Volume 4 - 2023 | https://doi.org/10.3389/fragi.2023.1148926
This article is part of the Research TopicInsights in Aging Interventions: 2022View all 12 articles
Aging is associated with a decline in the regenerative potential of stem cells
several clinical trials have been launched in order to evaluate the efficacy of mesenchymal stem cell interventions to slow or reverse normal aging processes (aging conditions)
Information concerning those clinical trials was extracted from national and international databases (United States
Mesenchymal stem cell preparations were in development for two main aging conditions: physical frailty and facial skin aging
positive results have been obtained in phase II studies with intravenous Lomecel-B (an allogeneic bone marrow stem cell preparation)
and a phase I/II study with an allogeneic preparation of umbilical cord-derived stem cells was recently completed
positive results have been obtained with an autologous preparation of adipose-derived stem cells
A further sixteen clinical trials for physical frailty and facial skin aging are currently underway
Reducing physical frailty with intravenous mesenchymal stem cell administration can increase healthy life expectancy and decrease costs to the public health system
intravenous administration runs the risk of entrapment of the stem cells in the lungs (and could raise safety concerns)
clinical research on facial skin aging allows direct evaluation of tissue regeneration using sophisticated and precise methods
research on both conditions is complementary
For years, the human umbilical cord was a waste material and, unlike hE-SCs, its use does not raise ethical concerns. In 1988, Gluckman et al. (1989) successfully performed the first human cord blood transplant in a child with Fanconi’s anemia. Since then, numerous public and private cord blood banks have been established worldwide for the cryopreservation of cord blood in view of its transplantation (Gluckman, 2011)
Mesenchymal stem cell (MSC) preparations in clinical development for aging conditions
MSC preparations are in development for physical frailty in older persons and facial skin aging
Reducing aging frailty can increase healthy life expectancy and decrease costs to the public health system
Clinical trials for facial skin aging are important because tissue regeneration is directly assessed by sophisticated and precise methods
and because cell entrapment in the lungs and safety issues of intravenous stem cells are avoided
Adult mesenchymal stem cells (MSCs) have been extensively investigated in clinical trials (Squillaro et al., 2016). In particular, human bone marrow MSCs (hBM-MSCs) have been widely used for clinical research, although they are obtained with low yields, through an invasive procedure (BM aspiration) (Varghese and Mosahebi, 2017) and their ability to proliferate and differentiate declines with age (Rao and Mattson, 2001)
In 2006, Lu et al., (2006) published a protocol to isolate abundant MSCs by enzymatic digestion of the human umbilical cord (hUC) and cell culture expansion. The UC is an easily accessible fetal tissue, and the hUC, which was previously discarded as waste material, quickly became an alternative source of MSCs to be investigated in clinical trials (Figure 1)
Another source of human SCs is adipose tissue (hAD-MSCs) (Coleman, 1994; Varghese and Mosahebi, 2017; Alexander, 2019; Khazaei et al., 2021; Surowiecka and Struzyna, 2022)
Subcutaneous fat tissue contains many more SCs than bone marrow
large amounts of autologous hAD-MSCs are easily obtained by liposuction
and autologous hAD-MSCs do not require cell expansion
Aging is associated with a decline in the regenerative potential of adult SCs, and this may play a crucial role in the pathogenesis of age-associated conditions (Rao and Mattson, 2001; Choudhery et al., 2014; Verdijk et al., 2014; Picerno et al., 2021; Zhu et al., 2021)
the use of SC preparations for aging conditions has a strong rationale:
3. Within the animal kingdom, the healthy life expectancy of different animal species depends to a large extent on the regenerative capacity of their SC, notably in invertebrates such as planarians and hydra (Handberg-Thorsager et al., 2008)
The WHO Clinical Trials Search Portal provided access to trials registered in 14 primary registries (Australia
the list of clinical trials was obtained by filling out the “Advanced Search” form (or “More Information” form)
compounds needed to be in clinical trials with SC interventions for aging conditions and satisfy the following criteria:
Trial declared with “Aging” as “Condition”
“stem cell” as “Other terms”
and “Interventional Studies (Clinical trials)” as “Study type”
the following relevant data were extracted: identifier number (and/or designated name
