Procaine as an Example of the Slow Reclassification of Known Small Molecule Drugs as Geroprotectors

The classification of "geroprotector" is fairly recent. In present use, it largely means a small molecule drug that can favorably target mechanisms known to be associated with aging. Some of these small molecules come with evidence for a slowing of aging in animal studies. A very few can boast evidence for the same from human trials. Most geroprotectors target stress response mechanisms, those involved in calorie restriction, but senotherapeutic drugs that reduce the burden of cellular senescence might also be classed as geroprotectors.

That a drug can be called geroprotective is no guarantee that it is actually useful, of course. Effect size matters! Aspirin can reasonably be classified as a calorie restriction mimetic drug, and there is evidence for reduced mortality in old people that is mixed but better than that for most putative geroprotectors. We all know that aspirin isn't going to help us change the shape of a human life to any meaningful degree, and most geroprotectors are probably worse than aspirin in terms of reliability and size of effect. Just because a mechanism can be linked to a small molecule doesn't mean that the outcome in human medicine will be anything to write home about.

Nonetheless, given the new classification of geroprotector, there are now growing databases of actual and potential geroprotectors, assembled from the literature where there is any evidence for interaction with areas of metabolism connected to aging, or animal or human data for signs of slowed aspects of aging. Some of the many drugs that have interested researchers in connection with aging, from time to time over the past century or more, coming and going as fashionable targets for scientific programs, can now be declared potential geroprotectors. Any specific case usually provides at least some interesting insight into just how slow and lengthy is the path to understanding any given drug, and how challenging it is to assess modest effect sizes in the matter of aging.

Procaine - The Controversial Geroprotector Candidate: New Insights Regarding Its Molecular and Cellular Effects

Procaine was synthesized in 1905 and introduced in clinical practice as Novocain, soon becoming a local anesthetic prototype. Around the 1950s, a large number of accumulated data emphasized the surprising diversity of nonanesthetic effects exerted by procaine, which came to the attention of various medical research schools in Eastern and Western Europe, many doctors exploring, regardless of borders, the beneficial properties of procaine. Between 1946 and 1956 researchers described a significant number of procaine beneficial actions exerted on cellular functions and metabolism, following long-term treatment in low doses, highlighting its "rejuvenating" effects, and developed Gerovital H3 (GH3) - an original procaine-based pharmaceutical formulation. Due to these findings, procaine which was known only for its anesthetic properties became one of the most disputed medical developments of the sixties and seventies in the field of "anti-aging" therapies.

Recent progresses in the field of aging research led to the development of a new class of drugs - geroprotectors, with the ability to target fundamental mechanisms of aging common to multiple age-related diseases, such as response to oxidative damage, inflammation, hypermethylation, cellular senescence, and autophagy. Researchers have established the first public database of geroprotectors that indexes the most relevant experiments involving over 200 well-established geroprotectors or possible candidates that could extend the healthy lifespan and repair or reduce aging-related damage in model organisms.

As primary selection criteria for the potential geroprotectors, the following characteristics were recognized: (1) the ability to increase lifespan; (2) the capacity to ameliorate molecular, cellular, and physiological biomarkers to a younger state or slow the progression of age-related change of these markers; (3) a therapeutic lifespan-extending dose of geroprotector, which should be several orders of magnitude less than the toxic dose; and (4) the capacity to improve the health-related quality of life of the patient, from a physical, mental, emotional, and social viewpoint. The compliance of procaine with most of these criteria would allow it to be a potential "geroprotector" candidate.

Although GH3 was internationally launched in 1956, simultaneously with the development of the Free Radical Theory of Aging, the study of the antioxidant action of procaine and GH3 was documented only after 1980, in various experimental designs, which proved its capacity of limiting the generation of reactive oxygen species (ROS) and lipid peroxidation. Besides its antioxidant, cytoprotective, anti-inflammatory, and antiatherogenic effects, at cellular and molecular levels, procaine has multiple targets, supporting a large number of potential "geroprotective" effects. Older and more recent data revealed that procaine and its metabolites modulate several biochemical and cellular processes like mitochondrial structure and function.

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