Longevity: Calorie-Restriction Mimetics Under the Microscope

A scientific review takes stock of calorie restriction mimetics

Published in 2026 in "Nature Aging", the review "Dietary restriction in ageing and longevity" summarises current knowledge on dietary restriction, its underlying biological mechanisms and its impact on markers of ageing (1).

In particular, the authors analyse the effects of calorie restriction in mammals. Special attention is also paid to ‘calorie restriction mimetics’, i.e. compounds capable of modulating certain biological pathways activated when energy intake is reduced (2).

Within the scientific literature on calorie restriction mimetics and longevity, several substances are regularly cited:

• resveratrol;
• spermidine;
• NAD+ precursors, such as NR and NMN.

Other molecules are also attracting growing interest in research into cellular ageing:

• fisetin;
• quercetin;
• apigenin.

These compounds are being studied in particular for their potential interaction with several biological processes associated with calorie restriction:

• cellular energy management;
• autophagy;
• NAD+ metabolism;
• sirtuins;
• metabolic homeostasis;
• oxidative stress;
• chronic inflammation;
• cell senescence.

Let us now review these various ‘mimetics’ and their respective effects.

The main compounds studied in research into calorie restriction mimetics and longevity

Resveratrol

Resveratrol is a polyphenol found naturally in certain plants. It is found in particular in grape skins, berries and peanuts.

It is often cited as one of the most well-known calorie restriction mimetics, as it has been extensively studied for its potential interaction with several biological pathways associated with cellular ageing (3). In particular, it is linked to research on sirtuins,AMPK, oxidative stress,low-grade inflammation andmetabolic homeostasis.

Spermidine

Spermidine is a polyamine found naturally in the body, but also in certain foods such as wheat germ, soya, mushrooms, certain mature cheeses and pulses.

It is attracting significant scientific interest in the field of longevity due to its link with autophagy, as well as with cellular stability, mitochondrial metabolism and protection against oxidative damage (4).

NAD+ precursors

NAD+ is a coenzyme essential for proper cellular function. It plays a role in numerous reactions linked to energy production and DNA repair (5).

However, NAD+ synthesis declines with age. Fortunately, it is possible to support its production by using NAD+ precursors, such as nicotinamide riboside (NR) and nicotinamide mononucleotide (NMN), which are available as supplements (6).

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Fisetin

Fisetin is a flavonol found in certain plants, particularly strawberries, apples, persimmons and onions.

It is one of the compounds most closely watched by longevity experts, who are particularly interested in its antioxidant activity, its potential influence on low-grade chronic inflammation and its interactions with senescent cells (7).

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Quercetin

Quercetin is a flavonoid that is fairly widespread in the plant kingdom. It is found in particular in onions, capers, apples, berries, tea and certain leafy vegetables.

At the heart of research into polyphenols, it is thought to have a certain ability to modulate several pathways involved in cellular protection, the inflammatory response and metabolic balance (8).

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Apigenin

Apigenin is another flavonoid found in several edible and medicinal plants, including parsley, celery, chamomile, oregano and certain citrus fruits.

It is attracting growing interest in the field of cellular longevity, particularly in relation to oxidative stress, sirtuin activity, mitochondrial function and NAD+ metabolism (9).

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How do these compounds aim to replicate certain effects of calorie restriction?

AMPK and cellular energy management

AMPK is an enzyme that can be likened to a cellular ‘energy sensor’. Its role is to detect changes in the level of available energy. When energy resources diminish, such as during fasting or calorie restriction, AMPK helps to redirect metabolism towards energy-saving and energy-producing functions (10).

It thus encourages the use of energy reserves and curbs certain energy-consuming pathways, such as the excessive synthesis of lipids or proteins. This adaptation enables the cell to better manage periods of reduced nutritional availability.

Resveratrol is one of the compounds most frequently associated with AMPK in scientific research (11). Other polyphenols, such as quercetin, fisetin and apigenin, are also regularly cited.

Autophagy and cellular recycling

Autophagy is a natural mechanism of cellular recycling. It enables the cell to break down and reuse certain damaged components, such as misfolded proteins or organelles that have become less functional. It is therefore essential for maintaining proper cellular function, as it helps to limit the accumulation of biological waste (12).

Calorie restriction appears to stimulate this very process. When energy intake decreases, the cell optimises its internal resources and thus mobilises its self-cleansing capabilities more effectively.

Whilst spermidine is very often highlighted in research on autophagy, resveratrol, fisetin and other flavonoids are also thought to play a role (13).

NAD+, sirtuins and cellular homeostasis

NAD+ plays a key role in cellular metabolism. It is involved in cellular energy production, as well as in certain functions related to DNA repair, the stress response and the maintenance of cellular homeostasis.

Sirtuins are enzymes that are highly dependent on NAD+. They help cells adapt to nutritional and energy fluctuations. They are therefore thought to be involved in regulating metabolism, genome stability and mitochondrial function (14).

It has been observed that calorie restriction leads to changes in the NAD+/sirtuin pathways. This is why NAD+ precursors, such as NR and NMN, are attracting particular interest (15).Apigenin is also attracting researchers’ attention for its potential ability to inhibit the enzyme CD38, which is responsible for breaking down NAD+ (16). Resveratrol, for its part, has historically been associated with research into sirtuins (17).

Oxidative stress, chronic inflammation and cellular ageing

Cellular ageing is often accompanied by increased oxidative stress, low-grade chronic inflammation and a gradual accumulation of senescent cells (18–19).

Oxidative stress refers to an imbalance between the production of free radicals and the body’s antioxidant capacity. In the long term, it can contribute to damage to cellular structures (lipids, proteins, DNA, etc.).

Chronic low-grade inflammation refers to a silent, persistent inflammatory response that often develops with age and/or accompanies certain chronic diseases. Over time, it tends to deteriorate the cellular environment and compromise the proper functioning of tissues.

Finally, cellular senescence is a state in which certain cells cease to divide but remain metabolically active. Over time, their accumulation can alter the tissue microenvironment, disrupt repair mechanisms and contribute to the gradual decline of certain biological functions.

In this field, fisetin and quercetin play a central role, alongside resveratrol, apigenin and other polyphenols associated with research into cellular ageing (20–21).

Key takeaways from the review

The review published in "Nature Aging" serves above all as a reminder that the presumed benefits of calorie restriction are based on a set of highly complex biological mechanisms: cellular energy management, autophagy, AMPK, NAD+, sirtuins, oxidative stress, chronic inflammation, senescence…

Whilst no single compound currently appears capable of replicating all the biological effects associated with calorie restriction on its own, research is continuing to better understand their potential contribution to longevity and cellular ageing.