Clinical trials were listed according to the aging condition and SC preparation investigated
Relevant articles related to the selected SC interventions were searched in the following biomedical literature databases: PubMed (https://pubmed.ncbi.nlm.nih.gov), Science Direct (www.sciencedirect.com/search), Cochrane Library (www.cochranelibrary.com), and Google Scholar (https://scholar.google.com)
relevant articles were found by using the name of the SC preparation
OR the clinical trial identifier number AND “aging condition”
Clinical trial information was also obtained by consulting the websites of pharmaceutical and biotechnology companies working in the field of stem cells and aging
The current treatment and therapeutic needs of each aging condition were identified in the corresponding clinical practice guidelines (CPG)
The therapeutic impact of the selected clinical trials was evaluated in the context of such competitive environment
Research analysis included four therapeutic aspects: 1) Key findings from SC interventions for aging
TABLE 1. Recent clinical trials with allogeneic stem cell preparations for physical frailty in older persons (2019 and later).a
TABLE 2. Recent clinical trials with stem cell preparations for facial skin aging and photoaging (2019 and later).a
Other clinical trials with stem cell preaparations for aging (2019 and later)
Eleven clinical trials selected for analysis were investigating SC preparations for aging frailty (Table 1)
These included six trials with allogeneic human bone marrow MSCs (hBM-MSCs)
three trials with allogeneic human umbilical cord MSCs (hUC-MSCs)
one trial with autologous adipose-derived MSCs (hAD-MSCs)
and one trial with plasma mobilized by the granulocyte-colony stimulating factor (GMFFP)
Objectives and rationale for clinical development of mesenchymal stem cell preparations for physical frailty and facial skin aging
Lomecel-B (or “allo-hMSCs”, Longeveron, United States) is a formulation of allogeneic hBM-MSCs sourced from the posterior iliac crest of healthy young adult donors (aged 18–45 years) and expanded in culture (Golpanian et al., 2016; Yousefi et al., 2022)
After a specific number of expansion cycles
Unlike an autologous bone marrow transplant (that is used for a single patient)
tissue from a single donor is used to obtain many doses of Lomecel-B for use in multiple patients
Longeveron has launched a clinical development program with intravenous Lomecel-B for aging frailty. The program includes five clinical trials designed to determine if Lomecel-B can improve physical function, reduce inflammation and improve quality of life in frail older adults (Table 1)
There were no signs of T-cell activation (a marker of graft rejection) at 6-month
Only one subject (20-million group) developed mild to moderate donor-specific antibodies
Significant increases in the 6-min walk distance (6 MWD) test were obtained: 1) in the group of 20-million hBM-MSCs at 6 months (mean value of the increase = 37.2 m), and 2) in the group of 100-million hBM-MSCs at 3 months (36.6 m) and at 6 months (76.6 m) (Golpanian et al., 2017). No significant increases were seen in the group of 200-million hBM-MSCs (Golpanian et al., 2017)
TNF-alpha levels (an inflammatory marker) significantly decreased in the groups of 100-and 200-million hBM-MSCs at 6-month. No significant changes were seen in Interleukin-6 (IL-6) or C-reactive protein (CRP) (Golpanian et al., 2017)
The phase II RCT (Tompkins et al., 2017) included 30 elderly subjects (mean age = 75.5 years) with frailty scores between 4 and 7 on the CFS (Rockwood et al., 2005). Subjects receiving 100 million cells (n = 10) or 200 million cells (n = 10) were compared with those receiving placebo (n = 10). The results confirmed those obtained in the phase I open label trial (Golpanian et al., 2017)
the 6 MWD significantly increased in the 100 M-group from baseline (mean value = 345.9 m) to 6-month (410.5 m)
Immuno-tolerability was acceptable (only three participants showed a mild to moderate increase in donor specific antibodies)
The CRATUS trial was limited by its small sample size (Golpanian et al., 2017; Tompkins et al., 2017). NCT03169231 is a phase IIb multicenter RCT evaluating Lomecel-B versus placebo (Yousefi et al., 2022) (Table 1). A total of 150 older adults with CFS scores of 5“mildly frail” or 6“moderately frail” (Rockwood et al., 2005)
and 6 MWD of >200 m and <400 m was included in the study
Primary outcome is the change from baseline in 6 MWD compared to placebo
Secondary outcomes are changes in overall physical function and TNF-alpha
HERA (NCT02982915) is a phase I/II RCT to test the safety and efficacy of intravenous Lomecel-B to improve influenza vaccine (fluzone) responses in subjects with aging frailty (Table 1)
