Chapter 187
Changing Aging — 24
The other drug that is being tested in dogs at some scale is a randomized trial of rapamycin for lifespan in the Dog Aging Project, an ambitious NIH-funded initiative that is tracking nearly fifty thousand pet dogs with a biobank of more than fourteen thousand tissue and blood samples, more than one thousand dog genomes sequenced, but its future funding is imperiled.
It’s good that rapamycin is being tested in dogs for lifespan and health span extension since there are no such large-scale studies in humans. Similar to the effects of caloric restriction for decreasing protein synthesis and improving waste removal (autophagy), rapamycin and its derivatives (rapalogs), inhibitors of the mTOR gene that influence so many key cellular processes, are good candidate drugs for promoting health span. Of the twelve hallmarks of aging that we’ve been discussing, rapamycin, by inhibiting mTOR, has the potential to favorably modulate many of them.
Lifespan extension has ranged from 20 percent in worms to 60 percent in mice. Studies with rapalogs in aged individuals indicate some reduction of immunosenescence in response to vaccination or to viral infection with improved interferon-induced response. Paradoxically, the drug induces some immunosuppression with increased vulnerability to infections, an unnerving side effect. An exhaustive review of all the literature on rapamycin showed lack of evidence of an effect for many age-related issues, such as cognition, memory, muscle mass, or glucose regulation. But topical rapamycin did reduce biomarkers of aging in skin. Despite all the data that has accumulated for rapamycin and its derivatives, the optimal dose is unknown, and there are no meaningful ongoing clinical trials to test the hypothesis of impact on an age-related disease or the aging process. Without such validation, and considering the known side-effect profile, there is no justification for its use at this juncture.
Metformin, on the other hand, with many overlapping biological effects on autophagy and mitochondria function, is being assessed in an ongoing trial of three thousand participants aged sixty-five to seventy-nine years. That study, however, is having difficulty getting fully funded and, even if successfully completed, is unlikely to be large enough to provide adequate evidence of efficacy. A systematic meta-analysis of 166 studies suggests this drug may be associated with a lower incidence of many types of cancer. But essentially all the data for this drug comes from observational, nonrandomized trials. Moreover, it has the especially counterproductive side effect of reducing the ability to build muscle mass with exercise in older adults.
Grouped here is also the nicotinamide adenine dinuclelotide (NAD+), produced by mitochondria and with a central role in energy metabolism. As one of the most common metabolites in our body, levels decrease with age, and more prominently among individuals with age-related diseases. Our cells are unable to take up NAD from our diet, but, ironically, the NAD precursors nicotinamide riboside (NR) and nicotine mononucleotide (NMN), marketed widely without clinical trial to show any benefit, are expected to reach over $1 billion in global sales in the next two years. A prime example of a market failing to guide us to the best product. NAD+ is also interconnected with the sirtuin pathway, a pathway once promoted as a critical lifespan expander (think of red wine’s resveratrol), but proof of such a role has failed to be reproducible. The Sir/sirtuin family of proteins is derived from the words silent information regulator. From all the evidence thus far, “silent” is a better way to think of the role of the sirtuin family in modulating much less reversing the aging process.