Mesenchymal Stem Cell Therapy for Aging Frailty

Kim J., Jo C.H., Kim H., Hwang Y.

Mesenchymal stem cells (MSCs) are of therapeutic importance in the fields of regenerative medicine and immunological diseases. Accordingly, studies evaluating MSCs for clinical applications are increasing. In this study, we characterized MSCs from the periodontal ligament, umbilical cord (UC-MSCs), and adipose tissue, which were relatively easy to obtain with limited ethical concerns regarding their acquisition, and compared their immunological characteristics. Among MSCs isolated from the three different tissues, UC-MSCs grew the fastest in vitro. The three types of MSCs were shown to inhibit proliferation of activated peripheral blood mononuclear cells (PBMCs) to a similar degree, via the indoleamine 2,3-dioxygenase and cyclooxygenase-2 pathways. They were also shown to inhibit the proliferation of PBMCs using HLA-G, which was most prominent in UC-MSCs. Unlike the other two types of MSCs, UC-MSCs showed minimal expression of HLA-DR after activation, suggesting that they pose minimal risk of initiating an allogeneic immune response when administered in vivo. These characteristics, the ease of collection, and the minimal ethical concerns regarding their use suggest UC-MSCs to be suitable MSC therapeutic candidates.

Bagno L., Hatzistergos K.E., Balkan W., Hare J.M.

Administration of mesenchymal stem cells (MSCs) to diseased hearts improves cardiac function and reduces scar size. These effects occur via the stimulation of endogenous repair mechanisms, including regulation of immune responses, tissue perfusion, inhibition of fibrosis, and proliferation of resident cardiac cells, although rare events of transdifferentiation into cardiomyocytes and vascular components are also described in animal models. While these improvements demonstrate the potential of stem cell therapy, the goal of full cardiac recovery has yet to be realized in either preclinical or clinical studies. To reach this goal, novel cell-based therapeutic approaches are needed. Ongoing studies include cell combinations, incorporation of MSCs into biomaterials, or pre-conditioning or genetic manipulation of MSCs to boost their release of paracrine factors, such as exosomes, growth factors, microRNAs, etc. All of these approaches can augment therapeutic efficacy. Further study of the optimal route of administration, the correct dose, the best cell population(s), and timing for treatment are parameters that still need to be addressed in order to achieve the goal of complete cardiac regeneration. Despite significant progress, many challenges remain.

Shi Y., Wang Y., Li Q., Liu K., Hou J., Shao C., Wang Y.

Mesenchymal stem cells (MSCs; also referred to as mesenchymal stromal cells) have attracted much attention for their ability to regulate inflammatory processes. Their therapeutic potential is currently being investigated in various degenerative and inflammatory disorders such as Crohn’s disease, graft-versus-host disease, diabetic nephropathy and organ fibrosis. The mechanisms by which MSCs exert their therapeutic effects are multifaceted, but in general, these cells are thought to enable damaged tissues to form a balanced inflammatory and regenerative microenvironment in the presence of vigorous inflammation. Studies over the past few years have demonstrated that when exposed to an inflammatory environment, MSCs can orchestrate local and systemic innate and adaptive immune responses through the release of various mediators, including immunosuppressive molecules, growth factors, exosomes, chemokines, complement components and various metabolites. Interestingly, even nonviable MSCs can exert beneficial effects, with apoptotic MSCs showing immunosuppressive functions in vivo. Because the immunomodulatory capabilities of MSCs are not constitutive but rather are licensed by inflammatory cytokines, the net outcomes of MSC activation might vary depending on the levels and the types of inflammation within the residing tissues. Here, we review current understanding of the immunomodulatory mechanisms of MSCs and the issues related to their therapeutic applications. Mesenchymal stem or stromal cells (MSCs) have attracted much attention for their ability to regulate inflammatory processes. Here, Shi et al. discuss current understanding of the immunomodulatory mechanisms of MSCs and issues related to their therapeutic application.

Voelker R.

Najar M., Krayem M., Merimi M., Burny A., Meuleman N., Bron D., Raicevic G., Lagneaux L.

Mesenchymal stromal cells (MSCs) are multipotent adult cells with relevant biological properties making them interesting tools for cell-based therapy. These cells have the ability to home to sites of injury and secrete bioactive factors as part of their therapeutic functions. However, depending on the local environment, diverse functions of MSCs can be modulated and thus can influence their therapeutic value. The specific cytokine milieu within the site of inflammation is vital in determining the fate and cell behaviors of MSCs. Indeed, inflammatory signals (called as inflammatory priming), may induce critical changes on the phenotype, multilineage potential, hematopoietic support and immunomodulatory capacity of MSCs. Thus, for appropriate clinical application of MSCs, it is important to well know and understand these effects. In summary, investigating MSC interactions with the inflammatory environment is necessary to empower the therapeutic value of MSCs.

Hulsmans M., Sager H.B., Roh J.D., Valero-Muñoz M., Houstis N.E., Iwamoto Y., Sun Y., Wilson R.M., Wojtkiewicz G., Tricot B., Osborne M.T., Hung J., Vinegoni C., Naxerova K., Sosnovik D.E., et. al.

