Inflammatory Aging & MSC Infusion for Frailty

Inflammatory aging (Inflammageing) is a sterile, low-grade chronic inflammation that gradually increases with age. Not only is it a sign of old age, it can also lead to decline in health, frailty, and age-related diseases.

Inflammatory drivers of aging: the 'garbage accumulation theory'

Why inflammatory aging occurs is unclear, but there is a hypothetical model of cellular debris accumulation , also known as the "garb -aging " theory . Intracellular macromolecules become damaged with age, and together with a progressive decline in repair and autophagy, this accumulated macromolecular damage leads to increased levels of cellular "junk" that triggers inflammation through innate immune signaling.

This theory is fully consistent with the subsequently identified hallmarks of aging, including loss of proteostasis , destabilization of the genome (including a decline in repair capacity) , and altered cellular signaling . Although, garbage accumulation may play an important role in local and systemic inflammation, it is unlikely to be the sole driver of inflammation.

Cytokines in Chronic Inflammation

Chronic sterile inflammation (inflammatory aging) increases with chronological age in most populations . The overall inflammatory state is not only related to the increase of individual inflammatory markers, but also to the complex interaction between various inflammatory mediators.

1. Elevated pro-inflammatory markers

With age, inflammatory factors in the blood increase, including IL-6, IL-8, IL-15, soluble glycoprotein 130 (SGP130, involved in IL-6 signal transduction) , sCD30 and MCP-1, etc.

Among the common clinical serum biomarkers used to assess inflammation, CRP and IL-6 are by far the most intensively studied among the pro-inflammatory factors. They ( especially IL -6) are strongly associated with aging , poor physical performance and mortality, and IL -6 can induce the production of acute phase proteins such as CRP .

IL-6 is an "aging factor" that affects the brain, bones and skeletal muscles of the elderly. IL-6 can pass through the blood-brain barrier(BBB), and can also be released by nerve cells to change the neural microenvironment and adversely affect neurogenesis and neurons. In bone tissue, IL-6 can affect the balance between osteoblasts and osteoclasts, which is related to osteoporosis and osteolytic diseases. In skeletal muscle, depletion of IL-6 levels can exert catabolic effects, altering the local redox balance. IL-6 can also induce further inflammatory signaling through SASPs; thus, locally high levels of pro-inflammatory cytokines have a self-reinforcing capacity.

Aging Research Reviews 80 (2022) 101697Plasminogen Activation Inhibitor-1 (PAI-1, also known as SERPIN1) belongs to the same cluster of pro-inflammatory cytokines as IL-6 and CRP, and levels of PAI-1 are associated with other aging features, including decreased walking speed and reduced grip strength , is a sign of weakness.

2. Anti-inflammatory cytokines

Anti-inflammatory factors, by their very nature, promise to reduce inflammatory aging .

IL-37 , a powerful anti-inflammatory cytokine , does, suppressing inflammation. Transgenic mice expressing human IL-37 rarely increase aging-associated proinflammatory cytokines, maintain B-cell progenitor function with age, restore T-cell function, and improve vascular, metabolic, and motor function.

Likewise, the level of IL-10 (an anti-inflammatory cytokine) was negatively correlated with increasing age, and IL-10 was included in the anti-inflammatory cluster along with high-density lipoprotein cholesterol and was associated with a good prognosis in patients with acute coronary syndrome.

With increasing age,Many anti-inflammatory factors become associated with poor physiological function. For example sTNFR ( soluble TNF receptor ) acts as an inhibitor of TNF-α pro-inflammatory signaling by preventing the interaction of TNF-α with membrane TNFR. Therefore, they would be expected to be anti-inflammatory factors that are strongly positively associated with increasing age and are associated with poor body condition.

IL-1RA (interleukin-1 receptor antagonist), which blocks IL-1 signaling and acts as an anti-inflammatory. However, IL-1RA levels were positively correlated with age and belonged to the same cluster as IL-6 and CRP, and were a significant predictor of mortality in older adults independent of inflammatory exposure or genotype.

Two other soluble interleukin receptors, IL-2sR (IL-2 soluble receptor) and IL-6sR (IL-6 soluble receptor) , belong to the same cluster as TNF-α and sTNFRs, and are associated with poorer related to bodily functions.

