Use of Mesenchymal Stem Cell Therapy for Aging Frailty

Frailty has been clinically defined as “a state of increased vulnerability resulting from aging-associated decline in reserve and function across multiple organ systems such that the ability to cope with everyday or acute stressors is compromised.”

Central to this geriatric medical syndrome is the notion that it has multiple causes and contributors that lead to the characteristic decreases in strength, endurance, activity, energy levels, and physiologic function, which increase the susceptibility to dependency and death. Although frailty is not characterized as a disability, it does increase the risk of disability in affected individuals. 

Patients also tend to show a greater risk of frailty when there are other comorbidities affecting their physical and psychological well-being, such as cardiovascular disease, diabetes, high blood pressure, cancer, or cognitive impairment. The main clinical presentations of frailty are falls, which are a result of impaired balance, gait, and awareness. Also other non-specific signs and symptoms, such as unexplained weight loss, infections and extreme fatigue.

“Inflammaging” is a term that has been used to depict the particular molecular and cellular inter-related events that promote the process of aging. With aging, there is a continuous accumulation of damaged macromolecules and cells, generation of toxic metabolites and microbial byproducts, and development of cellular senescence and immunosenescence. 

Not only does inflammaging accelerate the aging process, it is linked with and accelerates the diseases associated with aging, including cardiovascular diseases, cognitive, and neurologic impairments, cancer, and degenerative joint disease. Importantly, the increased susceptibility to disease and death is a result of these molecular inflammation-related changes in physiological systems.

There is evidence that some inflammatory biomarkers such as TNF-α, interleukin-6 (IL-6), and C-reactive protein (CRP) increase during aging and that they can be independent predictors of mortality. This same inflammatory response underlies the tissue damage linked to various age-related chronic diseases. 

An individual’s endogenous stem cell production and function decreases with age and this decrease likely contributes to reduced ability to regenerate and repair organs and tissues. For instance, there is evidence that mesenchymal stem cells (MSCs) undergo senescence, their multilineage differentiation and homing capacity and immunomodulatory and wound healing properties gradually disappear. 

The use of mesenchymal stem cells for frailty therapy has been under study for a while. Some specific features of the frailty syndrome support a potential role of MSCs to ameliorate or improve frailty. MSCs are drawn to sites of injury, where they act to reduce inflammation and promote cellular repair. MSCs improve cardiovascular outcomes in patients with acute myocardial infarction, as well as, ischemic and non-ischemic cardiomyopathy, reduce TNF-α

and CRP levels, and are safe in patients irrespective of age. 

MSCs have effects in different frailty phenotypes such as: 

• Unintentional weight loss: they decrease chronic inflammation, onset of sarcopenia, and also decrease TNF-α, CRP and increase IL-10 and TFG-ß (which are anti-inflammatory cytokines).
• Low energy levels or exhaustion: they increase pulmonary function and decrease chronic inflammation. Increase endothelial function and decrease inflammatory biomarkers. 
• Weak grip strength: they can increase physical performance and endogenous stem cell function. 
• Slow gait speed: they can increase the 6 minute walk distance, increase endothelial function, cardiac performance and skeletal muscle performance.
• Low physical activity: they can decrease chronic inflammation and increase quality of life. 

MSCs can evade and modulate the host’s immune system to prolong their therapeutic effects without being detected and eliminated. The absence of major histocompatibility complex (MHC)/human leukocyte antigen (HLA) class II and associated costimulatory molecules and low levels of MHC/HLA class I molecules expressed by MSCs enables them to evade detection by the host immune system.

Currently there is no specific treatment approved for frail patients and therefore no established standard of care. The ultimate goal is to lengthen the healthy lifespan and restore or maintain cognitive and physical functionality of patients. Phase I studies using between 20 up to 200 million MSCs IV were reported to be well tolerated with no serious adverse events, indicating their safety, and patients had reductions of inflammatory biomarkers and increase in physical function. Several phase II trials are under development due to the good and promising results of phase I studies.

---

Source: Schulman IH, Balkan W, Hare JM. Mesenchymal Stem Cell Therapy for Aging Frailty. Front Nutr. 2018;5:108. Published 2018 Nov 15. doi:10.3389/fnut.2018.00108

Source link: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6249304/