Macrophages populate the healthy myocardium and, depending on their phenotype, may contribute to tissue homeostasis or disease. Their origin and role in diastolic dysfunction, a hallmark of cardiac aging and heart failure with preserved ejection fraction, remain unclear. Here we show that cardiac macrophages expand in humans and mice with diastolic dysfunction, which in mice was induced by either hypertension or advanced age. A higher murine myocardial macrophage density results from monocyte recruitment and increased hematopoiesis in bone marrow and spleen. In humans, we observed a parallel constellation of hematopoietic activation: circulating myeloid cells are more frequent, and splenic 18F-FDG PET/CT imaging signal correlates with echocardiographic indices of diastolic dysfunction. While diastolic dysfunction develops, cardiac macrophages produce IL-10, activate fibroblasts, and stimulate collagen deposition, leading to impaired myocardial relaxation and increased myocardial stiffness. Deletion of IL-10 in macrophages improves diastolic function. These data imply expansion and phenotypic changes of cardiac macrophages as therapeutic targets for cardiac fibrosis leading to diastolic dysfunction.

Kojima G., Avgerinou C., Iliffe S., Walters K.

Objectives: To conduct a systematic review of the literature on prospective cohort studies examining associations between adherence to a Mediterranean diet and incident frailty and to perform a meta‐analysis to synthesize the pooled risk estimates. / Design: Systematic review and meta‐analysis. / Setting: Embase, MEDLINE, CINAHL, PsycINFO, and Cochrane Library were systematically searched on September 14, 2017. We reviewed references of included studies and relevant review papers and performed forward citation tracking for additional studies. Corresponding authors were contacted for additional data necessary for a meta‐analysis. / Participants: Community‐dwelling older adults (mean age ≥60). / Measurements: Incident frailty risk according to adherence to a Mediterranean diet. / Results: Two reviewers independently screened the title, abstract, and full text to ascertain the eligibility of 125 studies that the systematic search of the literature identified, and four studies were included (5,789 older people with mean follow‐up of 3.9 years). Two reviewers extracted data from the studies independently. All four studies provided adjusted odds ratios (ORs) of incident frailty risk according to three Mediterranean diet score (MDS) groups (0–3, 4–5, and 6–9). Greater adherence to a Mediterranean diet was associated with significantly lower incident frailty risk (pooled OR = 0.62, 95% CI = 0.47–0.82, P = .001 for MDS 4–5; pooled OR = 0.44, 95% CI = 0.31–0.64, P < .001 for MDS 6–9) than poorer adherence (MDS 0–3). Neither significant heterogeneity (I2 = 0–16%, P = .30) nor evidence of publication bias was observed. / Conclusion: Greater adherence to a Mediterranean diet is associated with significantly lower risk of incident frailty in community‐dwelling older people. Future studies should confirm these findings and evaluate whether adherence to a Mediterranean diet can reduce the risk of frailty, including in non‐Mediterranean populations.

Berglund A.K., Fortier L.A., Antczak D.F., Schnabel L.V.

Autologous and allogeneic adult mesenchymal stem/stromal cells (MSCs) are increasingly being investigated for treating a wide range of clinical diseases. Allogeneic MSCs are especially attractive due to their potential to provide immediate care at the time of tissue injury or disease diagnosis. The prevailing dogma has been that allogeneic MSCs are immune privileged, but there have been very few studies that control for matched or mismatched major histocompatibility complex (MHC) molecule expression and that examine immunogenicity in vivo. Studies that control for MHC expression have reported both cell-mediated and humoral immune responses to MHC-mismatched MSCs. The clinical implications of immune responses to MHC-mismatched MSCs are still unknown. Pre-clinical and clinical studies that document the MHC haplotype of donors and recipients and measure immune responses following MSC treatment are necessary to answer this critical question. This review details what is currently known about the immunogenicity of allogeneic MSCs and suggests contemporary assays that could be utilized in future studies to appropriately identify and measure immune responses to MHC-mismatched MSCs.

Bortolotti F., Ruozi G., Falcione A., Doimo S., Dal Ferro M., Lesizza P., Zentilin L., Banks L., Zacchigna S., Giacca M.

Background: Transplantation of cells into the infarcted heart has significant potential to improve myocardial recovery; however, low efficacy of cell engraftment still limits therapeutic benefit. Here, we describe a method for the unbiased, in vivo selection of cytokines that improve mesenchymal stromal cell engraftment into the heart both in normal conditions and after myocardial infarction. Methods: An arrayed library of 80 secreted factors, including most of the currently known interleukins and chemokines, were individually cloned into adeno-associated viral vectors. Pools from this library were then used for the batch transduction of bone marrow–derived mesenchymal stromal cells ex vivo, followed by intramyocardial cell administration in normal and infarcted mice. Three weeks after injection, vector genomes were recovered from the few persisting cells and identified by sequencing DNA barcodes uniquely labeling each of the tested cytokines. Results: The most effective molecule identified by this competitive engraftment screening was cardiotrophin-1, a member of the interleukin-6 family. Intracardiac injection of mesenchymal stromal cells transiently preconditioned with cardiotrophin-1 preserved cardiac function and reduced infarct size, parallel to the persistence of the transplanted cells in the healing hearts for at least 2 months after injection. Engraftment of cardiotrophin-1–treated mesenchymal stromal cells was consequent to signal transducer and activator of transcription 3–mediated activation of the focal adhesion kinase and its associated focal adhesion complex and the consequent acquisition of adhesive properties by the cells. Conclusions: These results support the feasibility of selecting molecules in vivo for their functional properties with adeno-associated viral vector libraries and identify cardiotrophin-1 as a powerful cytokine promoting cell engraftment and thus improving cell therapy of the infarcted myocardium.

