Multi-morbidity as a Definable Antiaging Target

Regulators such as the FDA do not consider aging to be a disease, and they only approve treatments for specific diseases, largely using the World Health Organization’s International Classification of Diseases as the basis for what is and is not a disease. The TAME (Targeting Aging with Metformin) trial came into being as a way to convince the FDA to approve a treatment on the basis of endpoints that approximated aging, rather than a disease.

The world Health Organization (WHO) describes aging as a gradual decrease in physical and mental capacity. In fact, the WHO recently included aging associated decline in intrinsic capacity as a disease code in the 11th edition of International Classification of Diseases (ICD).

The general door is slightly open. The FDA indeed agreed with the TAME trial design, and so in principle anyone else with deep pockets could now adopt the same approach if they wanted to stand behind a treatment for aging. The biotech industry and those who fund it are highly conservative, however. Companies working on therapies that can in principle slow or reverse aspects of aging have all chosen to pick one or more specific age-related diseases, and quietly plan for off-label use following approval, as it is unlikely that they could otherwise have convinced investors to back their clinical and regulatory development.

The TAME trial remains incompletely funded. Metformin is a poor choice of treatment. It was selected because it is so very widely used, for so long, and with such an abundance of safety data. Rapamycin is more effective.

We may be a few well-designed studies away from FDA acceptance of aging as a drug target.

Here’s what we could expect:

* The market for regenerative therapies will expand to nearly the entire adult population. Regenerative therapy companies targeting the biological process of aging are currently limited to addressing specific diseases or medical conditions to obtain FDA approval. Drugs or therapies that get to market are typically limited in approved use for one disease; approval for additional diseases often comes years later.

* Removal of the disease-specific regulatory barriers would make regenerative therapies available as preventative care solutions.

Work to develop medicines that could prevent many diseases is going far slower than it should be, because aging is not recognized as a medical condition.

Therapies that target the process of aging itself will enjoy a nearly unlimited market, compared to therapies with the same mechanism that target a single disease.

What is the TAME Trial?
The Targeting Aging with Metformin (TAME) Trial is a series of nationwide, six-year clinical trials at 14 leading research institutions across the country that will engage over 3,000 individuals between the ages of 65-79.

Wake Forest University School of Medicine will be the coordinating center. These trials will test whether those taking metformin experience delayed development or progression of age-related chronic diseases—such as heart disease, cancer, and dementia.

Delaying Multimorbidity is the Target

The aging definition team settled on incident multimorbidity as the endpoint for the trial that would become TAME. Multimorbidity means suffering from two or more of the supposedly independent diseases of aging at once. More than two thirds of Americans over the age of 65 have two or more chronic diseases, and half of those who have at least two have four or more. And the prevalence of multimorbidity rises exponentially with age, just as individual diseases of aging do.

IF a single therapy were to delay the onset of any of several seemingly-independent diseases of aging — plus death from any cause, the risk of which is increased by multimorbidity and accelerated by aging — it would put the lie to the very idea that these diseases truly are independent. In the process, it would mark the therapy as a credible anti-aging drug.

The TAME team had considered this carefully, and had designed a simple multimorbidity composite score to serve as the trial’s endpoint. The trial would track how long it took people taking either metformin or placebo to be newly diagnosed with some particular “disease of aging” (selected from cardiovascular disease, cancer, or cognitive disease). The analysis would be based on the delay in developing each additional diagnosed disease (or death), rather than simply whether the volunteers developed one or more of them (or not) over the course of the trial.

Importantly, while the subjects in the trial will not have diabetes or a recent cancer diagnosis, they may be at elevated risk (over and above their ages) for diseases of aging based on conventional risk factors, such as being prediabetic (but not full-on diabetic); overweight (but not obese); or having high LDL cholesterol or blood pressure.

IF a candidate longevity therapeutic (metformin in this case, or a future candidate in a trial modeled on the TAME template) delays the onset of these diseases, it would likely be for a reason that doctors could not cover by just managing “the usual [risk factor] suspects.” Instead, the reason for the delay would presumptively be that the drug was impacting aging.

Espeland MA, Crimmins EM, Grossardt BR, Crandall JP, Gelfond JA, Harris TB, Kritchevsky SB, Manson JE, Robinson JG, Rocca WA, Temprosa M, Thomas F, Wallace R, Barzilai N; Multimorbidity Clinical Trials Consortium. Clinical Trials Targeting Aging and Age-Related Multimorbidity. J Gerontol A Biol Sci Med Sci. 2017 Mar 1;72(3):355-361. doi: 10.1093/gerona/glw220. PMID: 28364543; PMCID: PMC5777384.