Mesenchymal Stem Cell Therapy for Aging Frailty

Abstract

Chronic diseases and degenerative conditions are strongly linked with the geriatric syndrome of frailty and account for a disproportionate percentage of the health care budget. Frailty increases the risk of falls, hospitalization, institutionalization, disability, and death. By definition, frailty syndrome is characterized by declines in lean body mass, strength, endurance, balance, gait speed, activity and energy levels, and organ physiologic reserve. Collectively, these changes lead to the loss of homeostasis and capability to withstand stressors and resulting vulnerabilities. There is a strong link between frailty, inflammation, and the impaired ability to repair tissue injury due to decreases in endogenous stem cell production. Although exercise and nutritional supplementation provide benefit to frail patients, there are currently no specific therapies for frailty. Bone marrow-derived allogeneic mesenchymal stem cells (MSCs) provide therapeutic benefits in heart failure patients irrespective of age. MSCs contribute to cellular repair and tissue regeneration through their multilineage differentiation capacity, immunomodulatory, and anti-inflammatory effects, homing and migratory capacity to injury sites, and stimulatory effect on endogenous tissue progenitors. The advantages of using MSCs as a therapeutic strategy include standardization of isolation and culture expansion techniques and safety in allogeneic transplantation. Based on this evidence, we performed a randomized, double-blinded, dose-finding study in elderly, frail individuals and showed that intravenously delivered allogeneic MSCs are safe and produce significant improvements in physical performance measures and inflammatory biomarkers. We thus propose that frailty can be treated and the link between frailty and chronic inflammation offers a potential therapeutic target, addressable by cell therapy.

Frailty and Rejuvenation with Stem Cells: Therapeutic Opportunities and Clinical Challenges

“…All of the cell intervention subjects received single peripheral intravenous infusion of Allo-BMMSCs with a total volume of 80 mL at an average speed of 2 mL/min, so the total infusion time was 40 minutes. 14,29–31 Within the 12-month follow-up period, primary outcomes include any incidence, mainly in the first 30 days postinfusion, expressed as treatment-emergent serious adverse events (TE-SAEs), such as death, stroke, hospitalization for worsening dyspnea, nonfatal pulmonary embolism, and clinically significant serum chemistry and hematology test abnormalities. Secondary outcomes include indicators for physical function, quality of life, exercise, change in ejection fraction, and inflammatory markers, assessed at 3 and 6 months postinfusion.…”

“…AGEs, advanced glycation end products; CRP, C-reactive peptide; CXCL-10, CXC chemokine ligand-10; DHEA & DHEAS, dehydroepiandrosterone and DHEA sulfate; E2 & T, estradiol and testosterone; FGF, fibroblast growth factor; GH, growth hormone; HASF, hypoxic-induced Akt-regulated stem cell factor; HGF, hepatocyte growth factor; HGF/SF, hepatocyte growth factor/scatter factor; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon-gamma; IGF-1, insulin-like growth factor-1; IGF-1/-2, insulin-like growth factor-1/-2; IL-6, interleukin 6; IL-1β, interleukin beta-1; IL-2, interleukin-2; IL-10, interleukin-10; LH & FSH, luteinizing hormone and follicle stimulating hormone; MHC I, major histocompatibility complex class I; NK cells, natural killer cells; NO, nitric oxide; PEG2, prostaglandin E2; PGF, placental growth factor; ROS, reactive oxygen species; Sfrp2, secreted frizzled-related protein 2; TEMRA T cells, antigen experienced CD8 + T cells re-expressing the naive marker CD45RA; TGF-β1, transforming growth factor-beta1; VEGF, vascular endothelial growth factor. It is based on the literature of López-Otín et al; Clegg et al; Fried et al; Schulman et al; Tompkins et al; Larrick et al 2,3,14,16,19,28 Color images are available online.…”

“…Nevertheless, the optimal preventions and treatments are still poorly explored, and there are no specific, effective, and pathophysiology reversing strategies for the treatment of frailty. 4,14…”

Senescence in Pulmonary Fibrosis: Between Aging and Exposure

“…A second potentially groundbreaking approach to reverse pulmonary fibrosis and aging induced senescence, is represented by allogeneic injections of mesenchymal stem cell/multipotent stromal cell/marrow stromal cell (MSCs). A number of experimental and clinical evidence reveals promising results in chronic pulmonary disease, fibrosis and age-related frailty (363)(364)(365). These cells can be obtained in vitro through expansion of adherent bone marrow mononuclear cells and may function as a trophic source to support immune-senescent inflammatory cells (366).…”

Cryopreservation of Mesenchymal Stem Cells Using Medical Grade Ice Nucleation Inducer

“…MSCs possess a multi-lineage differentiation capability and immunomodulation effect through production of molecules such as PGE2, IL-6 and nitric oxide. Through these mechanisms, MSCs have demonstrated possible positive effects against human age-related diseases [4] and have already reached the clinic for diseases like Alzheimer's [5]. Minimal criteria to characterize MSCs were laid out by the International Society for Cellular Therapies (ISCT) in 2006 including, plastic adherence, tri-lineage differentiation (osteoblast, adipocyte, chondroblast) and positivity for surface markers of CD90, CD105 and CD73.…”