Tompkins B.A., DiFede D.L., Khan A., Landin A.M., Schulman I.H., Pujol M.V., Heldman A.W., Miki R., Goldschmidt-Clermont P.J., Goldstein B.J., Mushtaq M., Levis-Dusseau S., Byrnes J.J., Lowery M., Natsumeda M., et. al.

Aging frailty, characterized by decreased physical and immunological functioning, is associated with stem cell depletion. Human allogeneic mesenchymal stem cells (allo-hMSCs) exert immunomodulatory effects and promote tissue repair.This is a randomized, double-blinded, dose-finding study of intravenous allo-hMSCs (100 or 200-million [M]) vs placebo delivered to patients (n = 30, mean age 75.5 ± 7.3) with frailty. The primary endpoint was incidence of treatment-emergent serious adverse events (TE-SAEs) at 1-month postinfusion. Secondary endpoints included physical performance, patient-reported outcomes, and immune markers of frailty measured at 6 months postinfusion.No therapy-related TE-SAEs occurred at 1 month. Physical performance improved preferentially in the 100M-group; immunologic improvement occurred in both the 100M- and 200M-groups. The 6-minute walk test, short physical performance exam, and forced expiratory volume in 1 second improved in the 100M-group (p = .01), not in the 200M- or placebo groups. The female sexual quality of life questionnaire improved in the 100M-group (p = .03). Serum TNF-α levels decreased in the 100M-group (p = .03). B cell intracellular TNF-α improved in both the 100M- (p < .0001) and 200M-groups (p = .002) as well as between groups compared to placebo (p = .003 and p = .039, respectively). Early and late activated T-cells were also reduced by MSC therapy.Intravenous allo-hMSCs were safe in individuals with aging frailty. Treated groups had remarkable improvements in physical performance measures and inflammatory biomarkers, both of which characterize the frailty syndrome. Given the excellent safety and efficacy profiles demonstrated in this study, larger clinical trials are warranted to establish the efficacy of hMSCs in this multisystem disorder.www.clinicaltrials.gov: CRATUS (#NCT02065245).

Sacha J., Sacha M., Soboń J., Borysiuk Z., Feusette P.

Frailty is a state that encompasses losses in physical, psychological or social domains. Therefore, frail people demonstrate a reduced potential to manage external stressors and to respond to life incidents. Consequently, such persons are prone to various adverse consequences such as falls, cognitive decline, infections, hospitalisation, disability, institutionalisation and death. Pre-frailty is a condition predisposing and usually preceding the frailty state. Early detection of frailty (i.e., pre-frailty) may present an opportunity to introduce effective management to improve outcomes. Exercise training appears to be the basis of such management in addition to periodic monitoring of food intake and body weight. However, various nutritional supplements and other probable interventions, such as treatment with vitamin D or androgen, require further investigation. Notably, many societies are not conscious of frailty as a health problem. In fact, people generally do not realise that they can change this unfavourable trajectory to senility. As populations age, it is reasonable to begin treating frailty similarly to other population-affecting disorders (e.g., obesity, diabetes or cardiovascular diseases) and implement appropriate preventative measures. Social campaigns should inform societies about age-related frailty and pre-frailty and suggest appropriate lifestyles to avoid or delay these conditions. In this article, we review current information concerning therapeutic interventions in frailty and pre-frailty and discuss whether a greater public awareness of such conditions and some preventative and therapeutic measures may decrease their prevalence.

Shigemoto-Kuroda T., Oh J.Y., Kim D., Jeong H.J., Park S.Y., Lee H.J., Park J.W., Kim T.W., An S.Y., Prockop D.J., Lee R.H.

Accumulating evidence shows that extracellular vesicles (EVs) produced by mesenchymal stem/stromal cells (MSCs) exert their therapeutic effects in several disease models. We previously demonstrated that MSCs suppress autoimmunity in models of type 1 diabetes (T1D) and experimental autoimmune uveoretinitis (EAU). Therefore, here, we investigated the therapeutic potential of MSC-derived EVs using our established mouse models for autoimmune diseases affecting the pancreas and the eye: T1D and EAU. The data demonstrate that MSC-derived EVs effectively prevent the onset of disease in both T1D and EAU. In addition, the mixed lymphocyte reaction assay with MSC-derived EVs indicated that EVs inhibit activation of antigen-presenting cells and suppress development of T helper 1 (Th1) and Th17 cells. These results raise the possibility that MSC-derived EVs may be an alternative to cell therapy for autoimmune disease prevention.

