Got Life?

Kyle M. Loh April 10, 2010 0

“Death, a metabolic affliction causing total shutdown of all life functions, has long been considered humanity’s number one health concern. Responsible for 100 percent of all recorded fatalities worldwide, the condition has no cure.” – The Onion (January 22 1997)

While great scientific, political, and social efforts have gone into ameliorating causes of death for the human race – such as crime, war, starvation, infection, or cancer – what we often forget is that the leading cause of death of humans is aging. Despite the proliferating number of treatments to treat diseases such as diabetes, neurological disorders, and hematological disorders, there has been relatively little research on the basis of aging and how to combat it. This becomes even more ironic when one considers that the above diseases are actually called “diseases of aging”, and are believed to be brought on by the aging process – this becomes logical when we consider the increased incidence of various diseases in older humans.

There is great interest in the molecules and processes that facilitate aging. It is hoped that if we can inhibit these identified aging pathways with specific drugs, that we could extend the lifespan of human beings by feeding them with such anti-aging drugs. Here, we review recent advances in the campaign of extending lifespan with drugs; our search for the pharmacological Fountain of Youth.

There has been a long-running interesting observation in scientists that there appears to be a relationship between aging and metabolism. For example, deletion of metabolism genes (such as those involved in the insulin or growth hormone pathways) doubles the lifespan of worms (C. elegans), increases the lifespan of flies by 80% (D. melanogaster), and leads to a slight increase in the lifespan of mice. This led to the popular hypothesis that there might be a “cost of living”.

In order to live, we need to burn ATP and other types of energy in order to power our organs, produce heat, and to move our muscles. However, it is known that this metabolism/cellular respiration, while necessary for life, produces harmful byproducts (such as reactive oxygen species; ROS) that are also harmful for cells. Therefore, it was posited that metabolism was a double-edged sword—essential for the immediate maintenance of life, but leading to deleterious effects (such as DNA damage) in the long term, and thus, there was a “cost of living”. While the exact details about this hypothesis have become debated recently, it is incontrovertible that there is some connection between aging/lifespan and metabolism.

While popularly, dieting has been thought to impart beneficial health effects, surprisingly, dietary restriction (also known as “caloric restriction” in the literature) has been scientifically found to extend the lifespan of yeast (S. cerevisiae), worms, flies, and rodents. Dietary restriction also forestalls the occurrence of aging-related diseases, such as cardiovascular disease, even in humans. This adds additional evidence that inhibition or repression of metabolism is beneficial for slowing aging and increasing lifespan.

In 2003-2006, David Sinclair’s group at Harvard Medical School published a series of landmark studies that showed that compounds that activate the protein SIRT1/Sir2 (sirtuin) extend the lifespan of yeast, flies, worms, and mice. The most well-known sirtuin activator is resveratrol, a naturally-occurring chemical compound found in red wine. It is believed that the presence of resveratrol in red wine accounts for red wine’s beneficiary properties for human health. In these studies, resveratrol was found to increase the maximum lifespan of yeast by 70%.

To try to move these sirtuin activators into the clinic to treat human beings, the pharmaceutical company Sirtis Pharmaceuticals published two papers in 2007 and 2008 describing the development of sirtuin activators that are a thousand times more potent than resveratrol. Their lead compound, SRT1720, a highly potent activator of sirtuins, was shown to combat obesity and diabetes in mice.

Altogether, there is considerable evidence to suggest that sirtuin activators such as resveratrol and SRT1720, may be useful to treat aging-associated diseases in humans, and perhaps even to extend the lifespan of humans. However, recently, the utility of sirtuin activators has come under some controversy, leaving this chapter still an un-finished one in the world of aging research.

In 2009, a popular study was published that reported than an immunosuppressant, rapamycin (an mTOR inhibitor), slightly extended the lifespan of mice—but only when these mice were fed the drug at old age. This was interesting, as it has been shown that mTOR is a cell growth controller. Thus, this provided further evidence that inhibition of cell metabolism and growth might be beneficiary to lifespan.

It has also been found in 2000 that compounds (such as EUK-134) that accelerate the breakdown of harmful metabolic byproducts (reactive oxygen species) increase the lifespan of worms by 44%. This provides further evidence that metabolism is a double-edged sword and that reducing the harmful byproducts of metabolism without slowing overall metabolism is an intelligent strategy to increase lifespan. However, it should be noted that these results have not been reproduced yet and have engendered some controversy.

Histone deacetylase (HDAC) inhibitors, which are anticancer drugs, have also been shown to increase lifespan. In 2002, the HDAC inhibitor PBA (4-phenylbutyrate) was been shown to increase the lifespan of flies by 41%. Ironically, it should be noted that these HDAC inhibitors are anticancer drugs because they inhibit cell survival promote the apoptosis (death) of cells, and thus their utility as lifespan-extending drugs seems initially contradictory.

The last and most exotic lifespan-extending drugs to date undoubtedly are neurological medications. It is extremely surprising that drugs that target the brain have an effect on lifespan, which has led to much speculation. An anticonvulsant, the T-type Ca+2 inhibitor ethosuximide, and an antidepressant, the serotonin receptor antagonist mianserin to extend the lifespan of flies and worms, respectively.

Altogether, a handful of drugs—several sirtuin activators, an mTOR inhibitor, two catalase mimetics, an HDAC inhibitor, several anticonvulsants, and several serotonin antagonists—have been shown to extend the lifespan of lower animals, such as yeast, worms, flies, fish, and mice. The identification of these lifespan-extending drugs is extremely exciting, and offers a potential avenue to possibly extend the lifespan of human beings.

How long will it take before we can extend the lifespan of human beings by feeding them with drugs? This is a difficult question – considering that it takes so many circumlocutions to get FDA approval for drugs to treat relatively “simple” diseases (such as bacterial infection), it is undoubtedly going to be much more difficult to get FDA approval for a drug that can “treat” the most complicated disease of all – aging. However, at the very least, there is the hope that these drugs (particularly sirtuin activators) can be rushed into the clinic to treat aging-associated diseases, such as diabetes, obesity, or cardiovascular disease.

The usage of lifespan-extending drugs to treat aging-associated diseases is a novel therapeutic strategy with significant potential to alleviate the disease and suffering of humans.

Correspondence should be addressed to: Kyle M. Loh (kyle.m.loh@gmail.com). Referenced scientific publications available upon request.

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