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Secrets of Caloric Restriction

Nicotinamide Improves Health and May Extend Life

Applying the Secrets of Caloric Restriction
By David Jay Brown
Many life-extension seekers have viewed the dramatic results from longevity studies involving caloric restriction as one of life’s cruelest jokes. Calorically restricted animals (that receive all their proper nutrients) develop fewer diseases in general and are known to live significantly longer than animals that are allowed to eat as much as they like. Numerous animal studies - dating all the way back to the 1920s - have shown this to be the case with worms, flies, mice, and monkeys.1

While living longer by adhering to a partial-starvation diet may not seem particularly appealing to most people, the results of these studies have been so impressive that anyone seriously interested in life extension has to be more than a little intrigued.

Caloric restriction doesn’t just increase average lifespan in animals; it also increases maximum lifespan - dramatically so. This means that animals on calorically restricted diets live significantly longer than the longest-lived members of their own species that are not calorically restricted. Many things increase average lifespan in animals - a healthy diet, nutritional supplements, exercise, good genes, etc. - however, increasing maximum lifespan is a whole new ball game. The maximum lifespan for a human being is somewhere between 110 and 120 years. The longest-lived human ever documented was a French woman who died in 1997 at 122 years. The rodents in the calorie-restriction studies lived to be the human equivalent of 140 to 160 years!3

Rhesus monkeys used in the NIA caloric-restriction study had much lower incidence of cancer and other diseases involving cell proliferation.

The primate studies involving caloric restriction suggest that these results probably apply to humans as well, and exciting new research suggests that the life-extending benefits of caloric restriction may be available without having to struggle with a near-starvation diet. New evidence from a recent study at the National Institute on Aging in Bethesda, Maryland sheds some light on the mechanism involved in caloric restriction and suggests thatnicotinamide supplements (with the proper cofactors) may mimic the benefits of caloric restriction.

Recently, Mark Lane, Ph.D., Angela Black, Ph.D., and colleagues at NIA revealed that calorically restricted monkeys develop fewer proliferative diseases (such as cancer and endometriosis) than controls.4 The NIA study, which followed 120 rhesus monkeys for more than a decade, found that monkeys who consumed 30% fewer calories than controls had fewer chronic diseases in general, but, more specifically, they had a much lower incidence of diseases involving cell proliferation. “I think the main implication for potential human application of this would be that it’s going to reduce the incidence of age-related diseases, in particular cancer. Cancerous tumors in the animals were noticeably reduced,” said Dr. Lane. This finding is not unique to the NIA study. It has been generally accepted that caloric restriction - the practice of undernutrition without malnutrition - doesn’t just slow the progress of cardiovascular disease; it slows cancer too.

Although there have been hundreds of studies on caloric restriction, the exact biological mechanism responsible for the increase in longevity and the reduction of proliferative diseases remains a mystery. However, a number of important clues are now available. “Caloric restriction reduces insulin, insulin-like growth factor-1 (IGF-1) [a measure of growth hormone release], and other growth factors in the body. That’s been shown many times. So that would have obvious effects on proliferative or runaway-growth kinds of diseases. That may be the proximate mechanism here, but we really don’t know that for sure,” said Lane. However, most longevity researchers agree that caloric restriction probably extends animal life because fewer calories means less energy production, less wear and tear, and less oxidative damage.5

MIT researcher Leonard Guarente, Ph.D., offers an alternative explanation.6 His gene-silencing theory proposes that caloric restriction reduces the overall metabolism of an essential cofactor called nicotinamide adenine dinucleotide, or NAD for short. NAD is normally shunted into the breakdown of glucose in cellular energy production. But when increased in availability through caloric restriction, there is an abundance of NAD beyond that needed for cellular energy production. This extra NAD is available to act as a catalyst for an enzymatic protein called silent information regulator no. 2 (Sir2p). NAD increases the effectiveness of Sir2p, and the result disables the transmission of certain genetic messages that ultimately lead to cell death.

The mechanism involves a process called deacetylation, in which acetyl groups are removed from a substance called chromatin, which normally fits around the chromosomes like a loose sleeve. However, once deacetylated, the chromatin tightens itself snugly around the DNA. This blocks the DNA from broadcasting genetic instructions that would ultimately have devastating consequences for the cell and are thought to be responsible for a cellular aging process. When the chromatin tightens itself snugly around the DNA, the instructions that would eventually lead to the cell’s death are squelched. When NAD is abundant, the effectiveness of Sir2p is increased, and cell life is preserved. Thus, NAD helps prevent the expression of certain genes responsible for a cellular aging process involving damage to DNA molecules.

When NAD is abundant, Sir2p prevents the release of circular DNA fragments that proliferate inside cells during the aging process. These replicating rings of genetic “noise” accumulate to the point where they eventually strangle the cell from within. However, when NAD and Sir2p join forces, the possibility of this happening is significantly reduced because of gene silencing. If caloric restriction helps increase longevity by decreasing the incidence of cancer, runaway cell proliferation - the mechanism of cancer - is likely to be fueled by more, rather than fewer, calories.

“A link between aging and cancer is suggested by the delay of cancers in calorically restricted mice,” write Drs. Leonard Guarente and Cynthia Kenyon (also an aging-gene researcher, but at University of California, San Francisco), “and by the striking correlation between physiological age and the likelihood of cancer in animals with very different lifespans. This suggests that any treatment that slows the aging process, whether it acts directly on hormone signaling, gene silencing, or oxidative stress, may have the potential to delay cancer and possibly other diseases of aging.7

Understanding the mechanism of slowing the aging process leads one to predict that caloric restriction might be most effective in slowing down the incidence of runaway cell growth and proliferative disease, and this is exactly what Lane and Black found in their most recent study.

These findings have stimulated an aggressive search for drugs that mimic the process of caloric deprivation. Lane is currently studying a synthetic molecule similar to the sugar glucose. He has demonstrated that cells take up this glucose analog as if it were glucose, but they cannot metabolize it to obtain energy, as they do from glucose.

In rodent studies, administering this synthetic molecule produces some of the same responses as caloric restriction, such as reducing body temperature and lowering the amount of insulin in the blood.4 Lane and his colleagues at NIA are now testing whether these treatments will extend the lifespans of rodents.

“By disrupting the normal metabolic pathway for the metabolism of glucose with a glucose analog,” Lane explained, “we were able to reproduce many of the biological effects of [caloric] restriction - such as a reduction in insulin levels, a reduction in body temperature, and even a slight reduction in body weight. Those animals did not exhibit any significant reduction in food intake, so they were essentially eating as much as they wanted of a diet with this glucose analog in it. . . . We think that caloric restriction has many of its effects by acting as a metabolic stressor on the body. You’re basically reducing metabolic output of the cells by inhibiting glycolysis, and this is what this glucose analog also does.”

It’s unfortunate that the glucose analog that Lane is studying has significant drawbacks; at high doses it’s toxic throughout the body and can kill brain cells. But there may be less toxic alternatives to mimicking the effects of caloric restriction. “There are other compounds that inhibit glycolysis as well that may not have these toxic effects,” said Lane. “Right now we’re focusing on really trying to study the mechanism using this glucose analog because it’s well characterized and well studied in other model systems. Once we get a better handle on its workings, and if indeed it is mimetic of caloric restriction, then we’re going to move into developing other compounds. The end point of this research would be to develop other compounds that are

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