Can nutrients mimic calorie restriction to extend healthspan? A review of calorie-restriction mimetics in humans

Original publisher: The Conversation. This article examines whether nutrients in foods can mimic calorie restriction to enhance healthspan, what human studies show, and how to apply these ideas in everyday diets and exercise.

• Calorie restriction in humans: The CALERIE trial showed reduced energy intake improved cardiovascular and metabolic health markers but did not demonstrate life extension or clear functional healthspan gains.
• Calorie-restriction mimetics (CRMs): Compounds such as spermidine, urolithin A, resveratrol, and quercetin have been studied for potential cellular effects similar to calorie restriction, but evidence for lasting healthspan benefits in humans remains inconclusive.
• Dietary patterns over supplements: Across large cohorts, diets rich in fruits, vegetables, whole grains, nuts and unsaturated fats, with adequate protein and resistance training, correlate with healthier aging outcomes more reliably than high-dose supplements.
• Practical guidance: Until more conclusive human data emerge, a varied, nutrient-dense diet plus physical activity remains the strongest recommendation for aging well. Original publisher: The Conversation.

Overview

As people increasingly encounter advice about living longer, the term healthspan has become central to research on aging. Healthspan reflects the years lived in good health, free from disability and chronic disease, and is influenced by diet, physical activity, sleep, and the broader environment. Researchers study calorie restriction, defined as a 20–40% reduction in energy intake while preserving essential nutrients, as a key aging intervention. Across species, calorie restriction can extend lifespan, but its impact in humans is far less certain and depends on genetics, sex, age, and dietary composition. The World Health Organization emphasizes healthy ageing as the set of abilities enabling people to do what they value, and functional healthspan describes the ability to live independently. A growing field of study asks whether specific foods or compounds could mimic calorie restriction at the cellular level, potentially delivering similar health benefits without reducing overall intake.

Two large human trials and numerous smaller studies form the backbone of current understanding. The CALERIE trial is the largest long-term study in adults without obesity to test calorie restriction in humans. It followed 218 participants for two years, with an average 12% reduction in energy intake among those assigned to caloric restriction. Health markers showed improvements in cardiovascular and metabolic health, including better insulin sensitivity, blood pressure, and inflammation markers. Participants also lost body fat and lean mass, while some bone density declined modestly. Importantly, CALERIE did not demonstrate improvements in functional healthspan or extended lifespan, and adherence to caloric restriction is challenging in real life. This highlights a recurring theme in aging research: cellular-level changes do not automatically translate into meaningful improvements in daily functioning or longevity.

Another line of inquiry investigates calorie-restriction mimetics (CRMs), compounds that influence cellular pathways affected by nutrient intake without requiring substantial dietary restriction. CRMs may reduce signals of cell growth, stimulate autophagy, or modulate cellular energy sensing, with many findings derived from cells or animal models. But translating these effects into tangible healthspan or lifespan benefits in humans remains uncertain, and most studies test specific compounds rather than whole foods.

What human studies have found

Among CRMs, spermidine is a polyamine found in foods such as wheat germ, mushrooms, legumes and nuts. An observational study of nearly 24,000 US adults linked higher spermidine intake with lower mortality risk, including from cardiovascular disease. However, this is correlational and cannot establish causation. A small three-month pilot suggested memory benefits, but a subsequent 12-month randomized trial in older adults with subjective cognitive decline did not show memory improvements from a spermidine-rich supplement compared with placebo.

Other proposed CRMs include resveratrol (grape products), catechins (green tea and cocoa), and quercetin (onions and apples). In a study of adults aged 65–80, resveratrol plus exercise improved muscle strength and fatigue resistance, while quercetin during resistance training enhanced knee muscle force but did not improve broader functional tasks. These studies investigate the cellular mechanisms associated with aging, yet they often involve supplements rather than foods, and do not confirm that the observed effects stem from the proposed calorie-restriction pathways.

Urolithin A, produced by gut bacteria from ellagitannins in pomegranates and walnuts, is another CRM candidate. In a trial of 66 adults aged 65–90, urolithin A improved muscle endurance and mitochondrial health but did not significantly improve six-minute walk distance or energy production. An industry-sponsored trial in middle-aged adults reported improvements in muscle strength, aerobic fitness and walking speed but not peak muscle power. These results show functional benefits in certain contexts, but they do not prove that consuming pomegranates or walnuts will replicate those effects, nor that urolithin A directly extends healthspan.

Overall, these investigations indicate some potential healthspan benefits linked to CRMs, but the evidence remains preliminary and limited when assessing whole-food intake versus concentrated supplements and when measuring functional outcomes relevant to independence and daily living.

Dietary patterns, protein, and physical activity

Beyond CRMs, reliable evidence points to the importance of overall dietary patterns. A large 2025 study followed more than 105,000 adults for up to 30 years and found associations between diets rich in fruits, vegetables, whole grains, nuts, legumes and unsaturated fats (including omega-3s) and aging with good cognitive, physical and mental health. Adequate high-quality protein intake supports muscle mass, especially when combined with resistance training. Physical activity remains central to preserving function, with guidelines recommending strength, balance and flexibility work at least twice weekly, plus regular aerobic activity.

When considering foods that may contain CRM compounds, Mediterranean-style diets and Okinawan dietary patterns provide a framework for aging well. Mediterranean diets emphasize vegetables, fruits, legumes, whole grains, nuts and olive oil, while Okinawan patterns focus on vegetables, soy foods and modest fish consumption. However, the associations with CRMs do not imply causation, and the beneficial effects of these diets likely arise from broad nutrient intakes and lifestyle factors rather than isolated compounds.

Practical guidance for aging well

For now, human research has not established that CRMs can replace caloric restriction or meaningfully extend healthspan on their own. The strongest evidence supports adopting a varied, nutritious diet and engaging in purposeful physical activity. When considering supplements marketed as CRMs, caution is warranted, and individuals should prioritize established dietary patterns and exercise.

Informed by findings from CALERIE and subsequent human studies, practical recommendations center on a balanced diet rich in fruits, vegetables, whole grains, nuts and legumes, with emphasis on adequate protein and regular resistance training to support muscle health. These strategies align with broader public health guidance and reflect the most reliable path toward aging healthfully, at present.

Overall, research into CRM nutrients remains scientifically intriguing but not yet clinically transformative. The best-supported route to aging well is an active combination of nutritious diet and physical activity, complemented by social and environmental factors that influence health across the life course.