From Benefit to Harm: Context-Dependent Responses to Dietary Interventions

Diet is a major determinant of human health and disease, and dietary interventions have emerged as promising adjunctive strategies to preserve neuronal function, improve metabolic control, suppress tumor growth, and delay aging. However, accumulating evidence indicates that their effects are critically dependent on the underlying metabolic, genetic, and pathological context. Beyond conventional adverse effects of excessive dietary restriction, such as nutrient deficiencies, muscle loss, and impaired immunity, recent studies have revealed novel context-dependent adverse effects with new mechanisms. Our study demonstrated that glucose restriction (GR) selectively induces degeneration of neurons with mitochondrial DNA (mtDNA) depletion by disrupting calcium homeostasis at mitochondria–endoplasmic reticulum contact sites (MERCS), revealing that the vulnerability to GR is critically determined by the pre-existing mitochondrial state. Another study showed that extreme GR promotes lung tumor metastasis by reshaping the pulmonary premetastatic immune microenvironment through tumor-derived exosomal tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), challenging the conventional view that GR is uniformly anti-tumorigenic. Together, these findings highlight that the same dietary intervention can produce divergent or even opposing outcomes depending on biological context.

Here, we review major dietary interventions, including calorie restriction (CR), fasting diet, ketogenic diet (KD), and GR,and extend a context-dependent framework in which their effects are shaped by mitochondrial integrity, hormonal milieu, tissue-specific metabolism, oncogenic alterations, and immune status. This review underscores the importance of patient stratification and biomarker-guided optimization for the safe and effective application of dietary interventions.