Cytotoxic T cells (CD8+) play an important role in warding off cells infected with intracellular pathogens and cancer cells1. The effectiveness of immune response by CD8+ T cells depends on the presence or absence of its co-receptor, CD28. CD8+cells expressing CD28 better proliferate upon antigen stimulation compared to CD8+ cells that lack CD282, in part due to difference in the telomere lengths. The CD8+CD28- cells have shorter telomeres compared to CD8+CD28+ cells, and the rate of telomere attrition is more pronounced in CD8+CD28- cells3. Accumulation of such immunosenescent cells is associated with reduced overall immune function4.
TA-65® has been proven to increase telomerase activity and lengthen telomeres in mice and humans 5, 6, 7. In 2013, TA-65®MD was granted Generally Recognized as Safe (GRAS) certification for use in a medical food. No product related toxicity was reported in two randomized placebo-controlled studies over one-year duration7, 8.
A previous observational study indicated that oral intake of TA-65® decreased CD8+CD28- senescent cell population6 which is associated with improved immune function9. Here we report a placebo-controlled study on the effect of oral intake of TA-65®MD capsules on the senescence of CD8+ T cells in humans.
This study was conducted by a contract research organization (CRO) in accordance with Good Clinical Practice (GCP) and approved by an Institutional Review Board. The study was registered in ClinicalTrials.gov (NCT02766790).
A total of 500 healthy volunteers were randomly allocated into one of the five arms: placebo, TA-65®MD (100 Units), TA-65®MD (250 Units), TA-65®MD (500 Units) or TA-65®MD (250 Units) b.i.d. All subjects took two capsules per day for nine months, one in the morning and the other in the evening. Placebo group took two placebo capsules per day; TA-65®MD (100 Units), TA-65®MD (250 Units), TA-65®MD (500 Units) groups took one placebo capsule and one active capsule per day; TA-65®MD (250 Units) b.i.d group took two TA-65®MD (250 Units) capsules per day. Blood samples were collected at baseline and at the end of the study.
Immune cells were analyzed by UCLA Immunogenetics Center, which is accredited by the American Society for Histocompatibility and Immunogenetics (ASHI) as well as Clinical Laboratory Improvement Amendments (CLIA).
Volunteers, investigators, UCLA Immunogenetics Center and T.A. Sciences Inc. remained blinded until the CRO collected all the data and locked the database.
Table 1 shows the multilevel model estimate of CD8+CD28- T cells for the difference between the end of the study and the baseline for subjects on TA-65® as compared to the placebo. In the pooled data that includes both men and women, Cytomegalovirus (CMV)-positive and CMV-negative subjects, the estimate of change from baseline to the end of the study for the placebo group was an increase in the mean (4.38 ± 6.93, SE), and this change is not statistically significant (p=0.52). This result indicates that placebo treatment does not significantly alter the number of circulating senescent T cells. In contrast, the number of senescent T cells significantly decreased in subjects on 100 Units of TA-65® (mean ± SE, -28.40 ± 9.39; p <0.001). Similarly, the estimate of change for senescent CD8+CD28- cells significantly decreased in subjects on other doses of TA-65® as well. Taken together, these results indicate that TA-65®, and not placebo, significantly decreased senescent CD8+CD28- T cells in all TA-65® groups, regardless of their gender and CMV status.
|Arms||n||Change in CD8+CD28- T cells (cells/ml)*||SE||p value †|
|TA-65® (100 Units)||86||-28.40||9.39||<0.001|
|TA-65® (250 Units)||94||-28.18||9.20||<0.001|
|TA-65® (500 Units)||92||-22.71||9.25||0.01|
|TA-65® (250 Units) b.i.d.||80||-21.40||9.58||0.02|
† p values <0.05 are indicated in bold fonts; * Change in mean = End of the study - baseline; n= number of subjects. Statistical analysis was performed using multilevel model.
No product related toxicity or serious adverse events were observed in this study.
In this study, daily intake of TA-65®MD capsules significantly decreased the number of senescent T cells and thereby improved immune function in humans.