Fight Aging!

Today's open access commentary is a good companion piece to a recent paper covering the use of mesenchymal stem cell therapies to suppress age-related chronic inflammation. These first generation stem cell therapies have proven to be unreliable when it comes to the original goal of regeneration of organ function, but they do reliably reduce excessive inflammation for some months. Transplanted stem cells near all fail to survive and engraft. Some clinics report better results than others on this front, but there is little understanding at present as to why similar cells sources and methodologies can produce wildly different outcomes in different hands. Benefits in most cases arise due to transient signaling by the transplanted cells that changes the behavior of native cells for some time.

The chronic inflammation of aging and physical frailty go hand in hand. Inflammation is disruptive of normal tissue maintenance, both of muscle tissue and in vital organs. Controlling inflammation can produce patient benefits. A great many clinical trials, including those aiming to treat age-related frailty, have been based on this approach of targeting regulatory mechanisms of inflammation. Still, first generation mesenchymal stem cell therapies are not yet as widely used as they might be, most likely due to the continued issues with consistency of outcomes from clinic to clinic and patient to patient. Much remains to be explored regarding the reasons why this variability exists.

Inflammation, a common mechanism in frailty and COVID19, and stem cells as a therapeutic approach

Many research labs have developed cell therapies in search for tissue homeostasis improvement. To date, there are more than 38 clinical trials using stem cells against the effect of aging or frailty, although there are far fewer with mesenchymal stem cells (MSCs). Recently, randomized double blind studies showed that intravenous administration of allogeneic MSCs is safe, renders improved physical performance, and reduces inflammatory markers increased in frailty states.

In the first of these trials, 15 patients with mild to moderate frailty were treated with MSCs. This phase 1 study focused on safety evaluating severe adverse effects during 12 months after the injection of 20 to 200 million MSCs. Besides safety, the results showed improvements in physical activity, cognitive hallmarks, and bloodstream TNF-α levels. In phase II (random, double blind with placebo), 30 frailty patients were injected with 100 to 200 million MSCs resulting in positive results in activity hallmarks and several immune biomarkers 6 months after the injection. These studies, together the other trials, support the safety and efficacy of the intravenous injection of allogeneic MSCs from bone marrow against frailty.

The downside of these studies is the lack of consistency among the methodology used, with significant variations in the number of infused cells, cell origin, quality of the donor and their MSCs, and hemocompatibility, all common problems of MSC therapies. Tolerance to these treatments, demonstrated in hundreds of patients in multicenter trials, and the reversion of some parameters compromised in frailty make these therapies a well-founded hope. However, to progress in this approach, the field will need the establishment of new and consistent animal models, as well as a better and systematized diagnosis of frailty conditions through more sensible and validated biomarkers.

In summary, MSC research during the last decades has been a rollercoaster of promises, controversies, and unexpected discoveries, which have changed our perspective of their potential use as a therapy on different human conditions and diseases. We believe that although the original promises have not been met, the intense dedication to their study has opened new alternatives to use their less known paracrine properties on immunomodulation and aging to find new solutions to extremely important challenges of public health, such as the increasing incidence of frailty conditions.