I wanted to cover this review to increase awareness of aging interventions and CR variations. Currently, Calorie Restriction is the most effective form of dietary intervention against aging. As confirming data continue to emerge, CR is gaining respect as not only a potential human life extension method, but a very viable method to increase health span. At the very least, Calorie Restriction can improve the quality of life and healthy years even if the longevity benefits are meager.

CR mimetic research continues try to find an agent able to reproduce the in vivo effects of CR without reducing calories. Understanding the mechanisms of CR would help lead to a CR mimetic. Non-CR dietary interventions against aging are known, but so far none are as effective. Below are the summaries of aging intervention agents and variations on CR.

Dietary Interventions to Extend Life Span and Health Span Based on Calorie Restriction

Antioxidants:

The free-radical theory of aging theorizes that reactive oxygen species (ROS) damage molecules and cell structures which in turn causes aging. Antioxidants are proposed to “neutralize” the oxidation species thus preventing damage. Despite the popularity of this theory, studies have not provided evidence that food based antioxidants prolong life or prevent aging, and some studies have even shown toxic effect of antioxidant supplementation. Given this information, antioxidant supplementation in humans is no longer recommended.

Glucose and Insulin Homeostasis:

Increased glucose intolerance and insulin resistance are often seen with aging. Because Calorie Restriction is known to improve or even reverse hyperglycemia and insulin resistance, CR mimetics targets for these results are being studied.

2-Deoxy-D-glucose (2DG):

2DG is a glucose analogue that inhibits glycolysis, and is being investigated as a CR mimetic due to its effects on energy metabolism. Preliminary findings have shown it’s ability to inhibit tumor growth, and increase stress resistance to neurotoxins and shock; however, recent finding have shown negative long term consequences and thus may only be useful in short term applications.

Biguanides:

The biguanide derivatives buformin, metformin, and phenformin are known to improve glucose homeostasis, and were effective treatment against diabetes mellitus and additionally showed promising tumor inhibition. Due to unfavorable side effects, metformin is the only compound still in use and is commonly used as treatment for type 2 diabetes. Metformin improves insulin sensitivity, and is known to reduce adiposity and mortality rates in diabetic people. However, it’s ability to actually extend life span in *healthy* rodents, primates, and humans is still unknown.

Advanced Glycation End Products:

AGEs are the product of excess glucose combining with proteins an can happen in vivo or during the cooking of food (although food items do have a smaller concentration of AGES even prior to cooking). These products then attract other proteins, forming web-like networks which in turn stiffen joints, block arteries, and could even cloud the eye lens thus leading to cataracts. Significant concentrations of AGEs are found in diabetic individuals as well as aging tissues. Componds that could prevent or reverse accumulation of such products may not only be an effect treatment for diabetes but also aging given the similarity of aging with diabetic complications. One study reported an increase in mean and max life span of rodents whose dietary intake of AGEs was reduced, and another reported that mice fed a high AGE CR diet did not receive the life extending benefits normally seen with CR.

Aminoguanidine:

Also known as pimagedine, aminoguanidine is no only the most studied AGE inhibitor, but also functions as a general antioxidant and inhibitor of diamine oxidase and nitric synthase. Even though this molecule was found to prevent arterial stiffening and cardiac hypertrophy in rats, it’s has not been proven to actually extend life span. Also in diabetic trials, despite it’s beneficial effects against retinopathy and serum lipids, negative side effects were reported.

Pyridoxamine (P5P):

Not only does this molecule inhibit AGEs, it also is known to prevent advanced lipoxidation reactions. This member of the vitamin B6 family has also been found to reduce the cross-linking associated with cataracts in mice, but further studies investigating the extent of its capabilities are required.

mTOR Signaling Pathway:

The mTOR pathway acts as a nutrient sensing pathway, and in mammals is now known to be a central regulator of energy homeostasis and cellular metabolism. The inhibition of this pathway in worms, flies, and yeasts is known to extend life span. Molecules that inhibit the mTOR pathway are becoming major candidates for CR mimetics as Calorie Restriction is known to inhibit mTOR signaling in multiple species.

mammalian target of rapamycin (mTOR)

Rapamycin:

This is a drug original used for it’s immunosuppressant actions, but it now known to selectively inhibit mTOR. Additional benefits include antibiotic, anti-tumor activity. Whether rapamycin could be used for long term human aging intervention is still unknown.

Sirtuin Activators:

On way Calorie Restriction is thought to extend life is though increasing the activity of sirtuins.  Specifically, the activation of human Sirt1 is thought to not only be able to increase life span, but also increase health span. Resveratrol was originally thought to be a Sirt1 activator, but recent studies have contradicted these findings.  Finding molecules that activate Sirt1 are of great interests for CR mimetics researchers.

Resveratrol:

Originally thought to be a legitimate CR mimetic after its ability to mimic CR in several short-lived species, this molecule that is found in red wine is now known not to carry it’s life extending properties to mice. However, it is able to mimic some health benefits of CR including glucose sensitivity, physical endurance, and gene transcription properties. In addition, resveratrol may be able to increase quality of life in overweight and elderly individuals.

Protein Restriction:

Several (but not all) studies have confirmed life extending benefits of low protein diets in rodents. Additional studies show evidence for the restriction of specific amino acids as a way to benefit health and longevity rather than protein restriction in general. Given that vegetarians have a reduced risk for for several chronic diseases of aging, more studies in this area are warranted.

Intermittent Fasting:

A similar but not equal dietary approach for human adaptation to a CR-like diet is intermittent fasting. By alternating ad lib and restricted eating periods, several benefits seen with CR may be attainable with this method. This is thought to be an alternative, easier long term solution for those who find practicing CR too difficult.

Conclusion:

Remember that CR is the only known way to extend life span and health span across species, but other methods mimicking some or -one day- all of the effects of CR may be able to pass on these benefits without restricting calories. Currently, there are many known ways to mimic some of the health span extending properties which still provide tangible benefits to humans. Both quality and quantity of life are important factors when considering both Calorie Restriction and CR mimetics.