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Clinical study to evaluate the anti-aging effects of a PAI-1 inhibitor (TM5614)

Anti-aging effects of PAI-1 inhibitor

20

The median age was 61.5 years (mean age 60.3 years), with 14 men (mean age 60.0 years) and 6 women (mean age 60.8 years). Six participants had diabetes, ten had hypertension, twelve had dyslipidemia, and four had chronic kidney disease. The median age of the 19 FAS participants was 62 years (mean age 60.4 years; 13 men and 6 women).

Consent was obtained from 20 subjects, and all 20 were enrolled and began receiving the study drug. There were no discontinuations, and safety was evaluated in all 20 subjects (SAS). One subject was diagnosed with pneumonia based on elevated inflammatory markers detected in blood tests conducted 4 months after the start of treatment; this subject was deemed unsuitable for analysis of immune function and other parameters and was therefore excluded from the full analysis set (FAS). The analysis was conducted on a total of 19 subjects. There was no rejection from the PPS.

In this study, adverse events occurred in 5 of the 20 subjects. Common cold 1 (Grade1) (5%), diarrhea 1 (Grade 1) (5%), pneumonia 1 (Grade 2) (5%), liver dysfunction 1 (Grade 2) (5%) , liver dysfunction 1 (Grade 1) (5%). One event (liver dysfunction) could not be ruled out as being causally related to the study drug; however, the subject has since recovered, and no serious or previously unknown adverse effects were observed. Thus, the safety of oral administration of TM5614 at doses up to 180 mg/day for 16 weeks in relatively healthy elderly patients has been confirmed.

[Primary endpoint] Assessment of immune cell counts: Flow cytometric analysis of blood cells revealed no significant changes in the counts of CD4+ T cells, CD8+ T cells, or B cells. In contrast, the number of NK cells decreased significantly (p<0.05; decrease in 14 of 19 subjects), while the number of dendritic cells increased significantly (p<0.05; increase in 12 of 19 subjects). [Secondary Endpoints] (1) Aging Markers: -Aging-associated small-molecule RNAs (SA-miRNAs): Analysis of serum SA-miRNAs detected six types of SA-miRNAs, all of which were significantly reduced. -G-tail Length: Measurement of telomere G-tail length using a G-tail telomere hybridization protection assay revealed significant shortening. -Plasma SA gene fragments: Quantification of cell-free DNA in plasma revealed no changes. -DNA Methylation: Biological age was estimated using the Horvath method and the PC-Horvath method based on DNA methylation, revealing a rejuvenation of 2-3 years. (2) Stem Cells: -Blood Stem Cell Count: Flow cytometric analysis of blood cells revealed a significant increase in blood stem and hematopoietic cells, as well as multipotent progenitor cells that produce lymphocytes. -Transcriptome analysis: RNA-seq analysis of peripheral blood CD34+CD38- hematopoietic stem and progenitor cells revealed a significant increase in multiple gene sets that could potentially reverse aging in these cells, and a significant decrease in multiple gene sets that promote aging. Gene set enrichment analysis based on this transcriptomic data showed that the ability to produce differentiated cells, similar to that observed in younger individuals, had been restored. -Clonal hematopoiesis: There were no eligible specimens. (3) Immunity and Metabolism: -Plasma Proteins: About 7,500 plasma proteins were analyzed using SomaScan. Among the proteins showing significant differences in paired t-tests, those associated with the improvement of mild chronic inflammation associated with aging, enhanced functional capabilities such as macrophage phagocytic activity, and the promotion of tissue (bone and muscle tissue), and improved cognitive function. The analysis suggested that systemic chronic inflammation was reduced, macrophage function, which removes senescent cells, was enhanced, and these effects had a positive impact on both muscle and bone tissue as well as cognitive function. -Total CD4 T-cell function: A trend toward improved proliferative capacity and a decrease in the rate of cell death (apoptosis) was suggested. -Monocyte-derived macrophage function: No significant changes were observed in glucose uptake, ROS production, or the expression of beta-galactosidase, a marker of aging. -Serum oxidative stress markers: A decreasing trend was observed in 8-hydroxy-2'-deoxyguanosine (8-OHdG) levels (p=0.118, decrease in 14 of 19 subjects), and a decrease in CML (N-carboxymethyllysine), an advanced glycation end product (AGE) (p<0.01, decrease in 16 of 19 subjects). GDF-15 levels were not changed. -Serum RNA-derived modified nucleosides: A slight to moderate increase was observed in six types of modified nucleosides in serum, suggesting changes in RNA-related metabolism. In particular, N6-methyladenosine (m6A), a major metabolite, increased in all subjects (p<0.001). -Serum trace elements: Serum trace metals were comprehensively measured. The results showed a significant decrease in molybdenum concentration (p<0.05, decrease in 13 of 19 subjects) and a tendency toward a decrease in copper (p=0.051, decrease in 13 of 19 subjects). [Conclusion] A 4-month administration of TM5614 suggested an improvement in innate immune function, as evidenced by an increase in the number of dendritic cells in the blood and a decrease in NK cells, which were the primary endpoints. These results were supported by secondary endpoints, including increases in multiple plasma proteins that enhance macrophage phagocytic function, as well as increases in hematopoietic stem and progenitor cells and multipotent progenitor cells that produce lymphocytes. Furthermore, reductions in oxidative stress and changes in plasma proteins associated with improvements in blood trace element levels, bone and muscle function, and cognitive function were observed, suggesting the potential for broad anti-aging effects. Changes in aging markers, particularly substances involved in gene regulation (DNA methylation, SA-miRNAs, and modified nucleosides), were observed as contributing factors. Furthermore, as a comprehensive assessment of youthfulness and aging, results from estimating biological age based on DNA methylation showed a rejuvenation of 2-3 years. Thus, it is considered that a 4-month administration of TM5614 induced biochemical changes demonstrating anti-aging effects across a wide range of organs-including the immune system, metabolism, bone and muscle, cognitive and neurophysiological functions, and hematopoietic stem cells-thereby exhibiting systemic anti-aging effects.

