Fasting for Longevity: What the Science Actually Supports

Understanding why fasting affects health and aging requires tracing our evolutionary history. Humans evolved robust mechanisms to survive prolonged food scarcity—mechanisms that now intersect uncomfortably with a modern environment of caloric excess. This 2025 critical review by Fazeli and Steinhauser synthesizes decades of fasting biology alongside emerging clinical trial data to assess whether intentional fasting genuinely promotes metabolic health and longevity.

The adaptive fasting response unfolds in three overlapping phases. First, glycogen stores in the liver and skeletal muscle are mobilized through glycogenolysis to maintain blood glucose. Second, as glycogen depletes, gluconeogenesis in the liver and kidney synthesizes glucose from amino acids (particularly alanine from skeletal muscle) and glycerol. Third, and most critically for prolonged survival, the body transitions to lipid catabolism: adipose triglycerides are hydrolyzed by sequential lipase action (ATGL, HSL, MGL), fatty acids circulate to peripheral tissues for direct oxidation, and the liver converts fatty acids to ketone bodies that cross the blood-brain barrier to fuel the brain. This metabolic shift, reflected in a declining respiratory quotient, is what enables humans to survive months of starvation. The review also highlights newly described lipolysis mechanisms including lysosomal acid lipase activity and a macrophage-mediated pathway where adipocyte-derived exosomes deliver triglycerides to resident adipose macrophages for extracellular lipolysis.

Hormonal orchestration is central to these transitions. The fed-to-fasted shift involves falling insulin and rising glucagon, activating cAMP-PKA signaling that phosphorylates and activates key lipolytic enzymes. Leptin, which drops with caloric restriction, is particularly important: leptin decline signals energy deficit to the hypothalamus, triggering suppression of energy expenditure through reductions in thyroid hormones, sex hormones, and the growth hormone/IGF-1 axis. This neuroendocrine adaptation conserves energy during starvation but is maladaptive when fasting is intended as a therapeutic intervention.

In model organisms, caloric restriction consistently extends lifespan across yeast, worms, flies, and rodents. Proposed mechanisms include activation of sirtuins and AMPK, suppression of mTOR signaling, enhanced autophagy, reduced oxidative stress, and improved proteostasis. Intermittent fasting in animals also activates many of these same pathways. However, the review emphasizes that translation to humans is uncertain: the lifespan effects are most robust in short-lived organisms, and the one major human caloric restriction trial (CALERIE) demonstrated cardiometabolic benefits without definitive longevity data.

For clinical outcomes, randomized controlled trials of intermittent fasting and time-restricted eating show improvements in body weight, blood pressure, insulin sensitivity, lipids, and inflammatory markers. However, a persistent methodological limitation is that it remains unclear whether these benefits are independent of weight loss or simply a consequence of reduced caloric intake. The review identifies bone loss as the most concerning underappreciated harm: fasting-associated weight loss suppresses bone formation markers, reduces bone mineral density, and may increase fracture risk—a risk amplified in older adults already experiencing age-related bone loss. The authors call for longer-duration trials with fracture endpoints and better-controlled comparators.