Following an initial phase I safety trial (30 days)
a phase II RCT will assess whether Lomecel-B may be an effective vaccine adjuvant to enhance influenza virus inactivation (assessed by hemagglutination inhibition assays) (time frame: 12 months)
Primary completion date was expected for September 2021
NCT05284604 is a phase I/II RCT investigating hBM-MSCs derived from vertebrae (hvBM-MSCs, obtained from the vertebral bodies of deceased organ donors) versus placebo (Table 1)
hvBM-MSCs are administered intravenously to older adults (65–85 years of age) who meet the following conditions: 1) Modified Physical Performance Test (mPPT) score of 18–31
2) Clinical Frailty Scale (CFS) score of 5 or 6 and
3) 6 MWD of >200 m and <400 m
The primary outcome is adherence (percentage of study visits attended)
Secondary outcomes include: number of participants recruited
Other secondary outcomes include: adverse events
Primary completion date is expected for June 2025
NCT04919135 is a phase I/II RCT investigating the safety and efficacy of adjunctive intravenous administration of allogeneic hUC-MSCs in patients receiving standard treatment for frailty in Vietnam [Hightamine (Hankook Korus Pharm, Korea), Total calcium (Nugale Pharmaceutical, Canada), and Bioflex (Ausbiomed, Australia)] (Table 1) (Hoang et al., 2022)
The intervention group will receive two doses of hUC-MSCs (1.5 × 106 cells/kg) separated by a time interval of 3 months
The primary outcome is the occurrence of treatment-dependent SAEs
Secondary outcome measures include the 6 MWD test and CD3+ cells
NCT05018767 is a single-arm, phase I trial designed to assess the long-term safety of a single intravenous infusion of cultured allogeneic hUC-MSCs (100 million cells) in subjects with aging frailty (Table 1)
Patients will be evaluated at baseline and at 1
NCT05018767 is currently recruiting participants and primary completion is expected in November 2025
NCT03514537 is an open trial to investigate the safety (and efficacy) of an autologous preparation of hAD-MSCs (cellular SVF, cSVF) for aging frailty (Table 1)
The study includes adult and older adults (40–90 years) who have noted compromise to activities or work requirements due to increasing age and loss of energy
Participants receive intravenous infusions of cSVF isolated from subdermal adipose tissue removed from the trunk or upper thigh area
The primary outcome is the occurrence of Treatment-Emergent Adverse Events (TEAEs) during 6 months following the infusion
NCT03514537 is currently recruiting participants and primary completion is expected in March 2023
Granulocyte-colony stimulating factor (G-CSF) stimulates the BM to produce granulocytes and SCs, and release them into the bloodstream (Patterson and Pelus, 2017). GMFFP (GCSF-Mobilized Fresh Frozen Plasma) is a fresh frozen plasma preparation harvested from young, healthy donors (Maharaj, 2020) (Table 1)
NCT03458429 is a single-arm, phase I/II trial of GMFFP in elderly (55–95 years) and frail people (score of 4–7 on the Clinical Frailty Scale and/or abnormal Immune Risk Profile) (Table 1)
Participants receive 12 once monthly transfusions of GMFFP (initial treatment period of 12 months) and are followed for a total of 24 months
The primary outcome is the number of participants with treatment-related adverse events
Secondary efficacy outcomes include frailty index (mobility
Primary completion date was expected for February 2023
Skin aging is due to natural causes, as well as extrinsic factors (especially Sun exposure: Photoaging) (Zhang and Duan, 2018; Wong and Chew, 2021). Several SC preparations are investigated for facial skin aging and photoaging (Table 2)
Long-term natural aging is a slow process of dermal atrophy due to elastin and elastic fiber degradation, lower collagen production and lower hydration levels, leading to loss of elasticity and wrinkles (Zhang and Duan, 2018; Wong and Chew, 2021). Clinical trials with MSCs preparations for facial skin aging are evaluating their efficacy in regenerating normal, youthful skin (facial rejuvenation) (Figure 2)
Exposure to ultraviolet (UV) radiation facilitates skin aging (photoaging), characterized by the degradation of collagen and elastin, with deposition of collagen breakdown products and abnormal elastin fibers in the dermis (solar elastosis) (Huang and Chien, 2020)
Clinical trials with MSCs preparations are evaluating their efficacy in restoring a normal skin
The “stromal vascular fraction” (SVF) is a preparation of autologous hAD-MSCs obtained by liposuction, followed by collagenase digestion, filtration, centrifugation and separation of the SVF (Coleman, 1994; Varghese and Mosahebi, 2017; Alexander, 2019; Khazaei et al., 2021; Surowiecka and Struzyna, 2022)
