Thursday, July 17, 2014

Life extension with anti-aging drugs

CR Drugs

There are a number drugs intended to slow the aging process currently being researched. One type of research is related to the observed effects a calorie restriction diet, which has been shown to extend lifespan in some animals. Based on that research, there have been attempts to develop drugs that will have the same effect on the aging process as a caloric restriction diet, which are known as Caloric restriction mimetic drugs. Drugs that have been studied for possible longevity effects on laboratory animals because of a possible CR-mimic effect include Rapamycin, Metformin, and Resveratrol.

Two drugs that may have potential benefits of combating age-related maladies are Resveratrol and Rapamycin. These drugs are considered to be the forefront drugs in anti-aging research. Before these drugs had been tested, the best-characterized anti-aging therapy was, and still is, calorie restriction or CR. Calorie restriction has been proven to extend the life of mice, yeast, and rhesus monkeys significantly. Long-term human trials of CR are now being done. It is the hope of the anti-aging researchers that Resveratrol and Rapamycin may act as CR mimetics to increase the life span of humans.


Resveratrol was first thought to be an activator of sirtuins, a family of deacetylases, that would promote anti aging effects without having to restrict caloric intake. However, recent replication studies have failed to show that Resveratrol increases the life span in yeast or mice and that Resveratrol may not activate sirtuins that are biologically beneficial to age reduction. Another study was done showing that Resveratrol activates or inhibits fifteen or more different enzymes. Of those enzymes, one stands out with potential for reducing age-related disease. AMP-activated protein kinase (AMPK) has shown to increase life span of nematodes and prevent obesity in mice. Although Resveratrol has not been proven to extend the life-span of mammals at the current doses tested, Resveratrol could be used to access some of the same molecular pathways that CR does. Several examples would include diet induced obesity, some cancers, cardiovascular disease, and neurodegenerative diseases.


While Resveratrol has not been proven to increase life span, Rapamycin has shown much more promise. Rapamycin is shown to increase longevity by inhibiting the target of rapamycin kinase (TOR) the same way CR does. Study systems including yeast, nematodes, flies, and mammals, have shown that reduction of TOR signaling will result in an increased life span. Additionally, Rapamycin has similar effects of Resveratrol in protecting against several cancers, cardiovascular, and neurodegenerative diseases. Rapamycin also has been shown to act as an immunosuppressant, however more testing is needed to show if the life extending dose comes at the cost of an impaired immune system.

Resveratrol and Rapamycin have both shown protection against cancers, cardiovascular disease, and neurodegenerative diseases in multiple study systems. Rapamycin looks to have more potential in life span extension than Resveratrol, but my come at a price of immune system impairment. Clinical trials are now being performed to see if Rapamycin or Resveratrol will have anti-aging effects in humans.
Other attempts to create anti-aging drugs have taken different research paths. One notable direction of research has been research into the possibility of using the enzyme telomerase in order to counter the process of telomere shortening. However, there are potential dangers in this, since some research has also linked telomerase to cancer and to tumor growth and formation.

Antioxidants and Others

One of the earliest classes of substances, which were put forward seriously as drugs against aging, were the antioxidants, while Vitamin E and BHT being the most well-known. Beginning about 1956, Dr. Denham Harman, of the University of Nebraska, put forward the hypothesis that at least some of the degenerations of aging arose through the same processes as those of radiation damage: that is, highly reactive chemicals (in the case of aging, created by our normal metabolism rather than radiation). A corollary of this hypothesis would be that drugs which protected against radiation would also protect against aging; antioxidants are a large class of such substances, well known to protect against radiation damage, and therefore against aging as well.

Since 1956 Harman himself has written extensively on his theory, and can produce some evidence for it. For instance, unsaturated fats should cause more chemical reactions of the kind antioxidants protect against (free radical reactions) and therefore animals fed high levels of unsaturated fats should show a higher mortality rate, which is indeed the case. One can also construct an argument that lipofuscin, a pigment that accumulates in animal tissues as they age, has formed because of these same free radical reactions.

As longevists we are interested in such drugs for their use on man. What kinds of evidence are there for effectiveness of antioxidants in aging? What needs to be done to find antioxidants suitable for use in man?

Harman's first experiments tested several drugs for effects on the lifespan of AKR and C3H mice. He obtained a lifespan increase in his mice of about 20 percent. The antioxidant BHT, and a radioprotective drug MEA, were tested. A second series of experiments, published in 1968, studied MEA, BHT, and several other drugs known to inhibit free radical reactions of the kind that, by Harman's theories, should play a role in aging. In some experiments, with some drugs and strains of mice, Harman could obtain an increase as high as 30 to 50 percent. There are numerous reports thereafter confirming lifespan increase in mice fed antioxidants.