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., Levis-Dusseau S., Byrnes J.J., Lowery M., Natsumeda M., Delgado C., et. al.

Impaired endogenous stem cell repair capacity is hypothesized to be a biologic basis of frailty. Therapies that restore regenerative capacity may therefore be beneficial. This Phase 1 study evaluated the safety and potential efficacy of intravenous, allogeneic, human mesenchymal stem cell (allo-hMSC)-based therapy in patients with aging frailty.In this nonrandomized, dose-escalation study, patients received a single intravenous infusion of allo-hMSCs: 20-million (n = 5), 100-million (n = 5), or 200-million cells (n = 5). The primary endpoint was incidence of any treatment-emergent serious adverse events measured at 1 month postinfusion. The secondary endpoints were functional efficacy domains and inflammatory biomarkers, measured at 3 and 6 months, respectively.There were no treatment-emergent serious adverse events at 1-month postinfusion or significant donor-specific immune reactions during the first 6 months. There was one death at 258 days postinfusion in the 200-million group. In all treatment groups, 6-minute walk distance increased at 3 months (p = .02) and 6 months (p = .001) and TNF-α levels decreased at 6 months (p < .0001). Overall, the 100-million dose showed the best improvement in all parameters, with the exception of TNF-α, which showed an improvement in both the 100- and 200-million groups (p = .0001 and p = .0001, respectively). The 100-million cell-dose group also showed significant improvements in the physical component of the SF-36 quality of life assessment at all time points relative to baseline.Allo-hMSCs are safe and immunologically tolerated in aging frailty patients. Improvements in functional and immunologic status suggest that ongoing clinical development of cell-based therapy is warranted for frailty.

Paneni F., Diaz Cañestro C., Libby P., Lüscher T.F., Camici G.G.

Cardiovascular disease (CVD) presents a great burden for elderly patients, their caregivers, and health systems. Structural and functional alterations of vessels accumulate throughout life, culminating in increased risk of developing CVD. The growing elderly population worldwide highlights the need to understand how aging promotes CVD in order to develop new strategies to confront this challenge. This review provides examples of some major unresolved clinical problems encountered in daily cardiovascular practice as we care for elderly patients. Next, the authors summarize the current understanding of the mechanisms implicated in cardiovascular aging, and the potential for targeting novel pathways implicated in endothelial dysfunction, mitochondrial oxidative stress, chromatin remodeling, and genomic instability. Lastly, the authors consider critical aspects of vascular repair, including autologous transplantation of bone marrow-derived stem cells in elderly patients.

Alcayaga-Miranda F., Cuenca J., Khoury M.

While mesenchymal stem cells (MSCs)-based therapy appears to be promising, there are concerns regarding possible side effects related to the unwanted suppression of antimicrobial immunity leading to an increased risk of infection. Conversely, recent data show that MSCs exert strong antimicrobial effects through indirect and direct mechanisms, partially mediated by the secretion of antimicrobial peptides and proteins (AMPs). In fact, MSCs have been reported to increase bacterial clearance in pre-clinical models of sepsis, acute respiratory distress syndrome and cystic fibrosis related infections. This article reviews the current evidence regarding the direct antimicrobial effector function of MSCs, focusing mainly on the role of MSCs-derived AMPs. The strategies that might modulate the expression and secretion of these AMPs, leading to enhanced antimicrobial effect are highlighted. Furthermore, studies evaluating the presence of AMPs in the cargo of extracellular vesicles (EVs) are underlined as perspective opportunities to develop new drug delivery tools. The antimicrobial potential of MSCs-derived EVs can also be heightened through cell conditioning and/or drug loading. Finally, improving the pharmacokinetics and delivery, in addition to deciphering the multi-target drug status of AMPs, should synergistically lead to key advances against infections caused by drug resistant strains.

Sotomayor-Lugo F., Iglesias-Barrameda N., Casado-Hernandez I., Villegas-Valverde C.A., Ventura-Carmenate Y., Rivero-Jimenez R.A.

We explore aging as a global phenomenon, questioning whether it constitutes a treatable condition or follows a natural course. Acknowledging its multifactorial nature, we delve into the challenges and opportunities inherent in this intricate biological process. The inclusion of old age in the 11th International Classification of Diseases sparks debate, categorizing it as a disease based on mechanistic explanations, blood-based biomarkers, and anti-aging products. Ethical dilemmas arise, emphasizing the difficulty of defining the transition from normal to pathological states during this process. We suggest that aging should be regarded as a treatable condition without necessarily labeling it a 'disease.' While anti-aging research unveils promising interventions like Metformin, Rapamycin, and cellular therapy, achieving biological immortality remains a formidable challenge. The future promises to prolong life and enhance quality by comprehensively understanding aging's implications for human health.

Shukla S., Kadian S., Narayan R.