The SVF represents about 10% of the adipose tissue volume
and a variety of immune cells (T-cells and M2 macrophages)
The efficacy and tolerability of SVF-enriched autologous fat grafting is currently being investigated in facial skin aging
NCT02923219 was an RCT comparing the efficacy of SVF-assisted autologous fat grafting (intervention) versus fat transfer alone (control) for facial volume restoration and improvement of skin quality (Table 2) (Yin et al., 2020)
Fifty women (mean age: 35.4 years) participated in the study
At 6 months: 1) Whole face volumes (assessed by 3D scanner and Geomagic software) were significantly higher in the intervention group (77.6%) compared to the control group (56.2%
2) wrinkles and texture (assessed by VISIA detector) improved significantly more in the intervention group than in the control group
and 3) graft survival rate was significantly higher in the intervention group than in the control group
RPCEC00000362 is an RCT (single-blind) comparing the efficacy of SVF-enriched fat transfer versus conventional fat transfer (Table 2)
Participants with facial aging (30–59 years of age) are included in the study and will be followed for 12 months
Outcomes include clinical evaluation and evolution of furrows and wrinkles
Trial completion date was expected for December 2022
IRCT20141007019432N2 is a single-arm clinical trial, designed to investigate the efficacy of autologous SVF transplantation in reducing facial wrinkles (Table 2)
Forty-six (46) participants with facial aging (35–65 years of age and with grade 2 to 4 wrinkle type) were included in the study and will be followed for 6 months
The primary outcome is biometric evaluation (with visioface and skin ultrasound) of the amount and extent of facial wrinkles
The trial completion date was not reported
NCT05508191 is a single-blind RCT comparing two methods of AD-MSCs “secretome” administration for facial aging (fractional CO₂ laser treatment on one side of the face and microneedle treatment on the other half) (Table 2; Figure 1). The term “secretome” designates the soluble paracrine factors produced by SCs (Xia et al., 2019)
Thirty female participants with facial aging (35–59 years) are included in the study and will be followed for 6 weeks
Primary outcomes are: 1) Skin aging changes evaluated by dermoscopy photoaging scale and by Janus-3Ⓡ skin analyzer
2) skin capacitance evaluated by the CorneometerⓇ and 3) total water content in the stratum corneum of the skin
Primary completion date was expected for October 2022
NCT01771679 is a phase I/II safety trial to evaluate the safety and efficacy of a single intravenous injection of allogeneic (non-hematopoietic) hBM-MSCs for the treatment of facial photoaging in men and women 40–70 years of age (Table 2)
SCs secrete exosomes (40–120 nm extracellular vesicles), which contain cytokines, growth factors, messenger RNAs, and different non-coding RNAs, especially micro-RNAs (mi-RNAs) (Hamdan et al., 2021) (Figure 1)
3.2.3.2.1 ChiCTR2200061216. ChiCTR2200061216 investigates if hAD-MSC derived exosomes loaded with circcol elns (a circular RNA, circRNA) can promote collagen and elastin synthesis in skin samples from 6 to 10 photoaged patients (55–75 years). The study compares samples of facial skin tissue (part exposed to light), with skin tissue of the hip or upper arm (part protected from light) (Table 2)
NCT01847027 is a phase II RCT that investigated whether NT-020 in combination with an exercise stimulus was able to increase blood levels of CD34+ and CD133+ SCs in persons aged 50–70 years (Table 3)
No significant increases in CD34+ and CD133+ SCs (primary outcome) were found at 2 or 4 weeks after starting the intervention
NCT04174898 is a single-arm, phase I trial investigating safety, quality of life and morbimortality risk of hUC-MSC and hAD-MSC infusion in adults and older adults (Table 3). Morbimortality risk is assessed by measuring inflammatory markers of aging (IL-6, CRP and TNF-alpha) (Giovannini et al., 2011; Puzianowska-Kuznicka et al., 2016; St Sauver et al., 2022)
Primary completion was expected in April 2021
Clinical research with SC interventions for aging has only recently begun
SC interventions are in development for the treatment of two important aging conditions: physical frailty and facial skin aging
This means a recovery of about 39% of normal values for the elderly
An important limitation of BM-MSC therapy is the low number of cells obtained. This requires extensive cell expansion ex vivo, with the risk of cell senescence and reduced regenerative potency (Ganguly et al., 2017). Barbanti Brodano et al. (2013) compared the biological properties of MSCs derived from different sites in the human body
