old-dogs-have-hope

The drug, rapamycin, is making headlines because of the Dog Aging Project. Researchers at the project have been studying the impact of rapamycin on dog health and longevity. Anecdotal results suggest that the effect is pretty dramatic: An old dog, close to death’s door gets resuscitated and is now running around in his yard. Another dog, named Momo seems to its owners to “run faster, farther and with far more vigor, energy, and youthfulness.” People reading this will undoubtedly be thinking, the heck with Fido, I want some of that drug for myself!

Seeing this story reminded me that I predicted the utility of rapamycin as an anti-aging therapeutic as far back as 2011 when I wrote a story called “Rapamycin: The Incredible Journey of a Drug.” In it, I described how a sequence of extremely random and unlikely events that conspired to give us a most amazing drug, the one that rejuvenated Momo, rapamycin. Here is the story:

 

From Taiwan to Easter Island

Archeologists and historians determined that migration from Southern China to Taiwan started about 12,000 years ago. About 3,000-4,000 years later (or about 8,000-9,000 years ago) ancient Taiwanese inhabitants set out by canoes or catamarans, and, about 3,500 years ago, reached the Bismarck archipelago on the eastern edge of Melanesia. Within a mere three or four centuries between about 1300 and 900 BC, they spread 3,500 miles further to the east from the Bismarck Archipelago until they reached as far as Fiji, Tonga, and Samoa—islands that were populated around 2,000 years ago (1st century AD). In this region, the distinctive Polynesian culture developed. About 800 AD, the Polynesian explorers finally reached Easter Island—or Rapa Nui as it is known in the Polynesian language—at the extreme west of the “Polynesian triangle”.

This is not meant to be a history lesson. But just consider the time scale, from 9,000 years ago out of Taiwan to 1,200 years ago to Easter Island, a total of 7,000-8,000 years. Now consider the vast distances of ocean covered by those intrepid voyagers. When you fly over the Pacific at 30,000 ft and see nothing but a blue expanse as far as the eye can see, you can’t help it but wonder: How did they ever find those specs of land (some no more than a mile wide) sailing in canoes, and without navigation equipment. Based on Polynesian folklore, these early navigators were fishermen who followed pelagic schools of fish or sea and shore birds, or, perhaps they were simply blown off course and happened upon the islands by sheer luck.

Here is another wrinkle to the story. As I mentioned above, Taiwan was inhabited 9,000 years ago, and it took the local tribes 3,000-4,000 years to venture out into the ocean in search of new territory. It also took them another 300-400 years to cover the distance to Fiji, Tonga, and Samoa, and another 800 years to fall upon this speck of land call Easter island. Why should they have waited so many years before embarking on each subsequent leg of the voyage? Was there some kind of resource depletion on the islands they inhabited? Not likely. The Pacific islands provided bounteous fruit and fish; all they had to do is climb up the coconut tree, or go fishing, and they had all the protein, carbohydrates, and fat they needed. A more likely explanation: The Polynesian fishermen never stopped exploring, never stopped following schools of fish and birds—they either thought better of it and returned home when supplies ran low or were blown off by the famous Pacific storms and perished. So the long hiatus between discoveries of new islands is not due to periods of inactivity, but a consequence of the incredibly low odds of surviving the voyage and discovering a small island to boot.

 

Easter Island and the discovery of rapamycin

Easter Island is one of the world’s most isolated inhabited islands. The closest island is Pitcairn, population less than 100, which is about 2,200 miles to the west. Santiago, Chile is 2,500 miles away, a five-hour flight. When you approach Easter Island, after endless vistas of blue ocean, you wonder how on earth did early adventurers ever come upon this 63 square miles speck of an island. The odds must be infinitesimal.

Fast forward to the year 1965, over one thousand years after the discovery of the island, another kind of explorers roamed the Pacific. These were Wyeth pharmaceuticals scientists combing the Pacific islands in search of soil bacteria having anti-fungal activity. Of all the thousands of soil samples they must have collected, only the ones collected from a certain hill on Easter Island yielded anything with any interest. But it wasn’t anti-fungal. The soil bacteria Streptomyces hygroscopicus secreted a compound that was a potent immunosuppressant. They named the compound rapamycin, after the island’s Polynesian name, Rapa Nui.

