This commentary makes the point that the development of interventions to slow and reverse aging is moving along at some pace in mice, the field expanding year after year, but the translation of this work into human medicine is very definitely lagging behind, yet to come up to speed. This is largely true for any comparatively new and growing field of medicine, given the enormous and excessive cost and delay imposed by regulators, but the study of aging has its own peculiarities in addition to that issue. For example, the lack of a good way to measure the outcome of a treatment on the mechanisms and progression of aging. Or the strong focus on approaches such as upregulation of the stress response mechanisms of autophagy, wherein the effects on aging and life span are much more pronounced in short-lived species, leading to comparatively poor results in humans. There will be a point at which the medical side of the field of aging research catches up, certainly, but exactly when that will start to happen is an open question.
Almost a century has passed since Clive McCay discovered that reducing the food intake of his rats increased their lifespan by up to 40%. Now we know that dozens of interventions extend the lifespan of organisms such as rodents, nematodes, yeast, and fruit flies. Aging is not as static as it once seemed. Clearly, we now know that several conserved molecular changes occur in organisms with age and we have developed interventions in animal models to impact almost all of them. Nevertheless, despite our great push for testing lifespan and healthspan altering molecules and growing knowledge of the underlying causes of aging, we still do not know if most of our interventions will work in humans. Why is that?
A major problem facing the field of aging is measuring the effect of an intervention. In short lived organisms such as fruit flies, nematodes, and yeast, effects are easy to measure simply by investigating how an intervention impacts the lifespan. However, with longer lived organisms this becomes challenging and surrogate markers are therefore needed that reflect biological aging. Ten years ago, the identification of single biomarkers of aging was a grand challenge when considering trials for aging in humans, however, landmark papers have since shown that we can quite accurately measure age by looking at the combined alterations in the epigenetic landscape. We can then use these biomarkers to test if we can reduce or reverse the biological age of an individual. With these tools at our disposal, we have truly moved into an era where biomarkers are no longer an issue.
Concurrent with the recent development in biomarkers the first trials targeting aging in humans are now being started. The need for testing a significant number of individuals have been a limiting factor for trial designs. This has been the case because trials are often designed for mortality endpoints or other relatively rare events for otherwise healthy elderly individuals which necessitates large cohorts. Based on recent trials, it appears that even relatively short treatments may be enough to see signs of epigenetic age-reduction in humans, however. In summary, we have all the tools available to begin transitioning to testing in humans.
Twenty years ago, the NIA funded Interventions Testing Program (ITP) was conceived to test interventions in mice with the specific goal of translating the findings to clinical trials in human. The program, which investigates the lifespan effect of proposed interventions in genetically diverse mice across multiple centers, has been a massive success with numerous groundbreaking findings, perhaps most notoriously the discovery that rapamycin extends the lifespan of mice. Nevertheless, the hope of real translation was never completely carried forward to humans even though some trials have been examining the effect of compounds such as rapamycin on age-associated diseases, but not aging itself. To tackle our grand challenge, I propose that the field funds a human interventions testing program that will investigate promising compounds in humans.