Does fasting up-regulate cellular senescence?

Does Fasting Up-regulate Cellular Senescence?

Fasting does not up-regulate cellular senescence but rather appears to reduce senescence markers and promote longevity through multiple cellular pathways. 1

Mechanisms of Fasting on Cellular Aging

Fasting affects cellular aging through several key mechanisms:

Nutrient-Sensing Pathways

• Fasting drastically reduces insulin/IGF-1 signaling (IIS) and mTOR signaling 1
• Activates sirtuins (NAD-dependent histone deacetylases) which are triggered by low energy status of cells 1
• AMPK signaling increases during fasting, which reduces mTOR activity and works with sirtuins to regulate energy metabolism 1

Cellular Stress Resistance

• Fasting induces hormetic effects - beneficial cellular stress resistance mechanisms 1
• Upregulates heat shock proteins, antioxidant enzymes, and detoxification enzymes 1
• Unlike supplemental antioxidants which can downregulate natural cellular defenses, fasting enhances endogenous protective mechanisms 1

Cancer Cell Vulnerability

• In hepatocellular carcinoma (HCC), fasting increases apoptosis and reactive oxygen species (ROS) accumulation 1
• Down-regulates NF-E2-related factor 2 (Nrf2)/antioxidant response element (ARE) signaling pathway 1
• Experimentally shown to decrease proliferation of hepatic stellate cells 1
• Synergizes with cancer treatments like Sorafenib in hampering HCC cell growth 1

Sex-Specific Effects on Frailty and Senescence

Research shows important sex differences in fasting's effects:

• Intermittent fasting in late life reduces frailty components in males but not females 1
• These effects depend on increased renal hydrogen sulfide (H2S) production, which was elevated only in males 1
• Enalapril (an angiotensin-converting enzyme inhibitor) reduces frailty index scores in both sexes, but through different mechanisms:
  • Reduces pro-inflammatory cytokines in females
  • Increases anti-inflammatory cytokines in males 1

Clinical Benefits and Metabolic Effects

Fasting demonstrates multiple beneficial effects on metabolic parameters:

• Reduces body weight, BMI, and waist circumference 1
• Improves cardiovascular markers like LDL cholesterol and insulin sensitivity 1
• Decreases coagulation factor VII activity and increases prothrombin time 1
• May increase total antioxidant capacity (TAC) levels 1
• Reduces fasting insulin concentrations and HOMA-IR values 1

Practical Considerations and Cautions

Despite benefits, fasting should be approached with caution in certain conditions:

• Contraindicated in patients with decompensated liver disease (Child class B or C cirrhosis) 1
• Requires medical supervision for liver transplant recipients 1
• May be safe for HCC patients on Sorafenib only if their liver is compensated 1
• Can cause changes in medication metabolism, requiring dose adjustments 1

Types of Fasting Regimens

Different fasting approaches may have varying effects:

• Intermittent fasting (IF): Fasting periods of 12-48 hours repeated every 1-7 days 2
• Periodic fasting (PF): Longer fasting periods of 2-7 days repeated monthly or less frequently 2
• Fasting-mimicking diet (FMD): Low in calories, sugars, and protein but high in unsaturated fats 3
• Time-restricted eating: Daily eating window (e.g., 12-hour restriction) 4

Molecular Mechanisms of Longevity

Recent research highlights specific molecular pathways:

• 10-day periodic fasting significantly increased Human Telomerase Reverse Transcriptase (hTERT) expression 4
• Fasting may regulate Forkhead Box O Transcription Factors (FOXO3a), though results show variability 4
• Modulates immunosenescence and inflammaging by affecting both adaptive and innate immune components 5

In conclusion, rather than up-regulating senescence, fasting appears to combat cellular aging through multiple pathways that promote stress resistance, reduce inflammation, and enhance cellular repair mechanisms. The effects are sex-specific and depend on the fasting protocol, duration, and individual health status.