Developing criteria for evaluation of geroprotectors as a key stage toward translation to the clinic

Abstract

SummaryIn the coming decades, a massive shift in the aging segment of the population will have major social and economic consequences around the world. One way to offset this increase is to expedite the development of geroprotectors, substances that slow aging, repair age‐associated damage and extend healthy lifespan, or healthspan. While over 200 geroprotectors are now reported in model organisms and some are in human use for specific disease indications, the path toward determining whether they affect aging in humans remains obscure. Translation to the clinic is hampered by multiple issues including absence of a common set of criteria to define, select, and classify these substances, given the complexity of the aging process and their enormous diversity in mechanism of action. Translational research efforts would benefit from the formation of a scientific consensus on the following: the definition of ‘geroprotector’, the selection criteria for geroprotectors, a comprehensive classification system, and an analytical model. Here, we review current approaches to selection and put forth our own suggested selection criteria. Standardizing selection of geroprotectors will streamline discovery and analysis of new candidates, saving time and cost involved in translation to clinic.

Chronobiology of Aging: A Mini-Review

“…This apparent paradox may reflect the existence of distinct networks of hypothalamic neurons governing consummatory and appetite behaviors [24,25] . Other studies showed that caloric restriction and physical exercise improved biomarkers of human aging such as body mass index, blood pressure, glucose, insulin, and lipids, and decreased the risk of aging-associated diseases such as diabetes and cardiovascular conditions [26] .…”

“…While caloric restriction and physical exercise are the only known nonpharmacologic interventions capable of delaying aging in rodents and primates, efforts have recently been made to evaluate the relative merits of pharmacologic interventions using geroprotectors as a key stage toward clinical applications [26] . Despite limited clinical investigations performed thus far, the mTOR inhibitor RAD001 (everolimus) was reported to have beneficial effects on immunosenescence in elderly volunteers [26] .…”

“…Despite limited clinical investigations performed thus far, the mTOR inhibitor RAD001 (everolimus) was reported to have beneficial effects on immunosenescence in elderly volunteers [26] . The oral antidiabetic drug metformin, which activates AMPK in the liver, was also reported to decrease cardiovascular disease risk, cancer incidence, and overall mortality as compared to other antidiabetic drugs [26,27] . Other candidate geroprotectors include glycolysis inhibitors, inhibitors of the GH/IGF-1 axis, activators of the sirtuin pathway, inhibitors of inflammatory pathways, and modulators of epigenetic pathways [27] .…”

Studying the geroprotective effects of inhibitors suppressing aging -associated signaling cascades in model organisms

“…The pharmacological agents that decrease the rate of aging and extend lifespan are called geroprotectors [36][37][38]. The term «geroprotector» (literally «protecting from aging») was first coined by the Nobel Prize laureate Ilya Mechnikov, an outstanding Russian and French scientist, in 1910 [35], but those times the concept had not been widely used before enough empirical data was accumulated.…”

“…Recently, the system of criteria for geroprotector identification and classification were proposed [37,38]. The main criteria are (1) the ability to prolong life, in addition, a potential geroprotector should (2) return the biomarkers of aging to the state characteristic of a young organism; (3) the dose providing effective use must be fundamentally lower than the toxic dose with (4) minimal side effects at therapeutic dosage, and, finally, (5) the quality of life in patients treating with geroprotectors should increase, and the physical, mental, emotional state should improve.…”