Ageing Frailty

About

The geriatric syndrome of frailty is a common clinical syndrome based on the accumulation of multi-systemic function declines and the increase in susceptibility to stressors during biological ageing [1-2]. This can manifest in a variety of symptoms, such as loss of muscle mass and decreased muscle strength, reduced mobility, and impaired cognitive function. Frailty leads to reduced resistance to stressors and diminished reserve capacity, which increases susceptibility to falls, hospitalisation, institutionalisation, disability and death. There are several factors that can contribute to the development of frailty in the elderly, including chronic health conditions, inadequate nutrition and a lack of physical activity. Identifying and addressing these underlying causes can help prevent or delay the onset of frailty and may improve quality of life and overall health. There are no specific medical treatments that ameliorate or reverse frailty. Therapeutic interventions have mainly focused on exercise, nutrition and multidisciplinary methods to extend the well-being and ability of a patient to regenerate functionality [3].

The Impact of Inflammation in Ageing Frailty

Chronic inflammation underlies the geriatric syndrome of frailty, leading to declines in mobility and gait, sarcopenia, osteopenia, and increased susceptibility to infectious diseases [1-2, 5-6]. In the process of ageing, genetic and environmental factors gradually result in loss of tissue homeostasis, stem cell depletion and organ dysfunction, ultimately leading to the progression of frailty in the aged individual [1-2].

As we age, there is a gradual build-up of damaged cells and macromolecules, toxic metabolites and byproducts in our bodies, and emergence of cellular senescence and immunosenescence [4-5]. Although the exact biological mechanisms underlying ageing frailty are not yet fully understood, it is thought to be caused in part by long-term, low-grade inflammation termed “inflammaging” [5-6].

Circulating levels of proinflammatory cytokines, particularly TNF-α, IL-6, and CRP, increase during ageing and are independent predictors of mortality in frail patients [7]. Not only does “inflammaging” accelerate the ageing process, it´s linked to chronic age-related diseases, like cardiovascular disease, cognitive and neurologic impairments, cancer, and osteoarthritis [8]. 

There is also a strong link between frailty, inflammation, and the impaired ability to repair tissue injury due to decreases in endogenous stem cell production [9]. 

The Potential of Mesenchymal Stem Cells in Ageing Frailty

MSCs hold great potential in the treatment of ageing frailty, given their anti-inflammatory, regenerative and immunomodulatory properties. MSCs are believed to help the body repair by creating a regenerative microenvironment that supports and promotes the natural healing of injured tissue. Numerous experimental studies have shown that MSCs migrate to sites of injury and inflammation in response to environmental signals, where they interact with the local microenvironment, primarily by secretion of numerous bioactive molecules and through cell-to-cell contact. The proposed mechanisms of MSC include modulating the immune system to attenuate harmful inflammation and promote regeneration, rescuing injured cells and promoting cell survival, stimulating endogenous progenitor cells, and inducing new blood vessels in damaged tissue [10-11]. MSCs communicate with immune cells of both the adaptive and innate immune system in a complex manner. Upon exposure to inflammation, MSCs secrete anti-inflammatory and immunoregulatory cytokines such as IL-10 and TGF-β1 and reduce levels of pro-inflammatory cytokines like TNF-α, IL-1β, IL-6 and CRP [12]. This leads to suppression of inflammatory immune cells and increase of regulatory cells, thereby promoting an anti-inflammatory milieu, which could prove beneficial in the context of “inflammaging” [13]. Cardiovascular disease is an especially common comorbidity of the frailty syndrome, and multiple clinical studies have indicated beneficial effects of MSC administration in various cardiovascular conditions [14-16]. MSC have also been postulated to ameliorate sarcopenia and osteoporosis in musculoskeletal frailty [17]. In animal models of sarcopenia, MSC treatment was associated with increased muscle strength and skeletal muscle weight [18]. Similarly, in mice models of osteoporosis, MSC from young mice administered to old mice improved osteoporosis and increased the life span of the older mice [19]. Globally, research on MSCs for diseases common in ageing frailty include: Alzheimer’s disease [20] Diabetes [21] Chronic lung disease [22] Osteoarthritis [23] Cardiovascular disease [15-16]

Clinical Trials

Intravenous MSC therapy for ageing frailty has undergone phase I, II and IIb clinical trials in the US [24-25]. The phase I pilot study included 15 patients and indicated that MSC therapy is well-tolerated in frail elderly and was associated with improvement in several measures of frailty, including physical performance, as measured by 6-min walking distance (6MWT), the physical component of the SF-36 quality of life assessment and forced expiratory volume in 1 second (FEV 1), as well as a significant decrease in TNF-α, an important biomarker associated with chronic inflammation and immunity. The following phase II study was a randomized, blinded and placebo-controlled trial of 30 patients with ageing frailty. The 6MWT, short physical performance exam and FEV-1 improved significantly, especially in the group that received an intravenous dose of 100 million MSC. Treated groups also had decreased levels of inflammatory markers, compared to placebo. A large phase IIb clinical trial including 148 patients has been completed, with preliminary results announced, indicating improved physical performance. Given the strong safety profile and indications of therapeutic potential of MSC demonstrated in these early phase trials, we are conducting our trial to evaluate the safety, tolerability and efficacy of human allogeneic bone marrow-derived mesenchymal stem cells in patients with ageing frailty.

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16. Perin E, Borow K, Henry T, et al. Randomized Trial of Targeted Transendocardial Mesenchymal Precursor Cell Therapy in Patients With Heart Failure. J Am Coll Cardiol. 2023 Mar, 81 (9) 849–863.https://doi.org/10.1016/j.jacc.2022.11.061

17. Mahindran E, Law JX, Ng MH, Nordin F. Mesenchymal Stem Cell Transplantation for the Treatment of Age-Related Musculoskeletal Frailty. Int J Mol Sci. 2021 Sep 29;22(19):10542. doi: 10.3390/ijms221910542. PMID: 34638883; PMCID: PMC8508885. 

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21. Li Y, Wang F, Liang H, et al. Efficacy of mesenchymal stem cell transplantation therapy for type 1 and type 2 diabetes mellitus: a meta-analysis. Stem Cell Res Ther. 2021;12(1):273. Published 2021 May 6. doi:10.1186/s13287-021-02342-5

22. Cruz, F.F. and Rocco, P.R.M., 2020. The potential of mesenchymal stem cell therapy for chronic lung disease. Expert Review of Respiratory Medicine14(1), pp.31-39.

23. Copp G, Robb KP, Viswanathan S. Culture-expanded mesenchymal stromal cell therapy: does it work in knee osteoarthritis? A pathway to clinical success. Cell Mol Immunol. 2023 Jun;20(6):626-650. doi: 10.1038/s41423-023-01020-1. Epub 2023 Apr 25. PMID: 37095295; PMCID: PMC10229578.

24. Golpanian, S., DiFede, D.L., Khan, A., Schulman, I.H., Landin, A.M., Tompkins, B.A., Heldman, A.W., Miki, R., Goldstein, B.J., Mushtaq, M. and Levis-Dusseau, S., 2017. Allogeneic human mesenchymal stem cell infusions for aging frailty. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences72(11), pp.1505-1512. 

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