The link between several anti-inflammatory factors and aging does not necessarily mean that these molecules are harmful and cause inflammation. Instead, their elevation may reflect an adaptive physiological response to pro-inflammatory stimuli in an attempt to suppress inflammation. If high levels of anti-inflammatory factors are associated with adverse outcomes, it may be that adaptive responses have failed to reduce inflammation below a destructive threshold.

3. Pro-inflammatory/anti-inflammatory dual cytokines

IL-18 and TNF-α can exhibit both anti-inflammatory and pro-inflammatory effects, among which IL-18 increases with age and is an independent risk predictor of 5-year and 10-year mortality.

Inflammatory aging and immune aging

Inflammatory aging, due to increased tissue immune cell senescence (immunosenescence) , and aging-related changes in the microenvironment and immune cells , which together lead to high levels of sterile inflammation, and many secreted inflammatory factors, these are inflammatory aging sign .

ImageCollectively, immunosenescence is intricately linked to inflammatory aging through interactions between all components of the innate and adaptive immune systems, and through inflammatory contributions from SASPs of senescent cells throughout the body.

Therefore, when the body is aging, adaptive immune cells increase autoimmunity to promote inflammation, and pro-inflammatory factors ( Th17 ) are activated. Pro-inflammatory response. Senescent macrophages may be unable to clear SASP-secreting senescent cells from tissues, and thus, senescence of innate immune cells can directly or indirectly promote inflammation.

Comment: As the human body ages, inflammatory aging occurs. Physical exercise (reduces chronic inflammation) , diet (Mediterranean diet, rich in plant foods, etc.) can play a role. Some corresponding drug development is also in progress, and good clinical results are expected.

Infusion of MSCs may extend the healthy lifespan of fragile individuals

Frailty, characterized by reduced physical and immune function, is associated with stem cell depletion. Human allogeneic mesenchymal stem cells (allo-hMSC) exert immunomodulatory effects and promote tissue repair, potentially extending the healthy lifespan of aging and fragile individuals.

Frailty is a constellation of clinical syndromes with corresponding clinical manifestations characterized by age-related decline in physiological function, endurance, and strength that may be secondary to multiple factors and is associated with a high risk of hospitalization, poorer clinical outcomes related to mortality. The overall prevalence of frailty is estimated at 9.9% and is more common in women and people with chronic diseases. People with frailty often have a shortened "lifespan" and a corresponding increase in dependence on others for daily living.

Impaired physiological functions over time, especially in the elderly and frail, increase the likelihood of death. It can be seen that frailty is one of the most serious global public health challenges that will be faced in the new century. The rapid growth of the aging population has brought about an increase in the number of elderly frail people, which in turn has brought greater challenges to the health care system. pressure. Therefore, it is necessary to tailor interventions to individuals to maintain good physical function and achieve independent living and cognitive abilities.

causes of frailty

There are many causes of frailty in the elderly, including: genetics, growth and development, coexistence of multiple diseases, malnutrition, and environmental factors. Therapeutic interventions for aging frailty focus primarily on exercise, nutritional supplementation, and a multidisciplinary approach. Therefore, the goal of any potential frailty therapy is to focus on extending the patient's healthy life and restoring physiological function.

Healthcare practitioners have long used the term “frailty” to describe a subset of older adults who appear to be frailer and more fragile than their peers. The latest standards for judging frailty are roughly based on the six dimensions in the figure below.

Taken together, key hypotheses that contribute to the frailty of aging include inflammation and accelerated depletion of endogenous stem cells, resulting in a reduced ability to regenerate or repair organs and tissues. Therefore, regenerative medicine based on cell therapy can improve debilitating signs and symptoms.

Mesenchymal stem cells ( MSCs ), as a type of multipotent adult stem cells, have the potential of self-renewal and multi-lineage differentiation. Furthermore, increasing evidence suggests that MSCs exert immunomodulatory, repairing, and regenerative effects through high paracrine activity. What's more, MSCs are immune-privileged, meaning that allogeneic MSC transplantation does not induce an inflammatory response. These characteristics make mesenchymal stem cells an ideal seed cell for cell therapy after hematopoietic stem cells.

Ongoing clinical trials have initially confirmed that mesenchymal stem cells are safe and effective in treating frailty in the elderly.

Mesenchymal stem cell infusion to treat aging and frailty

Phase 1 clinical study

In July 2017, a Phase 1 clinical study published in the Journal of Gerontology evaluated the safety and potential efficacy of intravenous allogeneic human mesenchymal stem cell therapy in patients with aging and frailty.

