Lancet commentary calls for immediate large-scale clinical trials of rapamycin and rapalogs, with geroprotective consequences.
In March last year, as the global coronavirus pandemic took hold and countries one-by-one went into lockdown, Alex Zhavoronkov PhD proposed that clinical trials for low-dose rapamycin, both individually and in combination with other geroprotectors, should get underway, in order to protect the elderly from C19 . Nearly a year later, Zhavoronkov, along with Evelyne Bischof MD, Richard Siow PhD and Professor Matt Kaeberlein, PhD, have published a personal view in The Lancet Healthy Longevity calling for immediate large-scale clinical trials of rapamycin due to its potential to enhance resilience against SARS-CoV-2 infection and reduce the severity of COVID-19.
Longevity.Technology: Back in November, Longevity.Technology spoke to Dr Lynne Cox about the importance of geroprotectors, especially during COVID-19, exploring her view, expressed in The Lancet, that trials of potential geroprotective therapies should begin as soon as possible. C19 and geroprotectors are intrinsically linked, and the wider ramifications for longevity of developing geroprotectors as a result of the current pandemic are a glimmer of hope in these current dark times.
According to the authors, preclinical and clinical evidence suggests that rapamycin and rapalogs (rapamycin derivatives) could slow or reverse “age-related declines in immune function .” This decline leaves older people more more susceptible to severe complications arising from disease – and at a greater risk of death.
Rapamycin and rapalogs work by inhibiting the protein mTOR – the mammalian target of rapamycin. This protein plays a role in age regulation, and as the authors say: “Inhibition of mTOR has been shown to delay or reverse many age-related phenotypes, including declining immune function .”
Indeed, rapamycin and rapalogs are already FDA-approved and in clinical use as immunosuppressants, such as sirolimus and everolimus. The authors describe them as having “broad clinical utility and well established dosing and safety profiles .”
“Novel and effective strategies for combating COVID-19 can be developed by directly targeting the hallmarks of aging to prevent or diminish inflammaging and immunosenescence.”
The authors note that “the relationship between chronological age and COVID-19 mortality is driven primarily by the biological mechanisms of ageing [hallmarks of aging] … Previous research has revealed that these hallmarks can be directly linked to the age-associated loss of immune function concomitant with increases in systemic inflammation (also referred to as inflammaging).
“Therefore, we and others propose that novel and effective strategies for combating COVID-19 can be developed by directly targeting the hallmarks of aging to prevent or diminish inflammaging and immunosenescence ”.
A personalised approach using AI and epigenetic and deep aging clocks is proposed by the authors. They conclude: “There is an urgent need for a precision medicine trial using a functional metric of ageing that investigates individuals assessed by biological age, who can then be further stratified into groups of those individuals who achieve optimal outcomes and benefit from the treatment .”
In terms of the benefits of geroprotection and the need for clinical trials, the authors’ conclusion is a strong one.
“It is also well established that the total economic benefit from a successful geroprotective therapy far outweighs the cost of development and implementation,” they write. “Work from Goldman and Olshansky done before the COVID-19 pandemic has estimated that the total economic benefit from such an intervention will exceed US$7 trillion over the next 3–4 decades. The total economic value of an effective geroprotective strategy is likely to be substantially greater today than before the pandemic.
“Based on pre-clinical and clinical evidence, a strong case can be made for immediate large-scale clinical trials to assess whether rapamycin and other mTOR inhibitors can enhance resilience towards communicable and non-communicable diseases, prevent COVID-19 infection in those most at risk, and improve outcomes in patients with COVID-19 .”