 

Rapamycin and mTOR

This story is amazing as it is considering the extremely unlikely event of Polynesian seafarers sailing and rowing their peanut-size canoes across the Pacific and discovering the remotest of the remote island, and surviving to tell the tale. And, the equally unlikely finding of the bacteria in the soil of one hill on this postage-stamp-size island.

But wait, there is more. Although it was quickly established that rapamycin is an immunosuppressant, nobody knew how it worked. Once it was found that it binds to a certain protein complex in the cell, another puzzle arose. Obviously, this protein was not present there just to bind this bacterial product, so what was its natural function? Not knowing the answer, the protein was dubbed mTOR, or mammalian Target of Rapamycin. Before long, anti-transplant rejection drugs were synthesized, based on the structure of rapamycin.

The biggest payoff came from basic molecular biology studies designed to uncover mTOR’s function in the cell. It turns out that it serves as a switch to turn cell growth on and off. It does it through its sensitivity to the nutrient and energy status of the cell. Does cell growth suggest some connection to cancer? Of course, cancer is unregulated cell growth. Several rapamycin-based drugs are already on the market and more are being tested for treatment of a variety of cancers.

 

How about longevity?

For several years, we’ve known that calorie restriction can significantly prolong lifespan in yeast, worms, mice, monkeys, and maybe humans. Have you seen those emaciated individuals living on the brutal diet of 800-1,000 calories a day? Even if they fail to extend their lifespan, life will feel long being constantly hungry. But they don’t have to be. It turns out that in response to calorie deprivation, cells have reduced protein supply and decreased growth and proliferation—precisely the functions controlled by mTOR. Indeed, mTOR level is significantly depressed in starving animals.

So why go through the torment of severe dieting to prolong lifespan? Why not inhibit mTOR and mimic the metabolic effects of calorie deprivation? A recent experiment with rapamycin indeed prolonged mice lifespan by about 30%. This is equivalent to increasing a person’s lifespan from, say from 90 to 120. Of all the candidate drugs being tested for their effect on longevity, so far, only rapamycin has been shown to work in mammals.

But don’t try it at home, yet. Rapamycin is a potent immunosuppressant, so if you take it, you may shorten your lifespan rather than prolong it, which coming to think of it, defeats the whole purpose of the “experiment.”

 

More and more on mTOR

I wrote in my original post from 2011 that

“More reports on the activity of mTOR are coming fast and furious. On February 21, 2011, a report from Boston University showed promising results of a rapamycin-based drug in the treatment of Alzheimer’s disease. On April 11 of the same year, an FDA panel voted unanimously to approve the rapamycin-based drug everolimus for treatment of pNET, (pancreatic Neuro Endocrine Tumor), the cancer that afflicted Steve Jobs, among others.”

Since that time, the science of rapamycin and other mTOR inhibitors has grown rapidly. Searching PubMed for articles on the topic reveals more than 30,000 scientific publications on rapamycin and almost 8,600 for mTOR inhibitors. You get the feeling that this is just the beginning, that this could well be a gift that just keeps on giving.

To me, it is astounding how a sequence of extremely random and unlikely events conspired to give us a most amazing drug; you almost feel that there must have been a guiding hand that made it happen. Of course, there wasn’t, which makes its discovery even more wondrous.

Dov Michaeli, MD, PhD

Dov Michaeli, MD, PhD loves to write about the brain and human behavior as well as translate complicated basic science concepts into entertainment for the rest of us. He was a professor at the University of California San Francisco before leaving to enter the world of biotech. He served as the Chief Medical Officer of biotech companies, including Aphton Corporation. He also founded and served as the CEO of Madah Medica, an early stage biotech company developing products to improve post-surgical pain control. He is now retired and enjoys working out, following the stock market, travelling the world, and, of course, writing for TDWI.

LEAVE A REPLY


All comments are moderated. Please allow at least 1-2 days for it to display.