and found that hvBM-MSCs: 1) Can be maintained in culture for a greater number of passages
and 2) more efficiently generate mature cells of all mesenchymal lineages (osteogenic
adipogenic and chondrogenic differentiation)
The number of hvBM-MSCs obtained from deceased donors is much higher than that obtained from traditional types of hBM-MSCs aspirated from living donors
NCT05284604 will assess the feasibility of hvBM-MSC therapy for aging frailty
An hUC-MSC preparation investigated by the Shanghai East Hospital (China) recently completed a phase I/II study (Table 1). Moreover, a phase I/II RCTs (NCT04919135) and a phase I safety trial (NCT05018767) have been recently launched to evaluate the efficacy and safety of hUC-MSCs in aging frailty (Table 1)
NCT03458429 investigates whether transfusion of GMFFP (GCSF-Mobilized Fresh Frozen Plasma) from young persons may be a safe and effective treatment for frailty and immune dysfunction in older people (Maharaj, 2020)
A great advantage of GMFFP is that it is easy to collect and prepare in large quantities
there are some limitations regarding NCT03458429 (see Section 4.1.3)
Current clinical trials with SCs for aging frailty use have three main limitations: 1) There is no standard protocol, 2) few pharmacokinetic and dosing data are available, and 3) SC interventions investigate older people, a “special population” who are poly-medicated and have comorbidities (Grimsrud et al., 2015)
The 6 MWD was one of the efficacy outcomes of the CRATUS trials with Lomecel-B (Golpanian et al., 2016; Golpanian et al., 2017; Tompkins et al., 2017)
and 6 MWD is the primary outcome measure in the current multicenter trial of Lomecel-B (NCT03169231)
Some but not all ongoing trials include 6 MWD as an outcome measure (see
These differences in evaluation tools do not allow for a precise comparison of efficacy results between clinical trials
A 6 MWD of >200 m and <400 m is an inclusion criterion of the current multicenter trial with Lomecel-B (NCT03169231), but this 6 MWD criterion was not included in the previous CRATUS trials (which included patients with CSF fragility scores of 4–7) (Golpanian et al., 2016; Golpanian et al., 2017; Tompkins et al., 2017)
Differences in diagnostic tools are also common in ongoing trials (see Section 3.1) and make clinical efficacy comparisons even more difficult
MSC distribution studies in rodents showed that 1) MSCs are transplantable by the intravenous route of administration, 2) more than 90% of intravenous MSCs are trapped in the lung and then cleared (by monocyte phagocytosis) with a half-life of 24 h and 3) local MSC administration is more appropriate for a regenerative effect in situ [for review, see (Elman et al., 2014; Salvadori et al., 2019)]
These results suggest that intravenous MSCs act
Commenting on the CRATUS trial, Larrick and Mendelsohn (Larrick and Mendelsohn, 2017) noted that “…modest improvement outcomes were limited to the lower dose
a finding that remains difficult to explain”
and suggested that “Future studies are definitely warranted given the magnitude of this increasingly important medical syndrome”
further studies in frail elderly are needed to optimize the dosage of intravenous MSCs
to find the intravenous dose and frequency of administration that guarantee an optimal efficacy/safety ratio
Elderly subjects frequently have comorbidities, are poly-medicated, have reductions in hepatic and/or renal function, and have changes in the bioavailability of concomitant drugs (Grimsrud et al., 2015). In addition, such harm is amplified in frail people (Ibrahim et al., 2021)
In multiple myeloma patients older than 65 years and treated with autologous SC transplantation, Marini et al. (Marini et al., 2019) found that a reduction in the conditioning dose of melphalan was needed to maintain a safety profile similar to that in young subjects
MSC therapy in a poly-medicated frail elderly patient may interact with concomitant medications
increasing or decreasing their bioavailability
Older adults are considered by regulatory authorities to be a “special population” that has a therapeutic profile that cannot be directly extrapolated from what is known in adults (Grimsrud et al., 2015). Regarding safety issues, MSC therapies have a good safety profile, both in adults and in the elderly (Marini et al., 2019; Wang et al., 2021)
severe comorbid disease is often considered an exclusion criterion in clinical trials
which carries the risk that the results obtained will be different from those obtained in “real life” conditions
and NCT03458429 does not have a control (placebo) arm to assess the intervention efficacy
The nutrient combinations of NT-020 (NutraStem®) stimulate hSC proliferation in vitro
