Can Starvation Make You Younger? Calorie restriction mimetics and the fight against aging

Our society today is obsessed with staying young. From Botox to anti-aging cream to plastic surgery, Americans are willing to try anything to fight the aging process. While most “miracle” procedures only work on a cosmetic level, the new wave of research aims to decelerate the actual biological mechanisms associated with aging.

The latest trend is calorie restriction (CR) mimetics, which make your body think that you are curbing food intake, even when you are eating normally. CR is known to increase the lifespan of certain animals, such as rodents and monkeys [1]. However, since CR would likely entail cutting back 30 percent from a nutritious diet, it would be an impractical strategy for humans [2]. Researchers are therefore exploring methods of mimicking CR so that we can reap the restorative benefits without cutting caloric intake.

Until recently, scientists could only speculate about why CR increased lifespan. It was thought that early humans went into protective mode in the presence of scarcity. By activating the body’s defense system, emergency situations could help slow the normal wear-and-tear associated with aging. The body’s energy would be focused more and more on repairing and avoiding damage [3].

Mechanistically, the so-called “mitohormesis” hypothesis posits that an increase in dangerous reactive oxygen species—the ones that antioxidants protect us against— would actually increase the body’s defenses against them. The net result would be increased oxidative stress resistance and reduced damage from reactive oxygen species [3]. By creating the illusion of crisis, CR mimetics could increase the body’s defenses against many of the damage associated with aging.

Free radicals (yellow) can attack DNA and produce mutations. Courtesy of www.nia.nih.gov

The mitohormesis hypothesis was virtually unsubstantiated before October 2007. However, a recent study by Tim Schulz at the University of Jena in Germany has finally provided the concrete evidence that scientists have been searching for. Schulz and his team mimicked CR by artificially impairing the breakdown of glucose in worms. Restricting glucose metabolism then activated an enzyme, AMP-dependent kinase (AMPK), known to respond to the decreasing energy (ATP) levels present in CR. AMPK subsequently induced mitochondrial respiration, which released dangerous reactive oxygen species as a by-product. Schulz found that the worms’ defenses were indeed elevated, meaning that their bodies became more resistant to damage in times of crisis [4].

While CR is now better understood from an evolutionary standpoint, researchers have significant work to do before releasing any type of “anti-aging pill,” which would mimic the effects of CR without actually requiring one to restrict caloric intake. It remains unknown, for example, whether CR will benefit humans as much as it benefits other species. Donald Ingram of the National Institute of Aging notes that CR may have more drastic effects in short-lived species, which would suffer greatly from a major loss of food supply. Since humans have developed strategies to deal with food shortage, mechanisms that defend against starvation may not be as responsive [3]. It has been estimated that mimicking CR in humans would be ten times less effective than in rodents [3].

Finally, scientists must develop CR mimetics that work in humans, not just worms. While early research shows promise, an anti-aging pill will not be widely available until extensive lifespan analysis and toxicity studies are performed [4]. Scientists are exploring whether CR would reduce fertility in the same way that anorexia makes it difficult to conceive a child [5]. The ideal CR mimetics would be inexpensive, cause little or no side effects, and be available over the counter [5]. Until anti-aging pills hit the market, though, consumers will only be able to fight aging on a cosmetic level. It looks like the era of Botox and plastic surgery is not over quite yet.

Sources:
[1] Phelan, J.P. “Why dietary restriction substantially increases longevity in animal models but won’t in humans” Ageing Research Review 4 (2005): 339-350.
[2] Lane, Mark, et. al. “The Serious Search for an Anti-Aging Pill.” Scientific American 287.2 (2002).
[3] Ingram, Donald, et. al. “Calorie Restriction Mimetics: An emerging research field.” Aging Cell 5 (2006): 97-108.
[4] Schulz, Tim, et. al. “Glucose restriction extends Caenorhabditis elegans life span by inducing mitochondrial respiration and increasing oxidative stress.” Cell Metabolism 6 (October, 2007): 280-293.
[5] Ristow, Michael. Email Interview. 16 Feb. 2008.