Progress in the healthcare industry corresponds to the contributions from biotechnological (BT) and information technology (ICT) to a certain viable extent. BT and ICT have revolutionized personalized medicine, biopharmaceuticals according to an individual's genetic makeup, autoimmune, rare genetically mutated disorders, and developed precision medicare vaccines. They have transformed genetic therapies, imaging technologies, formulation of pharmaceutical dosages, and digital delivery of medical services. A significant evolution in electronic health record management, secure data exchange, real-time monitoring device development, better prognosis with predictive data analytics, image analysis with machine and deep learning networks, and patient safety by automated pharmacy and blockchain technologies. Further, the combination of biotechnology and ICT plays a crucial role in enhancing the quality of life and increasing the independence of individuals with mobility disorders, hearing impairments, vision impairments, and speech disabilities. Ongoing research and development in these areas continue to drive innovation, making technology an increasingly powerful tool for improving accessibility and inclusion.

Varalda M., Venetucci J., Nikaj H., Kankara C.R., Garro G., Keivan N., Bettio V., Marzullo P., Antona A., Valente G., Gentilli S., Capello D.

Metabolic syndrome (MetS) is a cluster of metabolic abnormalities, including visceral obesity, dyslipidemia, and insulin resistance. In this regard, visceral white adipose tissue (vWAT) plays a critical role, influencing energy metabolism, immunomodulation, and oxidative stress. Adipose-derived stem cells (ADSCs) are key players in these processes within vWAT. While second-generation antipsychotics (SGAs) have significantly improved treatments for mental health disorders, their chronic use is associated with an increased risk of MetS. In this study, we explored the impact of SGAs on ADSCs to better understand their role in MetS and identify potential therapeutic targets. Our findings reveal that olanzapine disrupts lipid droplet formation during adipogenic differentiation, impairing insulin receptor endocytosis, turnover, and signaling. SGAs also alter the endolysosomal compartment, leading to acidic vesicle accumulation and increased lysosomal biogenesis through TFEB activation. PKCζ is crucial for the SGA-induced nuclear translocation of TFEB and acidic vesicle formation. Notably, inhibiting PKCζ restored insulin receptor tyrosine phosphorylation, normalized receptor turnover, and improved downstream signaling following olanzapine treatment. This activation of PKCζ by olanzapine is driven by increased phosphatidic acid synthesis via phospholipase D (PLD), following G protein-coupled receptor (GPCR) signaling activation. Overall, olanzapine and clozapine disrupt endolysosomal homeostasis and insulin signaling in a PKCζ-dependent manner. These findings highlight SGAs as valuable tools for uncovering cellular dysfunction in vWAT during MetS and may guide the development of new therapeutic strategies to mitigate the metabolic side effects of these drugs.

Matsuoka T., Itohara T., Hara Y., Kobayashi N.

Background: Mesenchymal stem cells (MSCs) have drawn significant attention for their regenerative potential and therapeutic applicability across a range of conditions, including cardiovascular diseases and age-related frailty. Despite extensive preclinical studies, there remain gaps in understanding the long-term safety and efficacy of MSC therapy in humans. This study aimed to assess the safety of intravenous MSC administration, evaluate the mean major adverse cardiac and cerebrovascular event (MACCE)-free period, and identify potential risk factors for MACCE development in patients receiving MSC therapy for various indications. Methods: A retrospective observational study was conducted on 2504 patients (mean age: 54.09 ± 11.65 years) who received intravenous adipose-derived MSC (AD-MSC) therapy between October 2014 and December 2023 at the Omotesando Helene Clinic, Tokyo, Japan. Patients received MSC doses ranging from 100 million to 2 billion cells, with the majority receiving 1–2 billion cells per treatment. Statistical analyses included multivariate Cox proportional hazards regression and Kaplan–Meier survival analysis to evaluate MACCE risk factors and event-free duration. Results: Over the follow-up period, the MACCE rate was exceptionally low at 0.2%. Multivariate analysis identified age as a significant risk factor for MACCE (hazard ratio: 1.127; 95% CI: 1.0418–1.219; p = 0.0029), while sex and MSC dose showed no significant association. Minor adverse events occurred in 0.8% of patients, with no severe adverse events reported. The study found MSC therapy to be safe, with a low adverse event rate and minimal risk of MACCE. Conclusions: This study demonstrates the safety of intravenous MSC therapy in a large cohort of patients, with a low incidence of MACCE and minimal adverse effects. Age was the only significant predictor of MACCE risk. Further prospective randomized studies are needed to validate these findings and explore the potential of MSC therapy in reducing MACCE risk and improving clinical outcomes across diverse indications.

Prasad P., Mathew A., Jose S., Akbarsh M.A., Panicker S.P.

