March 15, 2015

No Quick Fix for Mortality

Quercetin hit the airwaves this week, when the media reported that scientists have found "a new class of drugs that dramatically increases healthy lifespan.” Not to be confused with Coenzyme Q10, another naturally occurring compounded touted as an antioxidant that delays aging, Quercetin is a “natural compound” sold in health food stores as an anti-inflammatory agent. But now it is has been dubbed a “senolytic,” a drug that slows aging by alleviating symptoms of frailty, improving cardiac function, and extending a healthy lifespan. Sounds great. But before you rush to buy some, lets look at the evidence.

The article on which this promising claim is based is a highly technical paper in the journal Aging Cell entitled, “The Achilles’ Heel of Senescent Cells: From Transcriptome to Senolytic Drugs.” The authors argue that aging is due in large part to cellular senescence, which in turn means the process by which cells lose the capacity to grow. These senescent cells secrete all kinds of chemicals that are hypothesized to produce decline and death. But not all the cells in an organism become senescent at once. In fact, only 15% of the cells of very old primates are “senescent.” The idea is to kill off these senescent cells, thus preventing them from making those disease-making chemicals. 

It turns out that a variety of drugs, all belonging to this new class of “senolytics,” selectively kill senescent cells. And indeed, when a combination of two drugs, a known cancer drug and the compound Quercetin, were given to old mice, they lived longer and had lower rates of “age-related symptoms and pathology” compared to old mice that didn’t get the cocktail. The two drugs worked especially well together, but each drug alone was effective. So where’s the rub? Why not rush out and buy some Quercetin, which is available now and without a prescription?

It’s not that Quercetin might be harmful. The FDA has studied the compound and determined that it has no significant toxicity because it is destroyed in the intestinal tract--before it can even get into the bloodstream. So while the drug might in principle do something if given intravenously, taking the currently available formulation won’t. Parenthetically, you certainly don’t want to buy some Dasatinib either, the other drug used in the study. Dasatinib is a “targeted chemotherapy” drug, used to treat the relatively rare blood cancer, Chronic Myelogenous Leukemia (CML), when the preferred drug, Gleevec, stops working. It costs roughly $10,000 for a thirty-day supply. It is approved only for use in blood cancers, though in principle it could be prescribed off- label for other non-proven indications.

Another reason for holding off on your Quercetin purchase is that its effectiveness has been demonstrated only in rodents. Using mice to explore the genetic underpinnings of mortality has a venerable history: the gerontologist David Sinclair, for example, has been using a mouse model to study Sirtuin genes, genes that appear to protect against aging. He has discovered "sirtuin-activating compounds," small molecules that decrease frailty--in mice. These frail mice exhibit muscle weakness, they get heart disease, and they die earlier than their non-frail counterparts. But whether frail mice are truly analogous to humans, in whom frailty entails heightened vulnerability to stressors, and in whom frailty translates into an increased risk of falls, delirium, and disability, is another matter.

The main reason for skepticism about the latest claims about an immortality pill goes back to the article written by Olshansky, Hayflick and Carnes in 2002 and republished by Scientific American in 2008 that debunks all claims to have discovered the fountain of youth. These scientists take seriously the desire to promote healthy aging. They see the virtue in postponing the aging process altogether rather than tackling the diseases of old age one at a time: if aging is a zero-sum game, then curing cancer, for instance, would simply mean that more people will die of Alzheimer’s disease. But they are horrified by the amount of money desperate people spend on anti-aging products that are no more likely to be beneficial and just as apt to be harmful as many of the quack nostrums of the nineteenth century.

Today, a number of companies are peddling “anti-aging” drugs. Elysium, cofounded by Lenny Guarante of MIT (David Sinclair’s mentor), makes “Basis,” a mixture of nicotinamide and pterostilbene (an anti-oxidant), which it sells on line. Even Novartis, a major drug manufacturer, is trying to get into the anti-aging market with rapamycin, as Bloomberg News reported with enthusiasm.

None of these drugs has been proven to work. Some may be harmful. All are costly. It's not necessary to discuss  the ethical concerns about trying to lengthen the human lifespan to have an opinion about Quercetin. It's an interesting chemical for scientists to study in the laboratory, but it's not ready for prime time.

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