equal to or better than human granulocyte-macrophage colony-stimulating factor (hGM-CSF)
NT-020 and exercise were unable to significantly increase blood levels of SCs in men and women aged 50–70 years
at two or 4 weeks from the start of the trial
hGM-CSF was not used as an active comparator
No clinical trials for aging using E-SCs or induced pluripotent stem cells (iP-SCs) were found. The main reasons for this are: 1) their teratoma-forming tumorigenicity (Miyawaki et al., 2017), and 2) that the use of E-SCs raises ethical concerns (Lo and Parham, 2009)
The present investigation has not identified any SC preparation in late clinical development (Phase III RCTs) for physical frailty in older adults. Lomecel-B showed modest, but significant results in recent phase II RCTs (Golpanian et al., 2017; Tompkins et al., 2017)
and if it successfully completes the current phase II RCTs
it would have the potential to initiate phase III trials and later become the first effective targeted intervention for aging frailty
SPRINTT has the advantage of including the assessment of sarcopenia as an inclusion criterion
FIGURE 3. Key aspects of physical frailty protocols for phase III trials with mesenchymal stem cell (MSC) preparations. Two study protocols appear suitable for conducting phase III RCTs for aging frailty: (i) SPRINTT (Multicomponent Intervention for Physical Frailty and Sarcopenia) (Marzetti et al., 2018; Bernabei et al., 2022) and (ii) that used by ongoing clinical trials for aging frailty
In the CRATUS trial, serum TNF-alpha levels were significantly decreased in the Lomecel-B groups, but no significant changes in IL-6 were observed (Golpanian et al., 2017; Tompkins et al., 2017). Most of the clinical trials in Table 1 are investigating the effect of SC preparations on cytokine levels
Their results may help confirm the reduction in TNF-alpha levels as a valid criterion of efficacy (and/or better understand the role of IL-6 in therapeutic response)
Most of the trials with MSC for aging frailty (Table 1) have not yet been completed (with results). If the results are not better than those obtained with Lomecel-B (Golpanian et al., 2017; Tompkins et al., 2017)
other alternative types of SC preparations could enter preclinical and clinical research development
Yoshida et al. (2019) reported that administration of nicotinamide phosphoribosyltransferase (NAMPT)-containing exosomes significantly enhanced wheel-running activity and prolonged lifespan in aged mice [for review of studies of MSC-derived exosomes in preclinical models of age-related diseases, see (Ahmadi and Rezaie, 2021); for perspectives and challenges of clinical trials with exosomes, see (Rezaie et al., 2022)]
MSC-derived exosomes constitute an additional option to enter in preclinical and clinical development for the fragility of aging
Repurposing medicinal agents means finding new therapeutic indications for existing ones (Ayyar and Subramanian, 2022). Repurposing is a cost- and time-effective mechanism that can be applied to develop new SC therapies for aging frailty (Begley et al., 2021)
Repurposing of approved SC products and related agents for physical frailty in older persons
Several biological candidates can be repurposed for aging frailty: (i) Hemacord and other FDA-approved HPC cord blood products
(ii) the granulocyte colony-stimulating factor (G-CSF)
Darvadstrocel (Alofisel®, Takeda Ireland) and holoclar (Holoclar®, Holostem Terapie Avanzate, Italy) are EMA-approved SC products, but neither manufacturer has announced the launch of clinical trials for aging conditions (https://www.takeda.com/worldwide/) (https://www.holostem.com/news/?lang=en)
Some nutraceuticals (carnosine, catechin, vitamin D3, spirulina) promote SC proliferation in vitro (Bickford et al., 2006; Bachstetter et al., 2010), and are candidates to be repurposed for aging frailty (Figure 4)
Before entering clinical trials for aging frailty
these compounds should show their ability to increase SC blood levels in animal models (using GM-CSF as active comparator)
MSCs can be considered as “longevity candidates”
The National Institute on Aging (NIA, United States) has launched an Intervention Testing Program (ITP) dedicated to identifying longevity drug candidates in mice (Nadon et al., 2017), for further testing in human clinical trials (Garay, 2021) (https://www.nia.nih.gov/research/dab/interventions-testing-program-itp)
MSCs deserve to be investigated for their ability to increase healthy lifespan in the ITP
Various non-invasive methods have been used to prevent or treat facial aging, such as creams and lotions, without really satisfying results. In contrast, autologous fat grafting is efficacious for facial plastic and reconstructive purposes, and is widely used to restore volume and improve skin quality (facial skin rejuvenation) (Vasavada and Raggio, 2022)
