Could Calorie Restriction Mimetics Hold the Key?

• What’s the Science Behind Calorie Restriction Mimetics?
• Which Compounds Most Interest Mimetics Researchers?
• How Will Calorie Restriction Mimetics be Used in Health Care?

For decades, researchers have studied eating patterns—what, when, and how much we eat—to see how they might help us avoid age-related diseases like heart disease, diabetes, and dementia. They are also interested in learning more about how different eating patterns might affect the health of our musculoskeletal system, which comprises the body’s muscles, bones, and connective tissue.

Of particular interest to researchers is calorie restriction, which involves reducing average daily caloric intake below what is typical or habitual without malnutrition or deprivation of essential nutrients. Calorie restriction can be also accomplished by not eating at all for a period of hours or days (known as “intermittent fasting”) or by eating less at some or all meals. Some studies in animals and humans have shown that calorie restriction can lead to improvements in a variety of health conditions. It also extends lifespan for many animal species, though there’s no evidence to confirm this happens in people.

Scientists are working to discover what it is about calorie restriction that may help animals and humans stay healthy as we age. Someday, this research could lead to the development of calorie restriction mimetics—medicines that mimic calorie restriction’s effects to slow the aging process.

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What’s the Science Behind Calorie Restriction Mimetics?

Researchers are exploring the theory that calorie restriction promotes a healthy lifespan by triggering changes in one or more biological pathways identified as playing a role in healthy aging. Biological pathways are a series of chemical reactions that occurs inside a body’s cells, much like a production line in a factory. It’s like instructions, with steps that must be followed to accomplish some function. For example, activity along a biological pathway might lead to the formation of a new cell, destruction or repair of an injured cell, movement of a signal along a nerve, production of a hormone, or the switching-on of a gene to activate another pathway.

Biological pathways that work smoothly promote good health. Those that do not may contribute to disease and aging. Calorie restriction mimetics research is the search for potential therapies that target the same pathways affected by calorie restriction, with the goal of finding ways to extend human healthspan, defined as how long people live in good health.

Key Biological Pathways in Calorie Restriction Mimetics Research

Researchers interested in calorie restriction mimetics focus mainly on four biological pathways:

• Insulin signaling pathway. When you eat, your body converts food into glucose, which is used for energy. Glucose in the bloodstream triggers the release of insulin, a hormone. Insulin signaling determines whether the glucose is used immediately or stored, as well as where it is stored. Impaired signaling along this pathway can lead to mismanagement of glucose and aging-related diseases like diabetes and heart disease.
• Mammalian target of rapamycin (mTOR) pathway. The mTOR pathway senses when nutrients are available. When it detects enough nutrients, it triggers cell growth. When it detects insufficient nutrients (which occurs with calorie restriction), the mTOR pathway triggers the cell’s defenses against stress. This enhances the cell’s ability to repair itself and to resist toxins and other challenges.
• Sirtuin-1 (SIRT1) pathway. Sirtuins are a group of enzymes involved in metabolic regulation and cellular health. They can increase cellular production of mitochondria, the cell’s powerhouses. SIRT1 is the most studied of the sirtuin group, and signaling along the SIRT1 pathway promotes the ability of cells to resist stress and to survive.
• AMPK pathway. AMPK is an enzyme that contributes to cell stability by triggering reactions that promote the efficient management of energy.

With calorie restriction, activity is reduced along the insulin signaling and mTOR pathways and increased along the SIRT1 and AMPK pathways. Researchers are looking for compounds that have similar effects to reduce or increase activity.

Which Compounds Most Interest Mimetics Researchers?

