Thus far, caloric restriction may be the most robust and convincing anti-aging intervention known so far, at least as observed in multiple animal models. Over the past fifty years, the effects of caloric restriction on extending lifespan, delaying aging and the onset of age-related diseases has been very well documented. In agreement with this concept, there is a plethora of scientific evidence showing that caloric restriction increases both the mean and maximal lifespan (20-40% lifespan extension depending on the animal species studied) in many animal models including worms, flies, primates and rodents (Mattson et al., 2005; Anderson et al., 2009). The data supporting the anti-aging benefits of caloric restriction in humans is scarce and somewhat cumbersome at this point. However, a recent study showed that a select group of overweight individuals that volunteered to undergo a rigorous caloric restriction diet, as achieved by a low fat, caloric restricted diet combined with moderate aerobic exercise led to increased mitochondrial mass in muscle, weight loss, and efficient aerobic respiration (read more on the Caloric Restriction Society and at ScienceDaily). This study may suggest that caloric restriction may improve health and lower the risk of developing age-related diseases. An explanation to the beneficial effects of caloric restriction on lifespan is partly attributed to enhanced sensitivity to insulin, a decrease in the levels of glucose and a decrease in insulin and insulin growth factor-1 (IGF-1) mediated signaling (Barbieri et al., 2003 ; Ansimove et al., 2003; Richardson et al., 2004; Holzenberger et al., 2004; Bartke et al., 2005). Conversely, it is well documented that chronic insulin and IGF-1 signaling contributes to aging in mammalian cells and a decrease in maximal and mean lifespan which supports the notion that inhibiting insulin/IGF-1 signaling should contribute to weight loss and increased longevity (Holzenberger et al.,
2004). The signaling pathway(s) that participate in the beneficial effects of caloric restriction is a hot topic in aging research. Caloric restriction leads to a shut-down of the mammalian target of rapamycin (mTOR) signaling pathway, a master regulator of cellular proliferation, protein synthesis, and transcription. The mTOR pathway also regulates the insulin and the IGF-1/IGF-2 pathways. Thus, by shutting down this ubiquitous and evolutionarily conserved pathway, caloric restriction leads to a global shut-down of protein synthesis, a decrease in glycolysis (glucose utilization), a compensatory increase in the levels of mitochondrial enzymes and antioxidants which lead to an enhanced oxidative (aerobic) cellular respiration.
However, undergoing such a strict caloric restriction regime may be the equivalent of skipping dinners and eating small portion meals for breakfast and lunch on a daily basis. Realistically, humans undergoing this military-like discipline is only reserved to a select group of highly motivated individuals given that humans are recalcitrant and non-compliant to undergo such rigorous diets. This begs the question of whether extreme caloric restriction is necessary to achieve the long-term anti-aging benefits or whether there are other feasible alternatives? Surprisingly, there is an alternative to caloric restriction without the uncomfortable and inconvenient side-effects of dietary restriction (possible malnutrition and an uneasy feeling of constant hunger). Scientists have shown that curtailing methionine, an essential amino acid, from a normal diet is sufficient to achieve the long-term beneficial effects of caloric restriction in rats (Richie et al., 1994; Oreintreich et al., 1993;Miller et al., 2005). Indeed, dietary methionine restriction is sufficient to increase mean and maximal lifespan in rats even when rats were allowed to eat as much (ad libidum) as they wanted (Miller et al., 2005). Moreover, dietary methionine restriction paralleled and recapitulated the beneficial effects of caloric restriction by robustly decreasing the serum levels of insulin, glucose and thyroid hormone and IGF-1 (Miller et al., 2005). Other benefits of methionine restriction in rodents included a significant decrease in body mass (about a 30% decrease in total body mass observed in rodents), preserving insulin sensitivity in old rats and a drastic reduction in adiposity (body fat) (Malloy et al., 2006).
