Aging Session at BIO Conference, June 3-6

By John S. James, 2019-06-26

Chemical structure of rapamycin

Chemical structure of rapamycin (Sirolimus). Wikimedia Commons.

Seventeen thousand people registered for the 2019 BIO (Biotechnology Innovation Organization), June 3-6 in Philadelphia. Only one presentation was specifically about slowing the aging process. But there was much other relevant information, which we will cover separately.

The session specifically on aging, Anti-Aging Therapies: Taking Action to Increase the Human Healthspan, had a 3-person panel moderated by Laura Deming, "an investor interested in ways to make people live longer." The three other panelists are CEOs of their companies: Unity Biotechnology, Navitor Pharmaceuticals, and resTORbio; all three have an experimental drug in clinical trials (meaning it is being tested in people).

Unity Biotechnology is testing a drug to clear harmful senescent cells. These are damaged cells in the body which have stopped dividing but refused to die, and churn out chemicals that cause chronic inflammation, which is widely believed to be an important cause of aging. The other two companies are testing drugs to affect the mTOR biochemical pathway. These are two of the most important anti-aging approaches at this time.

A major focus at this meeting was how for sure that a drug or other intervention actually does affect human aging. A clinical trial to randomly give some people the intervention and others a placebo, and see who lived longest, would take decades and be impossibly expensive. So companies that want to develop a product need to find some "rapid readout" that gives important information much earlier.

Senescent Cells

So on senescent cells, clearing a significant fraction of them from the body might have many benefits for health. But Unity Biotechnology first looked for a quickly measurable outcome: could its experimental treatment, UBX0101, improve osteoarthritis of the knee?

Two weeks after the BIO meeting preliminary results were released - resulting in a drop in the company's stock price, which fully recovered later. We believe the results had been misinterpreted. Apparently the first phase of the trial did show statistically significant improvement - but a second phase at a higher dose did not reach significance. The second phase had fewer subjects, and was run for a shorter time, making it more difficult to reach statistical significance even if the drug worked.

And there's a more interesting possibility, as we see it. Killing too many of the senescent cells at once could release more of the harmful chemicals, causing a temporary increase in symptoms that would tend to reduce any improvement seen. So we will be looking for longer-term results.

One point from the discussion in the meeting is that you want to remove senescent cells - but probably not prevent them from being created in the first place. The reason is that cell senescence is one way the body protects itself against cancer. Senescent cells cannot reproduce, so they do not start tumors. But some of the chemicals they produce are believed to drive the aging process; and once the cells have become senescent, they appear to be both harmful and unnecessary.

The mTOR Pathway

The other two companies on the panel are currently doing human trials of another major approach to understanding aging.

Rapamycin (Sirolimus) is an approved drug used for immune suppression. In animals and humans it has shown unexpected health benefits, increasing both lifespan and healthspan. But it can have serious side effects, and is usually considered too risky to use long-term in hopes of unproven anti-aging benefit. Much research is now trying to understand the exact mechanisms of how the drug works, in hopes of finding other drugs that will have more benefit and less risk.

The abbreviation 'mTOR' stands for metabolic target of rapamycin. Why the odd name? That is because it took 30 years from the discovery of the drug (from bacteria on Easter Island) to begin to understand how it works. Researchers knew that there was some target of the drug, and guessed (correctly) that the target was a protein, but they did not know what the protein was.

Then they discovered the protein that was the target of rapamycin, and have spent decades since working out the very important (and complicated) mechanisms of action. The same protein works in two different complexes, called MTORC1 and MTORC2; MTORC1 is the most important. It seems to be a master regulator of the cell, which senses whether or not nutrients are available at the time, so that the cell can grow and divide if they are. But otherwise (in a time of famine) the cell should break down unneeded structures to re-use their nutrients. MTORC1 is part of evolutionary adaptation over billions of years to a world where starvation is usually the greatest threat to survival.

There can be either too much or too little MTORC1 activity, in different diseases. Various clinical trials of drugs intended to influence MTORC1 have been conducted. Some have succeeded but some have failed and had to be stopped for safety reasons. This field is confusing and we will report later on possibilities of getting the anti-aging effects of rapamycin without the side effects. The two companies who discussed their MTOR work at the BIO meeting are working on very different approaches with different goals.

There are many YouTube videos on this subject. For a technical scientific introduction and history, we suggest Introduction to mTOR and the Regulation of Growth.

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