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Scientist studying effects of caloric restrictions on senescent cells

Nutrients that Provide Benefits of Caloric Restriction

Caloric restriction extends healthy lifespans. Researchers have identified plant-derived compounds that activate similar cellular responses.

Scientifically reviewed by: Dr. Crystal M. Gossard, DCN, CNS, LDN, in August 2023. Written by: Nancy Kovacs.


Published studies on a wide range of organisms show:

Caloric restriction can improve health and extend life.1-3

But people are challenged when trying to chronically reduce their food intake.1

Even those who initially succeed often return to regular eating, losing out on the longevity benefits that caloric restriction can offer.

Researchers have identified plant-derived compounds that help activate similar health-promoting cellular responses as caloric restriction.

How Caloric Restriction Prolongs Life

Gynostemma pentaphyllum leaf

Caloric restriction means limiting the number of calories consumed each day, while avoiding malnutrition.

Restricting calories extends life and reduces age-related chronic disease in many organisms.2,3 These effects have been observed in a wide range of animal models, including mammals.

When caloric intake is low, during what’s known as a fasting state, cells switch into protective mode. They activate processes that rejuvenate themselves and defend against potential threats and stressors.

These changes have long-term benefits for overall health, and possibly for life extension as well.

On the flip side is the dietary excess plaguing modern societies. This chronic, surplus calorie ingestion contributes to a variety of health problems.

Surging rates of obesity, type II diabetes, neurodegenerative disorders, and cancer have all been linked to excessive calorie intake.

Scientists have pinpointed some of the specific cellular changes that occur with caloric restriction. The most practical ways of achieving these benefits are:4-10

1. Boosting function of sirtuins, proteins that regulate cellular health,

2. Increasing activity of AMPK, an enzyme that regulates metabolism,

3. Reducing activity of mTOR, a protein linked to aging and chronic disease,

4. Blocking cellular senescence, when older cells become dysfunctional, and

5. Encouraging autophagy, cellular “housekeeping.”

These actions protect against many forms of chronic disease and accelerated aging.4,6-10

Caloric Restriction and Intermittent Fasting “Mimetics”

Sticking to a restrictive diet is difficult.

It can also be unpleasant. For some, substantial caloric restriction may lead to loss of strength and stamina, loss of libido, loss of bone density, depression, and other undesirable effects.1

Research is increasingly finding that there are alternatives to severe dietary restriction. Several compounds have been shown to target some of the same cellular pathways as caloric restriction, without side effects.5,7-9,11

These compounds are known as caloric restriction mimetics. A mimetic is something that mimics the effects of something else.

Some of the nutrients found to be caloric restriction mimetics are health-promoting polyphenols.

For each of the five major cellular changes spurred by caloric restriction, science has discovered mimetics that have the same effects.

1. Boosting Sirtuin Function

Husband and wife making dinner

One way caloric restriction extends lifespan is by ramping up the activity of signaling proteins called sirtuins, particularly SIRT1.6-8

Sirtuins regulate cellular health and defend cellular components in times of stress. They shield DNA from damage that speeds the aging process and makes cells susceptible to disease.12,13

Studies show that improving sirtuin function extends lifespan of various organisms.12,14-18

The polyphenol resveratrol, found in minute quantities in red wine, grapes, and berries, activates SIRT1.14-16,19,20

In mice, resveratrol helps mimic the changes induced by dietary restriction, reducing the signs of aging.11

Resveratrol has been shown to stabilize DNA and extend lifespan of yeast by a whopping 70%.19

While resveratrol activates sirtuins, a cofactor called NAD+ (nicotinamide adenine dinucleotide) is required for sirtuins to function properly. With advancing age, NAD+ levels drop.12,13

The oral NAD+ precursor nicotinamide riboside boosts NAD+ cellular levels rapidly, helping to support healthy sirtuin function.21-23

Taken together, resveratrol and nicotinamide riboside maximize the benefits for cellular health and longevity.

2. Activating AMPK

Another longevity-promoting change spurred by caloric restriction is increased activity of an enzyme called AMPK.

Stimulating AMPK has a critical impact on metabolism. It helps prevent weight gain, improves insulin sensitivity, and reduces high blood glucose levels.24-27

The most commonly prescribed medication for type II diabetes is metformin, which works partially by activating AMPK.

A number of plant-derived compounds are also potent activators of AMPK.

Gynostemma pentaphyllum is known as the “immortality herb” in some Asian cultures. Cell and animal studies have shown that Gynostemma extracts activate AMPK, resulting in health benefits that include reduced body weight and improved cholesterol levels.28-32

In a 2019 study of mice fed an obesity-inducing diet, Gynostemma prevented weight gain, reduced fat mass, and improved blood lipid markers.33

AMPK also stimulates SIRT1. In this 2019 study, animals receiving Gynostemma had an approximately 4.5-fold increase in SIRT1 expression compared to untreated animals.

