, safe supplement represents one of the most cost-effective interventions in oncology, yet NICE does not recommend vitamin D supplementation for cancer prevention.

The thirteen per cent reduction came from oral D3 because that is what the underlying RCTs randomised. The same serum levels are reachable through adequate sun exposure across the year and through traditional fat-soluble foods where sun is geographically scarce. The Aajonus standard rejects isolated synthetic D3 in favour of dietary cholesterol from raw animal fats plus sunlight as the hormone substrate; the supplementation studies are the modern indoor population's proxy for what should already be present.

Esposito et al.'s 2012 meta-analysis in Endocrine pooled 116 cohort studies and found that metabolic syndrome (the combination of insulin resistance, central obesity, hypertension and dyslipidemia) was associated with a 2.1-fold increased risk of cancer mortality across all sites. The association was particularly strong for liver cancer (×2.8), colorectal cancer (×2.0) and bladder cancer (×1.9). The metabolic syndrome components that drove the cancer risk most strongly were hyperglycemia and hyperinsulinemia, not hypertension or HDL cholesterol.

Insulin and IGF-1 are mitogenic hormones: they signal cells to grow and divide. Chronically elevated insulin, the hallmark of metabolic syndrome, creates a sustained growth signal that promotes both cancer initiation and progression. Insulin resistance affects approximately one in three UK adults, creating a population-level elevation of cancer risk that is modifiable through diet and lifestyle. The NHS Diabetes Prevention Programme addresses cardiovascular risk and glucose control but does not mention cancer risk reduction as an outcome, despite the strength of the association documented across 116 studies.

Ibrahim and Al-Homaidh's 2011 meta-analysis in Medical Oncology pooled six prospective cohort studies with 12,108 breast cancer patients and found that post-diagnosis physical activity reduced breast cancer-specific mortality by forty-one per cent (HR 0.59, 95% CI 0.45 to 0.78) and all-cause mortality by thirty-four per cent (HR 0.66, 95% CI 0.57 to 0.77). The protective effect was dose-dependent: women meeting the equivalent of three to five hours of moderate-intensity walking per week showed the greatest benefit.

The mechanisms include reduced circulating insulin and IGF-1 (cancer growth factors), decreased systemic inflammation (IL-6, CRP, TNF-alpha), improved immune surveillance (increased NK cell activity), reduced oestrogen levels in post-menopausal women and improved insulin sensitivity. Despite this evidence, the standard NHS oncology pathway focuses almost exclusively on surgery, chemotherapy, radiotherapy and hormonal therapy. Exercise is mentioned in patient leaflets but is not prescribed, monitored or funded as a component of cancer treatment. A forty-one per cent mortality reduction from walking represents an effect size comparable to some adjuvant chemotherapy regimens.

Rinaldi et al.'s 2010 meta-analysis in the International Journal of Cancer pooled seventeen prospective studies with 5,073 colorectal cancer cases and 9,904 controls. Individuals in the highest quartile of circulating insulin-like growth factor 1 (IGF-1) had a 49 per cent increased risk of colorectal cancer compared with the lowest quartile (OR 1.49, 95% CI 1.31 to 1.69). The association was consistent across subgroups stratified by sex, study design and adjustment for confounders.

This is because IGF-1 is a potent mitogen that promotes cell proliferation and inhibits apoptosis in colonic epithelial cells. High-glycemic diets, insulin resistance and obesity all elevate circulating IGF-1. The pathway runs through the PI3K/AKT/mTOR signalling cascade, the same pathway that rapamycin (an anti-cancer immunosuppressant) was designed to inhibit. Fasting and caloric restriction lower IGF-1 by 20 to 40 per cent within seventy-two hours, directly suppressing this mitogenic signal.

Colorectal cancer is the fourth most common cancer in the United Kingdom, with approximately 42,900 new cases per year. NHS bowel cancer screening detects cancer after it has developed. The IGF-1 pathway represents an upstream modifiable risk factor that is driven by dietary glycemic load, insulin resistance and body composition. NICE guidance on colorectal cancer prevention does not mention IGF-1, insulin or glycemic load as risk factors, despite a seventeen-study meta-analysis demonstrating a 49 per cent risk increase.

Hursting et al.'s 2003 review in Annual Review of Medicine synthesised over sixty years of animal studies showing that caloric restriction (typically 20 to 40 per cent below ad libitum intake) reduces spontaneous tumour incidence by 30 to 60 per cent across virtually every cancer model tested, including mammary, colon, liver, skin, prostate and haematological malignancies. The effect has been replicated in mice, rats, non-human primates and fish. No other single intervention has matched this breadth and consistency in preclinical cancer prevention.

This is because caloric restriction activates autophagy (cellular self-digestion), a process by which damaged organelles and misfolded proteins are degraded and recycled. Autophagy was the subject of the 2016 Nobel Prize in Physiology or Medicine (awarded to Yoshinori Ohsumi). In cancer, autophagy serves a tumour-suppressive function by removing damaged mitochondria that produce reactive oxygen species, clearing protein aggregates that can activate oncogenic signalling and eliminating cells with DNA damage before they can proliferate. Fasting for 24 to 72 hours induces robust autophagy in humans.

No long-term human RCT has tested caloric restriction or fasting specifically for cancer prevention, and conducting one would require decades and tens of thousands of participants. However, the mechanistic pathway is well characterised: caloric restriction lowers IGF-1 (a mitogenic signal), reduces mTOR activity (a cell-growth signal targeted by multiple cancer drugs) and activates AMPK (a metabolic sensor that suppresses anabolic metabolism in cancer cells). Three of the five hallmarks of metabolic cancer biology are directly modulated by energy restriction.

Fiolet et al.'s 2018 prospective cohort study in the BMJ followed 104,980 French adults (NutriNet-Santé cohort) for a median of five years. A ten per cent increase in the proportion of ultra-processed food (UPF) in the diet was associated with a twelve per cent increase in overall cancer risk (HR 1.12, 95% CI 1.06 to 1.18) and an eleven per cent increase in breast cancer risk (HR 1.11, 95% CI 1.02 to 1.22). The association remained significant after adjustment for fat, sodium, sugar and carbohydrate intake, suggesting that processing itself, not merely nutrient profile, drives the risk.

Ultra-processed foods account for approximately fifty-seven per cent of calories in the average UK diet, one of the highest rates globally. These products contain additives (emulsifiers, artificial sweeteners, preservatives), neoformed contaminants from processing (acrylamide, heterocyclic amines, acrolein) and packaging migrants (bisphenol A, phthalates) that are not present in minimally processed equivalents. The twelve per cent risk increase per ten per cent dietary proportion means that an individual deriving sixty per cent of calories from UPF faces an approximately seventy-two per cent increase in cancer risk compared with someone eating no UPF, a population-level exposure that dwarfs many regulated carcinogens.