Scientists at the Salk Institute have identified a new subclass of anti-aging geroprotector compounds that can slow aging in mice and could represent promising drug candidates for Alzheimer’s disease (AD). Early studies in different rodent models suggest that the compounds, termed geroneuroprotectors (GNPs), improve memory and reduce hallmark toxicities associated with AD. Preclinical studies are ongoing with a view to taking the two most promising compounds into clinical development.
“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, commented Dave Schubert, Ph.D., head of Salk’s Cellular Neurobiology Laboratory, and first author of the team’s published paper in Trends in Pharmacological Sciences, titled, “Geroneroprotectors: Effective Geroprotectors for the Brain.”
The ability to prevent or hold back diseases related to aging is one of the greatest challenges in modern medicine, the authors write, and “the most recalcitrant of these is Alzheimer’s disease.” One potential approach to treating AD is the identification of drug candidates that slow aging and extend lifespan in model organisms, and so may represent geroprotectors that support healthy aging in humans. “The hypothesis is that by delaying biological aspects of aging there will be a simultaneous delay in the chronic diseases associated with aging because they share the same physiological risk factor, the aging process itself,” according to the team.
To date, about 200 compounds have been found to extend average or maximum lifespan in organisms including yeast, flies, and worms. And while some of these compounds appear to impact on common pathways, it isn’t yet clear whether aging is slowed in all tissues, or whether, as some analyses indicate, different geroprotectors act in a tissue-specific manner to reduce overall mortality.
The Salk Institute researchers focused on identifying geroneuroprotector candidates that might specifically protect the brain as well as aging pathways shared by other tissues. To identify potential candidates they developed a phenotypic screening platform using cell culture assays to recapitulate different age-associated toxicities of the brain. “Importantly, all of the assays reflect conditions that are more robust in the aged and diseased brain relative to age-matched controls,” they explained.
Using the platform to screen natural product libraries highlighted two plant-derived compounds, fisetin, a bioflavonoid that is found in fruits and vegetables, and curcumin (diferuloyl methane), which is found in the spice turmeric. Both compounds are available as dietary supplements, and the Salk Institute holds a patent—invented by co-author Pamela Maher, Ph.D.—covering fisetin as a memory enhancer. From these two compounds the team’s screens also highlighted three synthetic AD candidates, CMS121, CAD31, and J147 which, along with fisetin and curcumin, reduced molecular markers of aging and dementia, and increased lifespan in mice and flies.
The three derivatives were effective in different rodent models of AD, improving memory, reducing inflammation, maintaining synapses, and removing toxic amyloid peptide. “More surprising was the finding that they and their natural product precursors extend lifespan and/or delay physiological and molecular aspects of aging,” the researchers noted.
The researchers also demonstrated that the candidates impacted on molecular pathways that are also engaged by metformin and rapamycin, both of which have been found to reduce the rate of aging in model organisms. Based on these new, and prior study results, the team suggests that fisetin, curcumin, and the three synthetic derivatives could be categorized as geroneuroprotectors. “Since we found that the natural products curcumin and fisetin are also GNPs and commercially available as supplements, they could provide some therapeutic benefits right now,” said Dr. Maher.
The researchers are working to progress the fisetin derivative CMS121 and the curcumin derivative J147 into human trials. CMS121 has recently received National Institutes of Health funding for IND studies, while an IND requesting approval to start clinical trials with J147 in Alzheimer’s disease, is under FDA review. J147 is the best-studied curcumin derivative, the researchers pointed out, and has been shown to be effective in over a dozen rodent models of neurodegenerative diseases and memory enhancement. CMS121 has the same GNP properties as its native fisetin, but a much higher level of potency.
The researchers are in parallel evaluating the effects of the GNPs on other organs. “If these drugs have benefits for other body systems, such as maintaining kidney function and overall muscle health, they could be used in additional ways to treat or prevent the diseases of aging,” suggested Dr. Schubert.
The Salk Institute scientists suggest identification of the Alzheimer’s disease candidates validates their drug discovery model, and could lead to the discovery of new GNP compounds that support healthy aging. The compounds identified to date “… define a new class of human GNP drug candidates that could be used alone or in combination with disease-specific compounds for the treatment of old-age-associated neurodegenerative diseases and, perhaps, aging itself,” they concluded.