Reviewing What is Known of the Mechanisms by Which Calorie Restriction Slows Aging
Reducing the dietary intake of calories while retaining an optimal intake of micronutrients is well established to slow aging and extend life in a number of species. In humans, studies have shown that reduced calorie intake improves health in ways that are likely result in an extension of life span. Short-lived species exhibit a greater relative extension of life as a result of calorie restriction than is the case for long-lived species. In mice, calorie restriction can produce as much as a 40% extension of life span. In humans, a few years of additional life seems the likely effect size, although the only thing we can say in certainty given the data to hand is that the benefit cannot be much larger than this. If humans robustly became centenarians given the right restrictions of diet, this would be have been well known to the peoples of the ancient world and every monastic order since then. Even a ten year gain would be hard to hide over this span of time, let alone from modern epidemiology.
From a mechanistic perspective, this smaller effect on life span in longer-lived species is likely the case because the long-lived species already benefit from a sizable fraction of the life-extending mechanisms that are indirectly triggered by a reduced calorie intake in the short-lived species. From an evolutionary point of view, the life-extending response to reduced availability of nutrients likely evolved because it raises the odds of successful reproduction following seasonal famine. A winter is a much larger fraction of a mouse life span than it is of a human life span, so the mouse has evolved to exhibit a much longer relative increase in life span than the human.
Much of the attention given to the mechanisms of the calorie restriction response is focused on autophagy, the collection of processes that recycle damaged or otherwise unwanted proteins and cell structures into the raw materials needed to synthesize more proteins. Up to a point, more autophagy improves cell function. Improved cell function means improved tissue function, greater resilience to the damage and dysfunction of aging, and thus a slowing of declines and extension of life. Autophagy is far from the only mechanism that is studied by the research community in this context, however, and today's open access paper is a review that covers a range of the others.
Among numerous genetic, pharmacological, and lifestyle interventions examined over the past decades, dietary restriction (DR) remains the most robust and evolutionarily conserved strategy for extending lifespan and improving healthspan. Originally described in rodents nearly a century ago, the beneficial effects of reduced nutrient intake have since been validated in a wide range of organisms, including yeast, nematodes, flies, and mammals. While often used interchangeably, it is critical to distinguish between different nutritional interventions to avoid conceptual overlap. Caloric restriction (CR) typically refers to a chronic reduction in total calorie intake (usually 20%-40%) without malnutrition. In contrast, Chronic Dietary Restriction (DR) is a broader term encompassing the restriction of specific macronutrients (amino acid restriction, protein restriction) regardless of total calorie count. Furthermore, long-term Fasting involves extended periods without food intake, triggering distinct periodic metabolic switches that differ from the continuous physiological adaptations induced by chronic CR or DR.
Genetic and transcriptomic studies have revealed that DR induces coordinated changes in gene expression, chromatin state, and metabolic wiring, leading to a systemic shift from anabolic growth toward cellular maintenance and stress resistance. Central to these are conserved nutrient-sensing pathways - such as insulin/IGF-1 signaling, the target of rapamycin (mTOR), AMP-activated protein kinase (AMPK), and NAD+-dependent sirtuins - that function as molecular hubs linking environmental cues to transcriptional and epigenetic regulation. These pathways regulate the activity of key transcription factors and transcriptional coactivators, thereby shaping long-term gene expression programs associated with longevity.
Downstream, these pathways enhance autophagy and proteostasis, remodel mitochondrial function and redox balance, reshape immune and inflammatory networks, and induce epigenetic and transcriptional reprogramming. Recent work further highlights amino acid-specific sensing mechanisms, endocrine mediators such as fibroblast growth factor 21 (FGF21), the gut microbiome, circadian regulators, and nuclear pore-associated transcriptional plasticity as integral components of DR responses. Importantly, the physiological outcomes of DR are context dependent and influenced by genetic background, sex, age at intervention, and the type and duration of restriction. In this review, we summarize current knowledge on the genetic and molecular architecture underlying DR-induced longevity and health benefits across species, discuss implications for aging-related diseases, and outline future directions toward precision nutrition and safe translational strategies.