Healthy longevity refers to the ongoing development and maintenance of the capacity to operate well in old age, specifically emphasizing optimizing social, mental, and physical well-being to achieve a high quality of life. The focus is not on increasing the number of years one lives but on enhancing the quality and vitality of those years. Regenerative medicine is a field that focuses on healing or rejuvenating damaged or aging tissues. It involves several treatments, including stem cell therapy, tissue engineering, and gene therapies. Regenerative medicine is transforming the aging experience by targeting age-related disorders, improving tissue regeneration, and prolonging the period of good health. Biodiversity, which refers to the wide range of species and genetic variety within ecosystems, is crucial in delivering environmental services that contribute to human well-being. Nevertheless, we are observing a growing decline in biodiversity due to causes such as population expansion, climate change, and expanding urbanization. Nevertheless, we are starting to comprehend the extensive range of health advantages that result from our affiliation with the natural world and its diverse ecosystems. Biodiversity encompasses many valuable products and resources, including forests, oceans, medicinal plants, phytochemicals, marine life, nutraceuticals, microbial diversity, and probiotics. These bioactive chemicals and resources enhance the aging process by providing nutritional assistance, managing diseases, improving cognitive health, and perhaps being used in regenerative medicine. Regenerative medicine plays a crucial role in achieving a healthy lifespan by harnessing natural resources from biodiversity to drive tissue repair, regulate age-related illnesses, and tailor treatments. Personalized medicine improves healthcare by utilizing advanced techniques to anticipate, avert, and manage diseases in a highly customized manner, prioritizing each person’s distinct needs. The system utilizes cutting-edge medical technologies and data analysis to deliver personalized, preventative care that promotes healthy aging. This includes early diagnosis of diseases, tailored treatments, coaching on lifestyle and nutrition, immunization plans, and consideration of social and environmental factors. Personalized medicine derives significant advantages from biodiversity through the exploitation of genetic variation, the utilization of biodiversity in discovering new drugs, the use of varied biological models, the recognition of the significance of ecosystem well-being, and the consideration of dietary variety. Ensuring the availability of biodiversity’s resources in regenerative and customized medical treatments is a scientific pursuit and an ethical obligation. By adhering to principles of fair distribution of benefits and promoting scientific collaborations, we ensure that the advantages gained from biodiversity’s resources are shared with local populations. This approach respects their knowledge and rights while also maintaining ecosystems. It is crucial to advocate for the ethical use of natural goods, disseminate information, and maximize the potential benefits for society at large. It is essential to take key actions to address healthcare disparities, ensure data privacy and security, enhance health literacy, diversify research participation, and make medicines cheap. By prioritizing these elements, we can work towards a future where regenerative and precision medicine benefit all individuals, regardless of their history or circumstances.

Mackie E.C., Cheng C., Alibrio M., Rutledge C., Xin H., Chopp M., McCann R., Rosene D.L., Yang Q., Zeldich E., Medalla M., Koo B., Moore T.L.

AbstractNormal aging in humans and non-human primates is associated with a decline in cognitive functions. Subject-wise differences in cognitive decline can be attributed to different degrees of damage to cortical white matter (WM) which is largely affected by neuroinflammation during aging. Mesenchymal stromal cell-derived extracellular vesicles (MSC-EVs) have recently been identified as a potential immunomodulatory therapeutic for brain damage and Alzheimer’s disease (AD) and related dementias by suppressing neuroinflammation. Here, we evaluated the efficacy of MSC-EVs for slowing or ameliorating cognitive decline during aging in rhesus monkeys, a well-studied model of normal aging that is free of extensive AD pathology. We report that late middle-aged monkeys treated with MSC-EVs every two weeks for 18 months showed improved performance on a task of spatial working memory relative to vehicle control monkeys. In addition, we used diffusion magnetic resonance imaging (MRI) and resting state functional MRI to evaluate structural white matter and functional network changes in vivo. Imaging data revealed that MSC-EV treatment preserved prefrontal and temporal WM structural integrity and large-scale functional network connectivity that are correlated with early, increased CSF levels of amyloid beta protein. Amyloid beta levels at 12 months are also correlated with improved cognitive performance at the end of the 18 months of treatment. These findings suggest that MSC-EVs can mitigate age-related cognitive decline by potentially enhancing the CSF clearance of neurodegenerative proteins, which correlates with greater WM integrity and functional brain connectivity.

Li Y., Jin M., Guo D., Shen S., Lu K., Pan R., Sun L., Zhang H., Shao J., Pan G.

Hou Y., Zhang X., Zeng D., Zhu S., Luo Y., Dang J., Wu W., Xiong Y., Zhao J., Huang J., Yuan J., Wang S., Wang J., Xu H., Zhang W., et. al.

AbstractA therapeutic strategy using mesenchymal stem cells (MSCs) has been accepted as a novel therapy for treating rheumatoid arthritis (RA). Human gingiva‐derived MSCs (GMSCs) are superior in regulating immune responses. Autologous MSCs are the optimal candidate to avoid the potential risks of allogenic MSCs. However, whether autologous GMSCs from RA patients are therapeutic remains unknown. In this study, we compared the therapeutic efficacy of GMSCs derived from patients with RA (RA‐GMSCs) and that from health donors (H‐GMSCs) in vivo and in vitro. Then, we utilized RNA‐sequencing, the molecular and cellular assays to determine the immunomodulatory molecules that contribute to the therapeutic effect of RA‐GMSCs on both collagen‐induced arthritis (CIA) and humanized synovitis models. We demonstrated that GMSCs derived from patients with RA (RA‐GMSCs) and health donors (H‐GMSCs) shared a similar expression of immunomodulatory molecules. Moreover, RA‐GMSCs were as effective as H‐GMSCs in suppressing T‐cell proliferation, proinflammatory cytokines secretion, as well as osteoclast differentiation in vitro. In addition, RA‐GMSCs had a robust therapeutic effect on the CIA model. Importantly, RA GMSCs can survive for at least 24 days in a CIA mouse model and can be distributed in the spleen, lymph nodes, and joints. Specifically, RA‐GMSCs decreased the frequency of Th1 and Th17 cells whereas enhanced Treg cells, reducing the joint histopathological scores of lymphocytes, osteoclasts, and cartilages. Moreover, RA‐GMSCs were also effective in suppressing inflamed synoviocyte proliferation, migration, and invasion in vitro, and cartilage invasion in a humanized synovitis model in vivo. Our study implies that manipulation of RA‐GMSCs is therapeutic in CIA mice and humanized synovitis models and may have therapeutic potential in RA patients using autologous GMSCs in the future.

