Application of mesenchymal stem cell therapy for aging frailty: from mechanisms to therapeutics

Abstract

Aging frailty is a complex geriatric syndrome that becomes more prevalent with advancing age. It constitutes a major health problem due to frequent adverse outcomes. Frailty is characterized by disruption of physiological homeostasis and progressive decline of health status. Multiple factors contribute to development of frailty with advancing age, including genome instability, DNA damage, epigenetic alternations, stem cell exhaustion, among others. These interrelated factors comprehensively result in loss of tissue homeostasis and diminished reserve capacity in frailty. Therefore, the aged organism gradually represents symptoms of frailty with decline in physiological functions of organs. Notably, the brain, cardiovascular system, skeletal muscle, and endocrine system are intrinsically interrelated to frailty. The patients with frailty may display the diminished reserves capacity of organ systems. Due to the complex pathophysiology, no specific treatments have been approved for prevention of this syndrome. At such, effective strategies for intervening in pathogenic process to improve health status of frail patients are highly needed. Recent progress in cell-based therapy has greatly contributed to the amelioration of degenerative diseases related to age. Mesenchymal stem cells (MSCs) can exert regenerative effects and possess anti-inflammatory properties. Transplantation of MSCs represents as a promising therapeutic strategy to address the pathophysiologic problems of frail syndrome. Currently, MSC therapy have undergone the phase I and II trials in human subjects that have endorsed the safety and efficacy of MSCs for aging frailty. However, despite these positive results, caution is still needed with regard to potential to form tumors, and further large-scale studies are warranted to confirm the therapeutic efficacy of MSC therapy.

Keywords: aging; aging frailty; mesenchymal stem cells; regenerative medicine; stem cell therapy.

Figure 1

Overview of Aging Frailty and its Pathophysiology. In the process of aging, several genetic and environmental factors gradually result in the loss of tissue homeostasis and organ dysfunction, ultimately leading to the progression of frailty in the aged organism.

Figure 2

Neuroprotective Effects of MSCs on Aging Brain. Administration of MSCs have shown therapeutic potential for the treatment of age- related brain dysfunction. The neuroprotective effects of MSCs include promoting neurogenesis, neural differentiation and anti-inflammation, and these effects are mainly associated with paracrine functions. In addition, MSCs could improve cognitive functions through reducing plaque deposition and enhancing synaptic stability. Abbr: NGF: nerve growth factor; VEGF: vascular endothelial growth factor; FGF2: fibroblast growth factor 2; IL-2: interleukin-2; TGF-β: transforming growth factor-β.

Figure 3

Cardioprotective Effects of MSCs. With advancing age, heart often develop decreased cardiac performance. The progressive cardiac structural remodeling results in low cardiac function and cardiovascular diseases that may contribute to aging frailty. After administration, MSCs home to the injured regions, where MSCs differentiate into endothelial cells and cardiomyocyte-like cells to promote neovascularization and cardiac functions. MSCs can suppress the excessive inflammatory responses and subsequent fibrosis via paracrine functions. MSC therapy show positive results by improving the prognosis of cardiovascular diseases.

Figure 4

Protective Effects of MSCs on Muscles. Sarcopenia is a major contributor to frailty in the elderly. Transplanted MSCs can exert protective effects on muscles, including inhibition of muscles apoptosis and regulation of chronic inflammatory as well as activation of resident skeletal muscle stem cells. Administration of MSCs can promote myogenesis and improve physical performance.

Figure 5

Therapeutic Effects of MSCs on Abnormal Hormones. Age-related alternation in hormonal networks include the decline in levels of circulating anabolic hormones and insulin resistance, which are associated with development of frailty. Administration of MSCs can increase the levels of anabolic hormones through paracrine functions and improve insulin sensitivity by regulating immune response. MSC therapy attenuate the age-related structural and functional changes of muscle and bone, thereby promoting the quality of life among the older adults.