Fight Aging!

The authors of today's open access paper argue for much greater effort to be directed towards the repurposing of existing drugs with the goal of slowing aging. I have mixed feelings about the prevalence of drug repurposing in the pharmaceutical industry. The FDA makes it so very expensive to introduce any new drug that industry of course responds to the incentives and spends a great deal of time digging through the existing library of approved drugs in search of those that can be used in different circumstances. It is a great deal easier to take a drug with established safety data and seek approval for a new use than it is to carry out the same regulatory process for a new drug.

On the one hand, this search of existing drug databases can turn up items like the dasatinib and quercetin combination, a senolytic therapy that is producing impressive displays of rejuvenation in old mice. This is an unusual outcome, and didn't exactly arise from the usual drug repurposing channels, but if it had arisen that way, then it might in and of itself justify much of the effort across the industry.

Looking at the broader picture, however, this part of the pharmaceutical industry appears to specialize in pushing entirely marginal therapies into the FDA process. The benefit of known safety data is balanced against (usually) poor performance in treating the target condition in question. If there are presently only poor options for the treatment of a given condition, then a still poor but incrementally better option can achieve regulatory approval. The treatment of aging is currently in this position, and hence the paper here puts forward a list of largely unambitious items - plus dasatinib and quercetin. We live in interesting times.

Geroscience-guided repurposing of FDA-approved drugs to target aging: A proposed process and prioritization

Geroscience represents a novel paradigm whereby biological aging is recognized as the major modifiable driver of age-related diseases and other late-life conditions. Widespread clinical use of geroscience-guided interventions could transform the public health landscape because the ability to target biological aging as a risk factor could simultaneously delay the onset and progression of multiple conditions, thereby enhancing health, function, and independence in late-life. A corollary is that targeting this biology will affect human healthspan (the portion of lifespan free of major disease and disability) most profoundly, and with a better prognosis than the current model of addressing one disease at a time.

While aging is unequivocally the major risk factor for age-related diseases, regulatory bodies around the world, such as the FDA or EMA, do not yet recognize geroscience-guided clinical outcomes as a path to regulatory approval. This is in part because the processes for validating specific compounds or combinations of compounds for their ability to delay the onset and progression of multiple chronic diseases have not yet been delineated in humans. Without regulatory approval, insurers will not pay for such treatments, which disincentivizes pharmaceutical companies from developing geroscience-guided approaches, simply because there is no path for them to develop a viable business plan. Therefore, there is an urgent need to demonstrate, in a well-designed clinical trial, that a cluster of age-related diseases can be significantly delayed by repurposing existing or developing novel gerotherapeutics.

Targeting Aging with MEtformin (TAME) is such a study that has been under development for the last few years, and whose basic principles have been developed in consultation with the FDA. We believe that efforts to test and repurpose existing, safe gerotherapeutics should be extended beyond TAME, not only to increase the number of drugs potentially available to target aging in humans but also to mitigate the risks to the field, should any such trials fail to reach their desired outcome.

We sought to identify such FDA-approved drugs or classes of drugs that had at least one publication showing extension of lifespan in rodents and data in humans suggesting the highest chance of success if tested in a well-controlled TAME-like clinical trial. We developed a 12-point prioritization scale that assigns equal points for the preclinical and clinical evidence for each of these candidates. Points on the preclinical side were assigned for effects on the hallmarks of aging, improvement in healthspan and extension of lifespan in rodents as part of the NIA's Interventions Testing Program (ITP), a well-characterized, multicentered study to evaluate gerotherapeutics, as well as non-ITP rodent lifespan studies.

We were able to prioritize nine drug classes. SGLT2 inhibitors (SGLT2i), a relatively new drug class, was the only one to receive the maximum score, owing to not only its robust effects on improving rodent healthspan and lifespan (including ITP) but also strong evidence for the extension of healthspan and reduction of mortality in humans. Metformin was next on the list, and it received a submaximal score, due to negative findings for rodent lifespan extension in ITP. Acarbose, rapamycin/rapalogs, and methylene blue (MB) all had strong preclinical data and promising findings for human healthspan (the latter being the most robust for acarbose), but sparse clinical data for human mortality. Angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) were found to extend preclinical healthspan and lifespan (outside of ITP) and had robust effects on extending human healthspan, but the studies on human mortality, while abundant, were predominantly negative. The last three drugs on our list, senolytics Dasatinib + Quercetin (D + Q), aspirin, and N-acetyl cysteine (NAC), all had strong preclinical data, but their effects on human healthspan and mortality have not yet been assessed in clinical studies or appropriate doses/populations. Obviously, future studies may change the priority order for drugs that did not receive points due to the paucity of clinical data.