Vitamin E

At present many theoretical arguments suggest that Vitamin E may have at least some effect on aging; there are even experiments with cell cultures and invertebrates which support these theories. Gershon has shown in 1972 that Vitamin E will increase both mean and maximum lifespan of nematodes. However only scanty evidence exists that Vitamin E will have similar effects on mammals. Two experiments are suggestive. McCoy in 1943, as part of work on lifespan increases in rats, fed male and female rats a diet enriched with wheat germ and found an increase of 20 percent over his controls. Unfortunately this result is clouded by the probability that his control diet was deficient in Vitamin E, which is an essential vitamin. A second experiment reported by Harman studied the effect of Vitamin E on the lifespan of LAF mice. The increase produced was small and not statistically significant; at 20 months 8.8 percent of control mice survived, compared to 13 percent of the Vitamin E mice. Lifespan increases in the same experiment with BHT were far greater, with better than 60 percent survival of treated mice at the same time.

At one time, some scientists raised doubts about high doses of Vitamin E because they increased blood cholesterol levels in rats, and so might cause increased heart disease. More recently, work reported in the NEW ENGLAND JOURNAL OF MEDCINE strongly suggests that Vitamin E at doses of 100 IU or above will protect humans against heart and artery disease. Unfortunately it does not discuss lifespans as such, nor does it discuss doses higher than about 400 IU/day.

On the other hand, the evidence for safety of Vitamin E is very strong. Vitamin E has already been used in human beings for several clinical conditions. Boyd reported treating patients with Vitamin E at 400 mg/day for 3 months with no ill effects; Haeger reported similar treatment at 300 mg/day for more than 2 years. Hoffer reported treatments of more than 800 mg/day with no measurable ill effects.

Since suppliers of Vitamin E often measure it in terms of I.U's (International Units) readers may wish to know that 100 I.U. Vitamin E equals about 2 mg.


A third antioxidant put forward for use against aging is ethoxyquin. Evidence for its efffectiveness comes from two experiments, the 1968 experiment by Harman, in which 74 percent of treated LAF mice survived for 20 months on the semisynthetic diet, as compared to 8.8 percent of controls, and the experiment of Comfort with C3H mice. With ethoxyquin, increased lifespan of treated animals compared to controls is quite clear.

Unfortunately ethoxyquin has severe toxicity problems. The earliest published study of toxicity of ethoxyquin was done by RH Wilson and F de Eds. They studied the chronic toxicity of ethoxyquin in albino rats at concentrations from 0.4 percent by weight of diet down to 0.1 percent and 0.0 percent. Although they found no difference in lifespans of treated and untreated rats, they found also clear injury to kidneys of animals fed the higher concentrations (0.2 and 0.4 percent) ethoxyquin. Kidneys showed irregular areas of fibrosis and signs of chronic kidney disease; liver cells showed changes in structure increasing in proportion to the amount of ethoxyquin received, and thyroid glands also showed signs of damage. Other studies of toxicity have basically confirmed this one.

Moreover the experiments showing increased lifespan of treated mice do not contradict these signs of toxicity. The study by Wilson and de Eds looked at toxicity of ethoxyquin when given for long periods, just the kind of treatment needed for aging. Harman's mice were fed semi synthetic diet, which decreases survival; Comfort's experiment studied ethoxyquin on C3H mice, known to have a short lifespan. We therefore cannot argue that lifespan increases in LAF or C3H mice will in any way prove that ethoxyquin might not be toxic to human beings when taken long-term. Ethoxyquin is unsuitable as a drug for prolonging our lives and could actually be dangerous on long-term administration.


Of all antioxidants studied so far, BHT perhaps has the best record. For its effectiveness we have several experiments of Harman, which show that at a minimum BHT has a protective effect against several deleterious environments. Toxicological studies of BHT treated animals suggest that its record is fairly good, though not at all perfect. One series of experiments studied the toxicity of BHT at concentrations of 0.1 percent by weight of diet and found no effect on any of the parameters studied.