One of the most popular theories of aging is that an increase in oxidative stress (due to an exposure to free radicals), in conjunction with a low and/or deficient maintenance/repair systems in the cell contributes to aging. In a similar manner to caloric restriction, methionine restriction leads to an increase in antioxidant defenses by increasing the levels of glutathione levels, an antioxidant, and leads to a more efficient mitochondrial/aerobic respiration (Pamplona et al., 2006; Gredilla et al., 2001) . It is worth noting that methionine is an essential amino acid and an intermediate precursor of cysteine, L-carnitine, taurine and of phospholipids such as phosphatidylcholine and lecithin. How is it possible to survive the lack of this essential amino acid is not known; however, some scientific data in animal models suggests that some kind of compensatory mechanism is upregulated following prolonged methionine diet restriction. Unexpectedly, curtailing the amount of dietary methionine leads to decreased levels of liver glutathione but an increase in the levels of gluthathione is observed in other tissues via a compensatory process (Richie et al., 1994). Moreover, it has been demonstrated that rats subjected to a long-term dietary restriction of methionine exhibit less oxidation of proteins and DNA damage (Lopez-Torres et al., 2002) .
In light of these observations, it is important to note that one needs to strike a balance in formulating methionine restricted or chemically defined diets since a diet with extreme low levels of methionine can also be detrimental. For instance, although dietary restriction in flies, achieved by restricting the amount of yeast flies ingest on a daily basis, leads to an increase in mean and maximal lifespan, an extreme reduction of methionine has the opposite effect. (decreased maximal lifespan).
Are these beneficial effects only specific for the dietary restriction of one amino acid or does limiting other amino acids achieve similar beneficial effects? It is not clear at this point but modest increases in mean and maximal lifespan extension has been observed in flies and in rodents that have diets lacking other amino acids such as glutamine and asparagine. However, another study showed that although limiting the amount of tryptophan in the diet increases the mean and maximal lifespan, this same study revealed that tryptophan restriction also leads to increased mortality early in life in rodents (De Marte et al., 1986).
With all the scientific data showing the benefits of methionine restriction on longevity in different animal models, is it conceivable to apply this diet in humans?
One major disadvantage of caloric restriction is that a high level of non-compliance and a lack of discipline is observed in humans that undergo such a rigorous ordeal. In addition, long-term caloric restriction leads to ravenous hunger and binge-eating behavior. On the other hand, an advantage of methionine restricted diets is that studies have shown that in rats fed an ad libitum diets low in methionine achieve significant weight loss and achieve a leaner muscle content suggesting that restricting the quality but not the amount of food may be a key to achieving the anti-aging effects of methionine restriction in humans (Miller et al., 2005).
More importantly, vegan diets are relatively poor sources of methionine. First of all, the methionine content of plant proteins tend to be lower than those of animal proteins. For instance, wheat and potatoes have about four times less methionine than eggs and chicken respectively (Morita et al., 1997). Secondly, plants have a high source of glycine, an essential amino acid that serves as functional antagonist to methionine. As previously mentioned in this article, methionine is a primary precursor to other amino acids and for synthesis of taurine and L-carnitine and human subjects undergoing methionine restriction may have to supplement these nutrients through other sources.
It is unrealistic that human beings will embrace a vegan diet and expect to give up their favorite succulent dishes at the expense of achieving a healthy and extended lifespan. Ultimately, the pharmaceutical industry has a vested interest in finding novel anti-aging therapies that may mimic the effects of caloric restriction by synthesizing the ideal “magic” pill. This “magic” pill may come in the form of the following possibilities:
1) It may be possible to generate a synthetic analog of methionine that may act as a dominant negative inhibitor in order to compete with endogenous methionine.
2) The powerful drug rapamycin, a strong inhibitor of the mTOR pathway, has been shown to increase longevity and confer neuroprotection in rodent models. Thus an FDA approved formulation of this drug could be available as an anti-aging intervention (click on this link to obtain the recently published newsletter on rapamycin). However, rapamycin is a strong immunosuppressant and prolonged administration in humans may increase the risk of developing infections. Thus administering low doses of a re-formulated version of rapamycin with immune boosters may be a viable strategy for extending lifespan in humans.
3) Resveratrol mimics the effects of caloric restriction and many of the signaling pathways that mediate the beneficial effects of this wonder drug are beginning to be unveiled. However, ingesting high amounts of this compound may induce renal toxicity.
In the end, there is a clear need to perform additional studies to analyze and determine whether the beneficial effects of methionine restriction not only parallels and recapitulates the beneficial effects of caloric restriction but whether converging beneficial mechanisms exists between these two anti-aging intervention therapies.
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For more information access the links below:
1. News release on the benefits of caloric restriction on cardiac health: www.medicalnewstoday.com/articles/7586.phphttp://www.medicalnewstoday.com/articles/7586.php
2. Effects of rapamycin on delaying age: news.bbc.co.uk/2/hi/health/8139816.stm
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