Four months of TM5614 administration suggested an improvement in innate immune functions, as evidenced by an increase in the number of dendritic cells in the blood and a decrease in NK cells. TM5614 also induced biochemical changes demonstrating anti-aging effects across a wide range of organs, including the immune system, metabolism, bones and muscles, cognitive and neurophysiological functions, and hematopoietic stem cells, thereby exhibiting systemic anti-aging effects.

July. 31, 2026

No

None

https://jrct.mhlw.go.jp/latest-detail/jRCTs021250011

Harigae Hideo

Tohoku University Hospital

1-1 Seiryo-machi,Aoba-ku,Sendai,Miyagi, 980-8574,Japan

hideo.harigae.e4@tohoku.ac.jp

Fujii Hiroshi

Tohoku University Hospital

1-1 Seiryo-machi,Aoba-ku,Sendai,Miyagi, 980-8574,Japan

+81-22-717-7165

hiroshi.fujii.d2@tohoku.ac.jp

Complete

Aug. 01, 2025

Interventional

single arm study

open(masking not used)

uncontrolled control

single assignment

basic science

1) Over 50 years old and under 75 years old
2) Patients diagnosed with one or more of the following diseases based on the definitions in the clinical guidelines and whose symptoms are stable: hypertension (The Japanese Society of Hypertension Guidelines for the Management of Hypertension 2019), type 2 diabetes (Japanese Clinical Practice Guideline for Diabetes 2024), chonic kidney disease (Clinical Practice Guideline for CKD 2023), hyperlipidemia (Japan Atherosclerosis Society (JAS) guidelines for prevention of atherosclerotic cardiovascular diseases 2022)
3) Patients who have obtained written consent from the individual to participate in this study

