According to Chaudhary and colleagues, promising calorie restriction mimetics include 

  • Metformin
  • Rapamycin 
  • Resveratrol 
  • D-allulose
  • Spermidine
  • NAD+ precursors 
  • Polyphenols 

For decades, scientists have observed that calorie restriction (CR) – significantly reducing calorie intake without causing malnutrition – consistently extends lifespan and improves health across a wide range of organisms. Eating less is not just about losing weight; it is about altering the body’s metabolism and stress responses in ways that promote longevity and protect against age-related diseases.

When food is scarce, our cells prioritize survival over growth and reproduction. This mode activates ancient cellular pathways that enhance repair mechanisms, reduce inflammation, and improve overall resilience. While highly effective, sustained calorie restriction is incredibly challenging for most to maintain in the long term, often leading to issues such as nutrient deficiencies, reduced bone density, and a persistent feeling of hunger. This is where calorie restriction mimetics come in.

What Are Calorie Restriction Mimetics?

Calorie restriction mimetics (CRMs) are compounds that aim to mimic the beneficial effects of CR without the need for drastic dietary changes. They achieve this by targeting the same molecular pathways influenced by reduced calorie intake. Essentially, CRMs signal cells to activate protective and repair systems, even when eating normally.

The mechanisms behind CRMs are complex, but generally revolve around modulating key metabolic and stress-response pathways: 

  • AMPK Activation: AMPK (AMP-activated protein kinase) is one of our body’s energy sensors, activated in response to low energy. When energy levels are low (like during CR), AMPK promotes the burning of fat for energy, improves insulin sensitivity, and boosts the efficiency of mitochondria, our cells’ primary source of energy. 

  • mTOR Inhibition: While essential for growth, overactivity of mTOR (mechanistic target of rapamycin) can contribute to aging and age-related diseases. CRMs can inhibit mTOR, promoting a crucial cellular process called autophagy. Autophagy is the body’s internal recycling program, where old, damaged cellular components are broken down and reused, leading to healthier, more efficient cells.

  • Sirtuin Activation: Sirtuins are a family of enzymes often referred to as ‘longevity genes.’ They play vital roles in DNA repair, metabolism, and inflammation. CRMs can activate sirtuins, enhancing their protective functions and contributing to anti-aging effects and increased stress resistance.

(Hall et al., 2013) Sirtuins. There are seven sirtuins (SIRTs) that are each linked to age-related conditions.
  • Glycolysis Inhibition: Glycolysis is the process by which glucose (sugar) is broken down for energy. Some CRMs can inhibit this process, leading to lower glucose levels and mimicking some of the metabolic benefits of CR, such as improved insulin sensitivity.

  • Antioxidant and Anti-inflammatory Effects: Many CRMs also possess powerful antioxidant properties, helping to neutralize harmful free radicals that contribute to cellular damage and aging. They can also reduce chronic inflammation, a silent contributor to many age-related diseases.

Calorie Restriction Mimetic Supplements 

Research into CRMs is ongoing, with several compounds showing significant promise: 

  • Metformin: A widely used pharmaceutical drug for type 2 diabetes, metformin is a well-known CRM. It partially works by activating AMPK and leads to improved insulin sensitivity and reduced glucose production in the liver. Beyond diabetes, studies suggest metformin may have broader anti-aging effects.

  • Rapamycin: This pharmaceutical drug is a potent inhibitor of the mTOR pathway. While currently used as an immunosuppressant, its ability to promote autophagy and extend lifespan in various organisms has made it a key focus in aging research.

  • Resveratrol: Found in red wine and grapes, resveratrol is a polyphenol that activates sirtuins and influences AMPK. It has been studied for its potential cardiovascular benefits and anti-aging properties.

(Prakash et al., 2024) Dietary Sources of Resveratrol.
  • 2-DG (2-Deoxy-D-glucose): This glucose analog is not metabolized into cellular energy and interferes with glycolysis. By inhibiting sugar metabolism, 2-DG can mimic some of the metabolic shifts seen in CR, such as reducing inflammation and killing cancer cells.

  • D-Allulose: A rare sugar with a unique metabolic profile, D-allulose has been shown to inhibit glucose metabolism and absorption, and has demonstrated lifespan-extending effects in some studies, partly through AMPK activation.

  • Spermidine: A naturally occurring polyamine, spermidine induces autophagy and has been linked to improved cognitive function and increased longevity.

  • NAD+ Precursors: NAD+ (nicotinamide adenine dinucleotide) precursors like NR (nicotinamide riboside) and NMN (nicotinamide mononucleotide) are compounds that boost NAD+, a crucial coenzyme involved in countless cellular processes, including those regulated by sirtuins. Increasing NAD+ levels is thought to enhance cellular repair and energy metabolism.

  • Polyphenols: This broad class of plant compounds, including curcumin (from turmeric), epigallocatechin gallate (from green tea), and quercetin (found in many fruits and vegetables), exhibit diverse CRM-like effects, such as antioxidant, anti-inflammatory, and metabolism-modulating properties.

Calorie Restriction Mimetics for Healthy Aging

The research into CRMs, summarized by Chaudhary and colleagues, is still in its early stages, especially concerning human applications. However, the potential is immense. These simple compounds could help protect us from age-related diseases like diabetes, heart disease, neurodegenerative disorders, and even some cancers, all by nudging our bodies towards a more resilient, survival state. While CRMs are not a magic bullet and more research is needed to understand their long-term effects and optimal dosages in humans, they represent a fascinating and promising avenue in the quest for healthy aging.