Facial skin rejuvenation is another area of clinical research with SC preparations [for a review, see (Surowiecka and Struzyna, 2022)]. Recently, an RCT by Yin et al. (2020) clearly showed that SVF-assisted autologous fat grafting increases graft survival
Two RCTs (NCT03928444 and RPCEC00000362) and one single-arm clinical trial (IRCT20141007019432N2) are investigating hSVF preparations for facial rejuvenation (Table 2). The positive results obtained by Yin et al. (2020) with autologous hSVF transplantation suggest that similar protocols could be used in other clinical settings for regulatory purposes (see Section 4.2.3)
The SC “secretome” comprises diverse soluble factors (chemokines, cytokines, growth factors, angiogenic factors, and exosomes) produced in the endosomal compartment, and released for SC migration, apoptosis, proliferation, and angiogenesis [for review, see (Xia et al., 2019)]. Recent work suggests that the regenerative mechanism of SC transplantation could involve a modulatory paracrine effect of the SC secretome (Xia et al., 2019)
Compared to SC preparations, SC secretome has several advantages, including ease of manufacture, freeze-drying, packaging, and easier transportation (Xia et al., 2019). In addition, the SC secretome has shown potential to counteract facial aging (Kerscher et al., 2022). PT Kimia Farma Tbk (Jakarta, Indonesia; https://www.kimiafarma.co.id/) develops an hD-MSC secretome preparation for facial aging
This preparation is being investigated in NCT05508191
which compares two methods of secretome administration (microneedle and fractional CO₂ laser)
The efficacy results of the available SC studies are difficult to compare due to the very different techniques used for the extraction of fatty tissue, and for preparation and injection of SVFs (Surowiecka and Struzyna, 2022). In addition, outcome results are not similar for all surgeons (Demange and Fregni, 2011). Robinson et al. (2021) analyzed 388 RCT in surgery and identified several limitations: 1) trial registration was suboptimal
3) only a few trials were focused on major clinical events
and 4) few trials controlled the quality of the intervention or the experience of the surgeon
Regardless of aesthetic considerations, clinical trials with SC preparations for facial rejuvenation are important because: 1) Tissue regeneration is directly assessed by sophisticated and precise methods and 2) SC trapping in the lung (Elman et al., 2014; Salvadori et al., 2019) and safety problems of intravenous MSC administration are avoided
The FDA regulates allogeneic SVF products as biologics (ASCS, 2019), but the risk of skin rejection prevents clinical development of allogeneic SVF preparations for facial rejuvenation. The final consequence is that the very numerous US clinical trials with autologous SVF preparations for facial rejuvenation (Surowiecka and Struzyna, 2022) are not registered on ClinicalTrials.gov
Some RCT with autologous SVF preparations have recently been registered on ClinicalTrials.gov (see Table 2). The application of similar RCT protocols could pave the way for autologous SVF preparations to be registered on ClinicalTrials.gov and comply with FDA regulations (Investigational New Drug applications and FDA-approvals)
Preclinical studies suggested that AD-MSC preparations possess anti-wrinkling properties (Chen et al., 2020), and Charles-de-Sa et al. (Charles-de-Sa et al., 2020) recently reported full regeneration of solar elastosis by subdermal AD-MSC injection
There are two ongoing clinical trials for cutaneous photoaging: 1) NCT01771679 which was evaluating intravenous allogeneic hBM-MSCs for the treatment of facial photoaging (recruitment was suspended), and 2) ChiCTR2200061216 which is currently exploring whether hADSC-derived exosomes (loaded with circcol elns) can promote collagen and elastin synthesis in photoaged skin (Table 2)
Circular RNAs (circRNAs) include a large family of non-coding RNAs, which can regulate gene expression (acting on transcription, mRNA turnover and translation, by sponging microRNAs and RNA-binding proteins) (Panda, 2018). Intensive research of non-coding RNA therapy for photoaging is currently being carried out at Sun Yat-Sen University Hospital (China) (ChiCTR2200061216, Table 2) (Peng et al., 2017; Hou et al., 2021)
If ChiCTR2200061216 yields positive results
treatment with circcol elns-loaded exosomes would hold great promise for cutaneous photoaging
Clinical research with SC therapies for aging focuses on two main objectives: Physical frailty and facial skin aging