Cristina Russu M.

High-rate complications and recurrences in reconstructive surgery using in situ synthetic/polypropylene meshes have driven to a new era of mesenchymal stem cells (MSCs) and/or their exosomes/microvesicles for tissue homeostasis restoration, in pelvic floor disorders (PFD) prevention and/or therapy: pelvic organ prolapse, stress urinary incontinence, and posterior compartment pathology. Molecular pathophysiology knowledge along a woman’s life and results from endometrial/menstrual MSCs (eMSCs/MenSCs) in small/large animal models facilitate the new concept of translation in human clinical practice. New strategies are cell-based – vaginal, urethral, anal injections or systemic introduced – tissue engineering with new generation meshes/scaffolds seeded with eMSCs/MenSCs or their exosomes which are proposed in PFD prevention/therapy. Being easily collected, isolated with specific markers, and cultured for number harvesting, without ethics, immune compatibility, genetic, and oncogenic issues, and with unique biologic properties, eMSCs/MenSCs differentiate in many cellular types, preserving shape and phenotype in collagen and elastin fibers. eMSCs/MenSCs influence the microenvironment by paracrine/bioactive molecules to facilitate tissue repair. The advantages of surgery/augmentation by new generation meshes/scaffolds include quick restoring effects, mediated by angiogenesis, cell proliferation/differentiation in native/original PF cells, apoptosis inhibition, no chronic inflammation, reduced foreign body reactions, less thick collagen fibers and fibrosis, improving connective/neuromuscular tissues, less PF stiffness, and more elasticity. eMSCs/MenSCs are appropriate for PFD management, respecting good protocols for women safety.

Trapana J., Weinerman J., Lee D., Sedani A., Constantinescu D., Best T.M., Hornicek F.J., Hare J.M.

Abstract A limited number of tissues can spontaneously regenerate following injury, and even fewer can regenerate to a state comparable to mature, healthy adult tissue. Mesenchymal stem cells (MSCs) were first described in the 1960s-1970s by Friedenstein et al as a small population of bone marrow cells with osteogenic potential and abilities to differentiate into chondrocytes. In 1991, Arnold Caplan coined the term “mesenchymal cells” after identifying these cells as a theoretical precursor to bone, cartilage, tendon, ligament, marrow stroma, adipocyte, dermis, muscle, and connective tissues. MSCs are derived from periosteum, fat, and muscle. Another attractive property of MSCs is their immunoregulatory and regenerative properties, which result from crosstalk with their microenvironment and components of the innate immune system. Collectively, these properties make MSCs potentially attractive for various therapeutic purposes. MSCs offer potential in sports medicine, aiding in muscle recovery, meniscal tears, and tendon and ligament injuries. In joint disease, MSCs have the potential for chondrogenesis and reversing the effects of osteoarthritis. MSCs have also demonstrated potential application to the treatment of degenerative disc disease of the cervical, thoracic, and lumbar spine.

Yusri K., Kumar S., Fong S., Gruber J., Sorrentino V.

Aging is a complex and time-dependent decline in physiological function that affects most organisms, leading to increased risk of age-related diseases. Investigating the molecular underpinnings of aging is crucial to identify geroprotectors, precisely quantify biological age, and propose healthy longevity approaches. This review explores pathways that are currently being investigated as intervention targets and aging biomarkers spanning molecular, cellular, and systemic dimensions. Interventions that target these hallmarks may ameliorate the aging process, with some progressing to clinical trials. Biomarkers of these hallmarks are used to estimate biological aging and risk of aging-associated disease. Utilizing aging biomarkers, biological aging clocks can be constructed that predict a state of abnormal aging, age-related diseases, and increased mortality. Biological age estimation can therefore provide the basis for a fine-grained risk stratification by predicting all-cause mortality well ahead of the onset of specific diseases, thus offering a window for intervention. Yet, despite technological advancements, challenges persist due to individual variability and the dynamic nature of these biomarkers. Addressing this requires longitudinal studies for robust biomarker identification. Overall, utilizing the hallmarks of aging to discover new drug targets and develop new biomarkers opens new frontiers in medicine. Prospects involve multi-omics integration, machine learning, and personalized approaches for targeted interventions, promising a healthier aging population.

Dinetz E., Zeballos-Palacios C., Martinez C.