1) Patients who are taking or receiving any of the following medications:
Warfarin potassium, Dabigatran etexilate methanesulfonate, and Rivaroxaban, Apixaban, Edoxaban Tosilate Hydrate, heparin and tissue-type plasminogen activator
2) Hypertensive patients with systolic blood pressure of 180 mmHg or higher and diastolic blood pressure of 110 mmHg or higher (so-called grade III hypertension)
3) Chronic kidney disease patients with eGFR less than 30 ml/min/1.73 m2
4) Patients with type 2 diabetes mellitus who are on insulin therapy and hospitalized
5) Familial hypercholesterolemia among hyperlipidemic patients
6) Patients who are participating in other clinical trials
7) Patients undergoing cancer treatment
8) Patients with autoimmune diseases
9) Patients with a history of transient ischemic attack or cerebral vascular attack within 180 days prior to enrollment in this study
10) Patients participating in other interventional trials
11) Patients with the following cardiovascular Diseases
-Have a history of myocardial infarction within 6 months prior to enrollment
-Symptomatic arrhythmia requiring treatment
-Have a history of severe thrombosis or thromboembolism such as pulmonary arterial embolism or deep vein thrombosis. However, those who have not had a history of thrombosis or thromboembolism for at least 90 days and have no concerns about recurrence may be enrolled.
12) Patients with a history of bleeding, such as intracerebral hemorrhage
13) Liver function and renal function test values are as follows:
-AST and ALT are more than 3 times the upper limit of the reference value of the institution
-Total bilirubin is more than 2 times the upper limit of the reference value of the institution
-Creatinine is more than 1.5 mg/dL or creatinine clearance (measured value or estimated value by Cockcroft/Gault formula) is less than 45 mL/min or less
14) Patients received radiation therapy within 28 days prior to enrollment in this study
15) Patients have bleeding tendency
16) Patients are pregnant, lactating or may be pregnant
17) Patients have a systemic infection requiring treatment
18) Patients requiring transplantation therapy or those with a history of transplantation therapy (excluding autologous transplantation)
19) Patients who are judged to lack the capacity to consent due to complications of dementia
20) Other patients who are judged to be ineligible for this study by the principal (sub)investigator

Both

N/A

TM5614 is started as 2 tablets (120 mg) once daily (4 weeks) and increased to 3 tablets (180 mg) once daily (12 weeks) if blood and biochemical tests after 1 month show no safety issues

Evaluation by FACS of surface markers of immune cells and their degrees of expression

Aging markers
-Senescence-associated small RNA (SA miRNA) screening: Quantification of SA miRNA in patient serum, plasma, peripheral blood lymphocytes (PBL), and T cells
-G tail telomere hybridization protection Assay (Gt telomere HPA): evaluation of G-tail and telomere length in PBLs that shorten with age-related diseases and cellular senescence
-Quantification of SA gene fragments in patient plasma
-DNA methylation

Stem Cells
-Evaluation of phenotypic markers and frequencies of HSCs and blood cells by FACS
-Evaluation of effects on the transcriptome by isolating HSCs and performing RNA-seq analysis
-Evaluation of effects on clonal hematopoiesis by exome analysis using peripheral blood differentiated blood cells (samples with drug effects found in 1) and 2) above)

Immunology and Metabolism
-SomaScan 11K Assay (serum senescence-related secretory phenotype)
-Senescence status and biological activities of total CD4 T cells (telomerase activity, telomere length, cell proliferation activity, cell death, gene expression)
-Monocyte-derived macrophages (MDM) Biological activities of monocyte-derived macrophages (MDM) (glucose uptake capacity, mitochondrial function, ROS production, beta-galactosidase staining, gene expression)
-Modomics analysis of RNA-derived modified nucleosides in serum (related to mitochondrial activity and inflammatory response)
-Metallomics analysis of trace elements in serum

+81-22-718-0461

July. 04, 2025

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