However in 1959 Brown called these experiments into question by observing that they had all been carried out using diets low in fats, unlike the normal human diet (which has at least 20 percent fat content). When they repeated the experiment on high fat diets they found some significant signs of toxicity, of which the most serious is that combination of high fat diets with BHT caused a marked rise in blood cholesterol levels in treated animals compared to controls. Since high blood cholesterol may correlate with heart disease we would have to take this seriously. This may mean very little; recall the similar questions raised about Vitamin E. However, even though many doctors do argue vehemently that cholesterol levels do not relate to heart disease in any simple way, these results should still make us cautious. At present, therefore, we have at least reasonable indications that BHT will be safe on low fat diets; however on high fat diets questions exist about its safety in long-term use.


As a drug for human use, NDHGA has some evidence of effectiveness and a long tradition of actual use as a food antioxidant. Effects on longevity appear good. Out of 12 controls at 796 days of age, 2 rats survived, while 8 rats out of 12 survived among the treated animals. Unfortunately the small number of rats studied makes this result suggestive but in no way conclusive. Dosage was notably less than that of mice in Harman's experiment: 20 mg/kg of food as against 1 gm/kg. Despite this low dosage, apparent increase in lifespan was relatively high. As mentioned, NDGHA has a long tradition of use as a
natural food antioxidant. It is made from an evergreen desert shrub, Larrea divarticata.

At concentrations of more than 0.5 percent by weight of diet, rats will develop inflammations in their caecum (the end of their intestines) and show inhibited growth. A different experiment has shown much worse results at these levels; in one 2-year test on rats, the rats developed massive hemorrhages in the caecum. Studies on mice at similar concentrations showed no deleterious changes in weight or tissues. At present there is little information on metabolism of NDHGA, although some studies have been made of its biochemistry in vitro. We can compare these results on toxicity with the dosage of the drug which may have an effect on longevity. Dose for longevity was about 0.02 percent; the lowest level causing signs of toxicity was

5 percent, about 20 times the therapeutic dose. NDHGA checks out as very probably safe, but at the same time we would like more work on its effectiveness, since 12 animals is a only small test sample.
NDHGA has also received surprisingly little interest from longevists generally. The experiment in which Buu-Hoi and Ratsimamanga showed that it increased lifespan was published in French in the French scientific literature. This may have delayed its notice by English- speaking scientists.

Vitamin C

One group of researchers has published a study showing a lifespan increase in mice with Vitamin C. They found an increase in lifespan by 8.6% (and if your computations count the early death of two control mice then the increase is 20% --- but the control mice failed to live as long as in other experiments done by this team).

It's reasonable to ask what this experiment may mean. For our use it had two problems: first, the doses scaled up by body weight could come to as high 100 grams per day; at best, 14 grams a day. Second, mice normally make Vitamin C themselves, although these experimenters cite papers suggesting that their ability to do so goes down as they age. However, this still remains a major metabolic difference between humans and mice. Not only that, but the only lifespan experiment done on animals that DON'T make Vitamin C showed a lifespan DECREASE. Vitamin C may prove to be one of the few cases in which our metabolism, and that of our test animals, differs so much that we cannot easily extend a result true for mice to one true for human beings.

Latest Development

Led by Medical School professor David Sinclair and published in 2013, the study identified compounds that may help extend the human life span and prevent debilitating diseases associated with aging like cancer, heart disease, and Alzheimer’s.

One of those preventative compounds, resveratrol, we mentioned earlier, has been directly linked with the prevention of age-related diseases.

Ana da Silva Gomes, a Medical School research fellow who co-authored the study, called the revelation “extremely important for drug development and the treatment of age-related diseases.”

“By fighting one disease we are actually preventing many other age-related diseases,” Gomes said.
In addition to the discovery regarding resveratrol, the study also identified specific synthetic compounds that accelerate the production of SIRT1, an enzyme that has proven beneficial for the treatment and prevention of age-related diseases.

Scientists have already begun to develop synthetic compounds mimicking resveratrol’s function that are “a hundred or a thousand times more potent” than naturally occurring compounds like resveratrol, Hubbard said.

Drugs containing such compounds, if successfully invented, will be a “real breakthrough” for in the process of preventing diseases related to aging, said Hubbard. Currently, such drugs are the subject of numerous clinical trials, although researchers are unsure how long it will be until they become readily available on the market.

Researchers found that obese mice fed resveratrol supplements had dramatically longer lives, because the resveratrol essentially counteracted the effects of the mice’s high-calorie diet—their arteries were cleaner, their hearts were stronger, and they demonstrated improved brain function.

The study identified specific compounds that accelerate the production of the enzyme SIRT1, which has been proven beneficial for the treatment and prevention of age-related diseases. These compounds can be used to create an “anti-aging” drug.

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