Discussing the Present State of Clinical Trials for Therapies that Target Mechanisms of Aging

Today's open access paper provides a conservative view of present efforts to run clinical trials for interventions that target mechanisms of aging. This is a thin field so far: largely calorie restriction, calorie restriction mimetics such as mTOR inhibitors, compensation for mitochondrial decline in the form of NAD+ upregulation, and senolytics. The latter are the only option likely to produce eye-opening results, at least going by the animal data. Only a few senolytic trials are underway, however, and results are arriving only very slowly.

I would say that the authors here put too much weight on the possible problems that lie ahead. But they are right in that the outcomes have been largely unimpressive so far. The majority of trials have used unimpressive approaches, such as NAD+ upregulation via vitamin B3 derivatives. When the therapy reproduces only a small slice of the benefits of exercise, it perhaps isn't surprising to find that only marginal benefits result. When there are side-effects and problems, even minor ones, therapies that produce only marginal benefits tend to fail the cost-benefit consideration. We should in any case be aiming higher.

Clinical Trials Targeting Aging

Clearly, several trials have shown that targeting aging is feasible in humans. Calorie restriction has been associated with protective cardiovascular effects (lowered blood pressure and improved lipid profile), improved mitochondrial biogenesis, and metabolic efficiency (increased insulin sensitivity). A drawback of calorie restriction is that the feasibility is quite low for most humans. NAD+ supplements are safe in humans and increase NAD+-related metabolites but the influence on cellular energy-sensing pathways, and aging itself, has not shown clear results. Trials with senolytics have shown promising systemic results in subjects with idiopathic pulmonary fibrosis, diabetes, and kidney dysfunction. Nevertheless, senescence is an essential anti-cancer mechanism and interfering with this may be associated with cancer development. Further, mTOR inhibition causes improved mitochondrial function, dermatological skin improvements, and overall improved immune function in elderly individuals, possibly by lowering immunosenescence.

An important feature of potential aging drugs must be a relative absence of side-effects. Here, the benefit of utilizing wide-spread drugs that are approved for treatment of other diseases is that safety and tolerability is already thoroughly investigated, making it possible to commence larger-scale trials sooner. However, if treatment duration is prolonged periods of time, the health gaining effects must outweigh potential side-effects. For example: Dasatinib can cause gastrointestinal bleeding and liver damage. A possible approach to avoid this may be combining medication, i.e., handling rapamycin-caused glucose dysmetabolism with metformin

A bump on the road for expansion of aging trials is the inclusion of mainly healthy subjects in current anti-aging clinical trials, as long lists of wide-spread morbidities and medication often are among exclusion criteria. Thus, studies may include only exceptionally healthy elderly where effects of therapies targeting aging may be less efficient. Further, this could cause a blind-spot in catching potential side-effects of aging treatments as the side-effects may be related to other conditions. Instead, one could consider having slightly less stringent inclusion criteria which would allow individuals with mild chronic diseases (eg. hypertension) to be included. Similarly, an estimated 1/3 of all elderly receive five or more prescription drugs, potentially resulting in missed drug-drug interactions.

Medication often has a therapeutical concentration window, where too little poses no effect and too much is toxic. The same principle is relevant in anti-aging treatment but may include an additional temporal aspect. Initiation of some anti-aging treatments may require early intervention and might not be efficient if subjects are already old, while other treatment forms may show promising results in the elderly but cause unwanted, harmful side-effects in healthy, young subjects. This temporal therapeutical window has been experimentally observed in cancers and could cause major issues for anti-aging clinical trials. If no effect of a treatment is observed due to "incorrect" age of subjects or if it simply has no effect in any age-group can only be investigated by comparing identical studies on different age-groups.

In conclusion, clinical trials targeting aging in humans have shown promising but limited results on biomarkers so far.

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