Based on current knowledge of key biological pathways (see box above), scientists are exploring many different medications and experimental compounds to see if they have effects similar to those of calorie restriction. Targets of research include pharmaceuticals; nutraceuticals (compounds found in food); plant extracts; and substances produced by the body such as hormones, peptides, and amino acids. Three of the most studied compounds are:

• Resveratrol
• Rapamycin
• Metformin

Resveratrol is a naturally occurring compound found in red wine and grapes, dark chocolate, blueberries, raspberries, and nuts. It activates the SIRT1 and other sirtuin pathways. Animal studies with resveratrol have demonstrated antioxidant, anti-inflammatory, and anti-cancer effects. However, the evidence from human studies is weak. For example, in the NIA-funded study, Aging in the Chianti Region, researchers followed 783 healthy people for 9 years and measured how much resveratrol they consumed through their diet. The study found no association between resveratrol consumption and health or longevity.

More research is needed to answer questions about whether certain dosages or formulations might promote healthy aging in humans and which populations might benefit. Clinical trials are underway to test synthetic versions of resveratrol that may be effective in staving off the aging process.

Rapamycin is a substance produced by bacteria found in soil. This compound reduces signaling along the mTOR pathway. Rapamycin has been shown to extend lifespan in mice and to have other beneficial effects. A recent study found that giving middle-aged rats rapamycin as they got older reduced age-related memory loss and prevented age-related reductions in blood flow to the brain.

Rapamycin is prescribed to people who have received an organ transplant because it helps the body accept the donated organ. It also is used to treat people with certain cancers. Severe side effects, such as insulin resistance, gastrointestinal disorders, and infections, can occur at the high doses prescribed in such cases, so researchers are exploring whether lower doses can be safely used as a calorie restriction mimetic.

Metformin targets multiple biological pathways to affect energy production, inflammation, cell health, and more. This medication, widely used to treat type 2 diabetes, has also been found to protect against other age-related diseases, such as heart disease and cancer. Researchers are seeking to better understand how metformin works and how its effects could vary based on a person’s age, gender, and other characteristics. They also want to determine the dosages that might be most effective to use as anti-aging treatments.

Many other compounds are also being studied for their potential anti-aging effects: 17-alpha-estradiol, a form of the hormone estrogen; NDGA (nordihydroguaiaretic acid), a potent antioxidant found in the leaves of the creosote bush; protandim, a mix of plant extracts including green tea and curcumin (a compound extracted from the spice turmeric); acarbose, a prescription drug used to treat type 2 diabetes; NAD (nicotinamide adenine dinucleotide), a form of vitamin B3; and fish oil.

It’s important to remember that noneof these substances has been proven to extend lifespan or healthspan in humans. They should not be taken without consulting a doctor.

NIA-Supported Animal Research on Calorie Restriction Mimetics

NIA’s Interventions Testing Program (ITP) conducts studies of oral treatments for their effects on disease and lifespan in mice. Findings from these studies help scientists pursue the most promising interventions for further testing in animals and, eventually, for clinical trials that test safety and effectiveness in people. Here are a few of the program’s findings so far on calorie restriction mimetics:

• Rapamycin’s life-extending effects occurred even when mice were given the compound in old age instead of when young. This finding suggests that some compounds may be worth exploring for use later in life.
• Rapamycin’s side effects were reduced in female mice that were given the compound with metformin. This finding points the way toward more research on combination drugs.
• Side effects were not reduced in male mice given the rapamycin–metformin combination. Different effects for male and female mice have also been observed in studies of other potentially mimetic compounds, including aspirin, estrogen hormones, and NDGA (an extract from the creosote plant). Further research is needed to understand why some effects may be sex specific.
• Treatment of mice with curcumin, green tea extract, and fish oil has not produced evidence of any significant life-extending benefits. More research is needed to figure out whether or not these compounds have any effects on health.

How Will Calorie Restriction Mimetics be Used in Health Care?

If and when calorie restriction mimetics are proven to extend human healthspan, they will probably be most useful for people who are unhealthy and unable to eat properly. For people in good health, sensible habits may be more effective at extending healthspan than taking a medication developed through mimetics research. This means eating healthy foods, exercising, drinking alcohol in moderation or not at all, not smoking, getting a good night’s sleep, and maintaining an active, social lifestyle.

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