Cell and Cell-Free Therapies to Counteract Human Premature and Physiological Aging: MSCs Come to Light

Abstract

The progressive loss of the regenerative potential of tissues is one of the most obvious consequences of aging, driven by altered intercellular communication, cell senescence and niche-specific stem cell exhaustion, among other drivers. Mesenchymal tissues, such as bone, cartilage and fat, which originate from mesenchymal stem cell (MSC) differentiation, are especially affected by aging. Senescent MSCs show limited proliferative capacity and impairment in key defining features: their multipotent differentiation and secretory abilities, leading to diminished function and deleterious consequences for tissue homeostasis. In the past few years, several interventions to improve human healthspan by counteracting the cellular and molecular consequences of aging have moved closer to the clinic. Taking into account the MSC exhaustion occurring in aging, advanced therapies based on the potential use of young allogeneic MSCs and derivatives, such as extracellular vesicles (EVs), are gaining attention. Based on encouraging pre-clinical and clinical data, this review assesses the strong potential of MSC-based (cell and cell-free) therapies to counteract age-related consequences in both physiological and premature aging scenarios. We also discuss the mechanisms of action of these therapies and the possibility of enhancing their clinical potential by exposing MSCs to niche-relevant signals.

Keywords: MSCs; cell therapies; cell-free therapies; extracellular vesicles; inflammation; paracrine mechanism; physiological aging; premature aging; stem cell exhaustion.

Figure 1

Age-related suitability of MSCs or derived products to be used as therapeutics to counteract human aging or age-related pathologies. MSCs’ number and functional capabilities diminish as the donor’s age increases, with those isolated from neonatal tissues, or their EVs, such as umbilical cord MSCs showing the greatest clinical potential. Thus, elderly individuals affected by systemic conditions such as inflammation and frailty or by age-related pathologies such as cardiovascular disease, acute respiratory distress syndrome (shown in severe COVID-19 patients) and musculoskeletal conditions (fractures, OA) among others, would be especially benefitted by young MSC-based treatments.