Hesperidin is a plant compound found in citrus fruits that has also been shown to amplify AMPK activity.34-37 In mice, it lowers body weight and lipid levels while improving insulin sensitivity and glucose control.35

In humans, 500 mg of hesperidin daily was found to lead to improvements including better blood vessel reactivity and reduced body-wide inflammation.36

What you need to know

The Benefits of Caloric Restriction Without Fasting

  • Caloric restriction has powerful anti-aging effects, reducing chronic disease and extending life, as shown in many studies.
  • Restrictive diets are difficult to adhere to and have potential unpleasant side effects.
  • Scientists have identified crucial cell changes that are induced by dietary restriction. These include sirtuin activation, boosting AMPK, reducing mTOR activity, protecting against cell senescence, and promoting beneficial autophagy.
  • Several plant-derived nutrients mimic the cellular effects of restricting calories, producing some of the same protective benefits.
  • Resveratrol, nicotinamide riboside, Gynostemma pentaphyllum, hesperidin, curcumin, quercetin, theaflavins, and apigenin are nutrients that closely imitate the beneficial effects of restrictive diets.

3. Decreasing mTOR Activity

mTOR stands for the “mechanistic target of rapamycin.”

In youth, balanced mTOR activity enables rapid growth.

If mTOR activity remains stuck in high gear as people age, it contributes to a number of deleterious effects.

When nutrients are plentiful, mTOR activity goes up.

If mTOR is not balanced, aging individuals could accumulate unwanted fat stores even when they don’t ingest calories excessively.

Caloric restriction decreases mTOR activity, protecting health.8

Research shows that resveratrol and curcumin, a compound found in turmeric root, have mTOR-inhibiting activity.38-42

4. Preventing Cellular Senescence

Senescent cells that promote inflammation

As cells age, many become dysfunctional and lose the ability to grow or divide. This is referred to as cellular senescence.

Senescent cells secrete compounds that damage surrounding cells and promote chronic inflammation.

Cellular senescence is a major driver of aging of tissues, loss of function, and development of disease.

Caloric restriction limits the development of senescent cells, shielding tissues from their harmful effects.6

Compounds called senolytics can help reduce the senescent cells’ burdens without caloric restriction.

The most studied senolytic therapy combines the plant pigment quercetin, found in many fruits and vegetables, with the chemotherapy drug dasatinib.

Several studies show this two-compound cocktail (dasatinib + quercetin) decreases the number of senescent cells in tissues, reducing signs of aging and diminishing the occurrence and severity of chronic disease.48-51

Early human trials of this therapy are showing promising results, but dasatinib is a synthetic pharmaceutical drug.48,52 As a result, many people today would prefer a safer senolytic compound.

Scientists have found another way to remove senescent cells, using plant-based nutrients found in commonly consumed food and beverages.

Quercetin on its own possesses senolytic properties,53 and theaflavins from black tea act in similar cell signalling ways as dasatinib.54-56

Recently, researchers have made another advance in senolytic therapy. They’ve found that apigenin (a plant compound) reduces harmful compounds that senescent cells emit.57,58

By combining a highly absorbable quercetin with theaflavins and apigenin, scientists have created a plant-based formula, available without a prescription, that provides senolytic action without resorting to pharmaceutical drugs.

And even more exciting is the advent of bioavailable fisetin that may be the most effective way to remove senescent cells from aging bodies. Look forward to a novel and low-cost bioavailable fisetin in the near future.

5. Enhancing Autophagy

As cells get older, they accumulate damaged and worn-out components that interfere with the proper functioning of the cell.

In earlier stages of their life, cells do a kind of “housekeeping” on a regular basis. This involves removing older, damaged components inside cells and replacing them with new, healthy components. This process is referred to as autophagy.

With advancing age and poor diet, autophagy declines and cell clutter builds up, robbing tissues of their healthy cellular function. Deficient autophagy contributes to many diseases of older age.59

Caloric restriction has been shown to stimulate autophagy, refreshing and rejuvenating cells.4

A number of nutrients found in plants, particularly resveratrol and curcumin, have also been shown to stimulate healthy autophagy.59-63

Studies indicate this has protective effects against cancer, neurodegenerative disorders like Alzheimer’s disease, and other chronic diseases.59-63

Look forward to specific plant-derived autophagy-inducers being introduced in 2021. In the meantime, it’s good to know that nutrients most readers of this magazine already supplement with have internal cell-cleansing properties.


Couple looking at recipe for caloric restriction

Caloric restriction is one of the most widely studied methods to prevent disease and extend lifespan.

For people, adhering to rigorous dietary regimens can be difficult, if not impossible.

Scientists have identified cellular processes that are favorably altered by calorie-restricting diets.

Several plant-derived nutrients have been shown to mimic many of the effects of dietary restriction.

Resveratrol and nicotinamide riboside boost and maintain healthy levels of protective sirtuin function.

Gynostemma pentaphyllum and hesperidin activate the metabolism-regulating enzyme AMPK.

Resveratrol and curcumin limit harmful activity of the protein mTOR, while stimulating autophagy, or cellular “housekeeping.”

Theaflavins and highly absorbable quercetin reduce the numbers of old, dysfunctional senescent cells in tissues. And apigenin reduces harmful compounds that senescent cells emit.

These effects help mimic the longevity-promoting impact of caloric restriction.

If you have any questions on the scientific content of this article, please call a Life Extension® Wellness Specialist at 1-866-864-3027.


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