In this non-randomized, dose-escalating study, a total of 15 eligible geriatric frailty patients were divided into 3 groups, receiving a single intravenous infusion of 20 million (2×10 7 ) and 100 million ( 1 ×10 8 ) and 200 million ( 2×10 8 ) MSCs. The study's primary endpoint is the incidence of any treatment-emergent serious adverse event 1 month after MSC infusion, with secondary endpoints measuring recovery of physiological function and inflammatory biomarkers at 3 and 6 months, respectively. The change.

The 6-minute walking distance increased significantly in all treatment groups, and the level of the inflammatory factor TNF-α in the MSC treatment group decreased significantly at 6 months.

Overall, the 100 million cell dose group performed best in all indicators, but the inflammatory index TNF-α was improved in both the 100 million cell dose group and the 200 million cell dose group. The 100 million cell dose group also showed significant improvement in physical scores on the SF-36 Quality of Life Assessment at all time points. One person in the 200 million cell dose group died 258 days after infusion, which was confirmed to be unrelated to the infusion of MSCs.

This Phase 1 study reveals MSC therapy is safe and tolerable in aging patients with frailty. Given the improvements in functional and immune status demonstrated, we believe continued clinical development of MSC therapies is necessary for frailty.

Phase 2 clinical study

Based on the results of the Phase 1 trial, the team continued and expanded a Phase II randomized, double-blind, placebo-controlled clinical trial comparing intravenous injection of allogeneic hMSC (100 million cell dose group and 200 million cell dose group ) Clinical outcomes in frailty patients compared with placebo. The subjects were 30 frail elderly patients with an average age of 75.5±7.3 years old. The study's primary endpoint is the incidence of serious adverse events ( TE-SAE ) 1 month after infusion , and secondary endpoints include physical performance, patient-reported outcomes and frailty immune markers measured 6 months after infusion.

Quality of life and functional status were monitored throughout the study. Interestingly, improvements were preferentially seen in patients in the 100 million cell dose group. There was no significant change in the 200 million cell dose group or the placebo group at 6 months.

In terms of sexual function, among female patients, the SQOL-F ( Quality of Sexual Life Questionnaire for Women ) score in the 100 million dose group increased significantly 6 months after MSC treatment, and conversely, the IIEF ( International Index of Erectile Function ) score in male participants No significant changes.

After making two important observations, the researchers came to preliminary conclusions. First, cell therapy improved a series of functional indicators, which supports the concept that MSC has anti-aging and anti-frailty biological activity; second, the 100 million cell amount represents the peak response dose for clinical effects, while the 200 million cell dose group appeared Negatively associated plateau and/or decreased efficacy.

The low-dose group experienced significant improvements in physiological and immunological markers of frailty, whereas the high-dose group showed only positive immunomodulatory effects. The researchers believe that the reasons behind this inverse dose relationship are still not fully understood, and it may be that cellular drugs have the same optimal reference dose as traditional drugs.

The researchers further speculated that the nonlinear dose-response curve in cell therapy may be related to the following factors:

1. Higher cell concentration may cause physical effects such as cell aggregation and damage cell activity;

2. Cell damage due to excessive shear force on cells during infusion affects the relationship between cell dose and clinical benefit;

3. Improve cell activity and/or genetic modification to enhance its activity, rather than simply relying on large doses to win.

summary

Older age and frailty are associated with increased inflammation in the body. Markers of chronic inflammation, such as TNF-α and leukocytosis, are associated with aging and age-related diseases. TNF-α in particular is associated with increased mortality in the elderly. MSCs have immunomodulatory properties and have been shown to reduce inflammatory markers in multiple studies. So it's not surprising that different cell doses in both studies significantly modulated the immune systems of participants.

Chronically activated T cells ( CD25 ) were suppressed after MSC infusion compared with the placebo group. MSC significantly reduced the percentage of CD8 T cells, and the immune risk phenotypes in different dose groups were significantly improved. These immune responses elicited by MSCs may have beneficial effects and may extend the healthspan of aging vulnerable individuals.

In conclusion, intravenous administration of MSCs is safe in aging vulnerable individuals. The treatment group showed significant improvements in physical performance measures and inflammatory biomarkers, both of which are hallmarks of frailty syndromes. Given the excellent safety and efficacy profile demonstrated in this study, larger clinical trials are needed to determine the efficacy of MSCs in this multisystem disease.