The advantages and disadvantages of these two objectives are complementary (which facilitates a global vision)
Physical fragility affects organs that are usually accessed parenterally
where the pulmonary filter makes it even more difficult for SCs to access the target organ
Rejuvenating the skin is above all an aesthetic objective
but the effectiveness is evaluated directly on a visible and easily accessible organ
Facial skin aging is another area of clinical research with SC preparations. An RCT conducted by Yin et al. (2020) has shown positive results with an autologous hSVF preparation. Several other clinical trials are currently underway for facial skin aging (Table 2)
This area of research has received a great initial impetus
as demonstrated by the twenty clinical trials launched worldwide and reviewed here
Let’s hope that all these efforts will be rewarded with the arrival of the first SC anti-aging product in the near future
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Citation: Garay RP (2023) Recent clinical trials with stem cells to slow or reverse normal aging processes
Received: 20 January 2023; Accepted: 24 March 2023;Published: 06 April 2023
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distribution or reproduction is permitted which does not comply with these terms
*Correspondence: Ricardo P. Garay, cmljYXJkby5nYXJheUBvcmFuZ2UuZnI=
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Because a title similar to a Jay-Z/Kanye West song just seems inappropriate.
“I have been a fan of the S2000 since its inception,” Nicolas explains. “I never thought I would ever own one but it became the car of my dreams. It didn’t even matter if it was modified or not, I just loved how it looked.”
“I was able to meet a number of S2000 owners through that forum. We often exchanged ideas on how to mod and make changes to our cars. Every year, we met up to make an S2000-dedicated cruise through various cities in France. The trips would last about a week and would take us to places like Cannes and Monaco. I had a lot of fun making these trips and met many great friends because of it.”
Even with constant input from his peers, it took Nicolas about three years to get his S2000 to its current stage. He didn’t want to change much at first but the bug eventually bit him. It may not seem like his AP2 was heavily-modded compared to the extensive builds you see here in the States, but for him it was more than enough.
The first thing that made its way off of the car was the OEM exhaust and suspension. In their place sits an HKS Hi-Power exhaust system and TEIN Monoflex set-up.
The most difficult decision was deciding wheels. Nicolas explains; “It took me six months to come up with the perfect wheel for the car. I wanted a five-spoke design with chrome and a really low offset. It also had to be rare in France and a high-quality wheel. The Work Meister S1 fit my criteria but it came down to the sizing of the rim that would make or break the flow of the car.”
Obviously, he could have figured out the specs on his own but you have to understand that other countries of especially non-English speaking origins don’t have as much information available to them as we do here. In addition, the wheel he desired also isn’t sitting on a shelf in France. These Works had to be special ordered from Japan. There was very little room for error so he felt it was smarter to ask another enthusiast who had already figured out the numbers.
“I came upon another S2000 belonging to Alex Zhao. Alex also had an S2000 but his wheel specs were way more aggressive than what I was looking for. I explained to him that I wanted something aggressive but still suitable for regular driving. He actually knew the exact wheel specs that Luteman ran. That gave me the confidence to order the wheels with the proper calculations.”
Engine2.0L F20C with HKS Hi-Power LM Edition exhaust; Megan Racing test pipe; Password:JDM reservoir tank covers and aluminum radiator stays; NRG hood damper; Skunk2 radiator cap
Footwork & ChassisTEIN Monoflex coilovers; Cusco carbon-fiber front upper strut tower bar; T1R half-shaft spacers
BrakesSportstop slotted/drilled brake rotors
Wheels & Tires18x8.5" front and 18x9.5" rear Work Meister S1 wheels; 225/40R18 front and 245/35R18 rear Goodyear Eagle F1 tires; Composite Racing R40 lug nuts
ExteriorOEM AP2 front lip; Downforce DF-R carbon side splitters; custom rear diffuser
InteriorSkunk2 shift knob; T1R suede shift boot; JVC KD-G632 head unit; Eminence 165mm front speakers
Thanks YouMy brother for always being there to help with the car; I love my wife who lets me do whatever I desire to my S2000; my friends Francois Law Lai and Julien Huet
WWW s2000-passion.forumactif.org; s2ki.com
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