Kumar R., Mishra N., Tran T., Kumar M., Vijayaraghavalu S., Gurusamy N.

Cardiovascular diseases continue to challenge global health, demanding innovative therapeutic solutions. This review delves into the transformative role of mesenchymal stem cells (MSCs) in advancing cardiovascular therapeutics. Beginning with a historical perspective, we trace the development of stem cell research related to cardiovascular diseases, highlighting foundational therapeutic approaches and the evolution of cell-based treatments. Recognizing the inherent challenges of MSC-based cardiovascular therapeutics, which range from understanding the pro-reparative activity of MSCs to tailoring patient-specific treatments, we emphasize the need to refine the pro-regenerative capacity of these cells. Crucially, our focus then shifts to the strategies of the fourth generation of cell-based therapies: leveraging the secretomic prowess of MSCs, particularly the role of extracellular vesicles; integrating biocompatible scaffolds and artificial sheets to amplify MSCs’ potential; adopting three-dimensional ex vivo propagation tailored to specific tissue niches; harnessing the promise of genetic modifications for targeted tissue repair; and institutionalizing good manufacturing practice protocols to ensure therapeutic safety and efficacy. We conclude with reflections on these advancements, envisaging a future landscape redefined by MSCs in cardiovascular regeneration. This review offers both a consolidation of our current understanding and a view toward imminent therapeutic horizons.

Zhu Y., Huang C., Zheng L., Li Q., Ge J., Geng S., Zhai M., Chen X., Yuan H., Li Y., Jia W., Sun K., Li Y., Ye T., Zhao Z., et. al.

Abstract Background Mesenchymal stem cells (MSCs) hold a great promise for cell-based therapy in the field of regenerative medicine. In this study, we aimed to evaluate the safety and efficacy of intravenous infusion of human umbilical cord-derived MSCs (HUC-MSCs) in patients with aging frailty. Methods In this randomized, double-blind, placebo-controlled trial, participants diagnosed with aging frailty were randomly assigned to receive intravenous administrations of HUC-MSCs or placebo. All of serious adverse events and AEs were monitored to evaluate the safety of treatment during the 6-month follow-up. The primary efficacy endpoint was alteration of physical component scores (PCS) of SF-36 qualities of life at 6 months. The secondary outcomes including physical performance tests and pro-inflammatory cytokines, were also observed and compared at each follow-up visits. All evaluations were performed at 1 week, 1, 2, 3 and 6 months following the first intravenous infusion of HUC-MSCs. Results In the MSCs group, significant improvements in PCS of SF-36 were observed from first post-treatment visit and sustained throughout the follow-up period, with greater changes compared to the placebo group (p = 0.042). EQ-VAS scores of MSCs group improved significantly at 2 month (p = 0.023) and continued until the end of the 6-month visit (p = 0.002) in comparison to the placebo group. The timed up and go (TUG) physical performance test revealed significant group difference and showed continual enhancements over 6 months (p < 0.05). MSC transplantation improved the function of 4-m walking test (4MWT) compared with the placebo group with a decrease of 2.05 s at 6 months of follow-up (p = 0.21). The measurement of grip strength revealed group difference with MSCs group demonstrating better performance, particularly at 6 months (p = 0.002). Inflammatory cytokines (TNF-α, IL-17) exhibited declines in MSCs group at 6 months compared to the placebo group (p = 0.034 and 0.033, respectively). There was no difference of incidence of AEs between the two groups. Conclusion Intravenous transplantation of HUC-MSCs is a safe and effective therapeutic approach on aging frailty. The positive outcomes observed in improving quality of life, physical performance, and reducing chronic inflammation, suggest that HUC-MSC therapy may be a promising potential treatment option for aging frailty. Trial Registration: Clinicaltrial.gov; NCT04314011; https://clinicaltrials.gov/ct2/show/NCT04314011.

Zeng M., Zhou T., Li Z., Li G., Zhang S., Wang L., Huang Q., Li J., Samarawickrama P.N., He Y., Wang G.

AbstractDomestic dogs have great potential to expand our understanding of the determinants of aging. To understand the aging pattern of domestic dogs and evaluate whether they can be used as an aging model, we performed RNA sequencing on white blood cells from domestic dogs aged 1–9 years and treated aged dogs with classical antiaging approaches. We obtained 30 RNA sequencing libraries and identified 61 age‐associated genes with dynamic changes, the majority of which were related to metabolism and immune function, which may be predominant biomarkers for aging in dogs. We next treated aged dogs with canine mesenchymal stem cells (cMSCs), nicotinamide mononucleotide, and rapamycin to determine whether and how they responded to the antiaging interventions. The results showed that these treatments can significantly reduce the level of inflammatory factors (IL‐6 and TNF‐α). MSCs effectively improved the heart functions of aged dogs. Three key potential age‐related genes (PYCR1, CCRL2, and TOX) were reversed by MSC treatment, two of which (CCRL2 and TOX) are implicated in immunity. Overall, we profiled the transcriptomic pattern of domestic dogs and revealed that they may be a good model of aging, especially in anti‐inflammatory investigations.