Mouse studies and safety to accelerate longevity drugs

Professor Mikhail Blagosklonny takes a look at therapeutic research done within the longevity field and concludes that there must be a re-focusing on lifespan extension.

Advancements in modern medicine and a focus on lifespan and healthspan medicine mean that people are living longer. Centenarians – people who live to be over 100 – are no longer uncommon, but could clinical trials for longevity be shorted when using repurposed drugs? One key opinion leader doesn’t think so and is advocating change.

Longevity.Technology: Prolonged life is accompanied by increased incidence of aging diseases. Elderly patients often suffer from co-morbidities including Alzheimer’s, cancer and frailty; the next logical step for medicine, therefore, is to make the added years healthier and for policy makers to drive this progress through regulation and funding.
longevity explainer
Longevity research has various hypotheses of just how aging comes to be. For instance, the geroscience hypothesis focuses on treating age-related diseases, such as cancer, by slowing down aging. However, one of the underlying flaws is that it assumes that aging must be caused by molecular damage that can be treated.

Indeed, many studies focus on anti-oxidant levels, telomere length and other hallmarks of aging; but mortality often occurs before those markers reach a critical and lethal level. This puts into question: is data for lifespan from non-lethal markers valid?

Hyperfunction theory of aging on the other hand puts “aging as a sum of all the age-related diseases and not their risk factors”. It also states that aging occurs due to overactivation, thus hyperfunction, of signalling pathways. Professor Mikhail Blagosklonny, of the Roswell Park Cancer Institute, Buffalo argues for hyperfunction theory in his recent research perspective The goal of geroscience is life extension, writing that “aging and diseases are two sides of the same coin: diseases are manifestations of aging [1].”

The goal of geroscience, writes Professor Blagosklonny, is the extension of lifespan by extending healthspan.

In reviewing FDA-approved drugs on the market (utilised in longevity research) Professor Blagosklonny came to the conclusion that, more often than not, the outcome of these preliminary trials does increase healthspan but decreases lifespan, thus ‘compressing’ the diseased aging period.

Professor Blagosklonny’s approach would, he argues, “make the current generation of adults live longer and healthier, without conducting lifelong randomized clinical trials.” Professor Blagosklonny explains: “Even if such trials would be started, only the next generation may benefit. But such clinical trials are not needed anymore.

For practical purposes, it is both necessary and sufficient that a drug consistently and significantly extend lifespan in mice (and other mammals, if tested) and be already approved for any indication in humans. Given that no proof of life extension in humans (and other long-lived mammals) can be available in our lifetime, we need strong evidence in rodents.”

He outlines one drug that is consistent in prolonging healthspan and lifespan across the literature in various murine models – rapamycin. This drug is normally used as an immunosuppressant in transplant patients. One of the proposed mechanistic pathways for aging according to hyperfunction theory is the mTOR pathway and rapamycin has coincidentally this specific target.

Indeed, there has recent focus on rapamycin as an anti-aging treatment; AgelessRx are conducting a Participatory Evaluation of Aging with Rapamycin for longevity (PEARL) trial. It’s a large-scale trial that will give volunteers rapamycin supplements and monitor them, which is the first intervention trial for longevity [2].

He believes that if drugs have been deemed safe by the FDA and equivalent health and safety organisations, then there is nothing preventing their prescription as supplements.

The Coronavirus has focused the world on the need for compressed trials in certain circumstances; longevity leaders have recently called for trials of rapamycin to treat COVID-19 to get underway as soon as possible, and Oxford’s Professor Lynne Cox wrote in The Lancet advocating for the imminent initiation of trials of potential geroprotective therapies.

Professor Blagosklonny argues that these kinds of trials are key for longevity as conducting conventional human trials and monitoring people throughout their lives is not a realistic goal. He believes that if drugs have been deemed safe by the FDA and equivalent health and safety organisations, then there is nothing preventing their prescription as supplements.

It seems logical that if rapamycin has shown healthspan and lifespan benefit in mice, and it is safe for human consumption with a known mechanistic target mTOR, then it would be safe and might well have the same beneficial effect in humans. As Professor Blagosklonny puts it: “We have one life to live and cannot wait for results in others, if we want to live longer ourselves.”