A Call to Test Combinations of Drugs Shown to Slow Aging in Animal Studies

I expect that little progress towards sizable human life extension will be achieved in the next few decades via pharmaceuticals that slow aging through triggering various stress response mechanisms. This includes calorie restriction mimetics, autophagy enhancers, exercise mimetics, and the like. It may well be the case that researchers come up with a few drugs that, if taken regularly for decades, reliably add a few years to life expectancy and improve health in old age to a degree that is in the same ballpark as the present results of exercise or eating a better diet. Is that worth billions in funding and decades of dedicated time from much of the research community, however? I think not, not when exercise and calorie restriction are free, and there is the much more promising field of rejuvenation research to focus on. Why tinker with slightly slowing the damage that causes aging when it is possible to work towards repair of that damage and thus reverse aging?

Still, the institutions focused on pharmaceutical recapture of stress responses are deeply entrenched, currently commandeering the majority of funding and attention. Even in failure, the work will continue out of sheer inertia. One would imagine that, in years ahead, researchers will start to try combinations of drugs that slow aging in mice and did not work out so well in humans, looking for synergies or additive effects. One would hope that at least some instead give up the strategy as a bad deal and turn their attention to rejuvenation research, but I expect that to be a slow and grudging process for much of the research community. The more support that we can give to organizations pushing the rejuvenation research agenda into clinical trials and proof of effectiveness, the better.

Aging is a complex multifactorial process, meaning that multiple pathways need to be targeted to effectively prevent or slow aging. A number of molecular pathways are well known for influencing aging, but only a few have been successfully targeted with individual drugs, and these drugs do not individually target all aging pathways. However, combinations of these drugs might have the potential of effectively broadening the scope of aging targets. There are a number of drug combinations that could be combined based on different but overlapping pharmacological activities. Since the number one criterion for selecting drugs should be based on known anti-aging effects, for example, in preclinical mouse studies, the number of drugs available to consider is markedly reduced. Three drugs with well-validated anti-aging effects in laboratory animals, rapamycin, acarbose, and SS31, are well suited to therapeutic multiplexing as a way to enhance healthy aging and stop the development of lesions associated with aging and physiological dysfunction based on interactive cellular mechanisms of each drug.

The concept of drug multiplexing to slow aging looks good on paper, but drug combinations have yet to be tested in any meaningful way. Historically, testing single drugs in mouse lifespan studies has provided useful information, but it is costly and time consuming. More importantly, lifespan studies are difficult to recapitulate in humans, making translation of the preclinical information challenging. And especially relevant is the fact that lifespan studies in mice are not well-suited to testing drug combinations that could more effectively target multiple factors involved in aging. Thus, new paradigms for testing therapeutics aimed at slowing aging are needed.

While the future for expanded use of drug combinations in treating various diseases and conditions, including aging, is highly promising the path toward eventual regulatory approval can be challenging and should be considered in any preclinical studies undertaken. The potential beneficial functional synergy gained from the logical and judicious use of rational drug combinations, such as rapamycin, acarbose, and SS31, is obviously complicated by the fact that different drugs with different metabolic, pharmacokinetic, and toxicity profiles are being superimposed on top of one another. Focusing not just on the benefits of combination products but also the potential liabilities early on can speed the development process.

In summary, the concept of drug multiplexing as a powerful platform to slow aging is promising but has not yet entered the mainstream of aging research. The combination of rapamycin, acarbose, and SS31, three drugs with individually documented anti-aging effects, is a logical approach designed to complement mechanisms of action of their molecular targets and robustly enhance a delay of aging and age-related disease not seen with mono-therapeutic approaches. Support for the preclinical investigation of this drug combination as well as other drug combinations is urgently needed to determine dosages, frequency of administration, and criteria for when to start administering the drugs, i.e. focus on treatment at older ages, or prevention at younger ages.

Link: https://doi.org/10.1080/20010001.2017.1407203

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