Growing Enthusiasm for the Development of Geroprotectors

A geroprotector is a drug or supplement that either slows the underlying causes of aging or produces a greater resistance to the damage of aging. In either case health is prolonged and mortality decreased. Calorie restriction mimetics are the best example of the type, but the category is expansive enough to include well known drugs such as aspirin. As you might imagine of a class of treatments that includes aspirin, the size of effect when it comes to additional years of life is fairly small, even in those cases in which the benefits are reliable. Geroprotectors largely work through upregulation of stress responses, something that has much larger effects in short-lived species, such as mice, than in long-lived species, such as our own.

Nonetheless, there is a growing interest in developing these compounds and bringing them to the clinic. Far more interest than is warranted, I'd say. If all of that attention was instead devoted to the SENS portfolio of approaches to rejuvenation, classes of therapy that are based on repair of the molecular damage that causes aging, then we might be moving a lot more rapidly towards reversal of aging and large gains in healthy life span, rather than towards the very modest, incremental slowing of aging that most research groups are aiming for. Repair and reversal will always be a much better approach to improving the function of complex machinery than a mere slowing of damage.

To confuse the nice neat line between two approaches to aging that I've drawn above, in the research here, the scientists are treating the senolytic compound fisetin as a geroprotector. It may well have effects that involve upregulation of stress responses, thus slightly slowing aging, but it would be hard to argue that those are large in comparison to its ability to destroy senescent cells, and thus reverse that cause of aging. That said, the senolytic dose is much larger than the usually explored dose, and so there may well be multiple mechanisms of interest involved.

Old age is the greatest risk factor for many diseases, including Alzheimer's disease (AD) and cancer. Geroprotectors are a recently identified class of anti-aging compounds. New research has now identified a unique subclass of these compounds, dubbed geroneuroprotectors (GNPs), which are AD drug candidates and slow the aging process in mice. "The argument for geroprotectors is that if one can extend the lifespan of model organisms, such as mice, and translate this effect to humans, then you should be able to slow down the appearance of many diseases that are associated with aging, such as Alzheimer's, Parkinson's, cancer and overall frailty."

The team started with two chemicals found in plants that have demonstrated medicinal properties: fisetin, a natural product derived from fruits and vegetables, and curcumin, from the curry spice turmeric. From these, the team synthesized three AD drug candidates based upon their ability to protect neurons from multiple toxicities associated with the aging brain. The lab showed that these three synthetic candidates (known as CMS121, CAD31 and J147), as well as fisetin and curcumin, reduced the molecular markers of aging, as well as dementia, and extended the median lifespan of mice or flies.

Importantly, the group demonstrated that the molecular pathways engaged by these AD drug candidates are the same as two other well-researched synthetic compounds that are known to extend the lifespan of many animals. For this reason, and based on the results of their previous studies, the team says fisetin, curcumin and the three AD drug candidates all meet the definition of being geroneuroprotectors. The group is now focusing on getting two GNPs into human clinical trials. The fisetin derivative, CMS121, is currently in the animal toxicology studies required for FDA approval to start clinical trials. The curcumin derivative, J147, is under FDA review for allowance to start clinical trials for AD early next year. The group plans to incorporate biochemical markers for aging into the clinical trials to assay for potential geroprotective effects.



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