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Reversal of epigenetic aging and immunosenescent trends in humans
During the first week of the trial, rhGH alone (0.015 mg/kg) was administered to obtain an initial insulin response, and during the second week, rhGH was combined with 50 mg DHEA to evaluate insulin suppression by DHEA alone. During the third week, the same doses of rhGH and DHEA were combined with 500 mg metformin. Beginning at the fourth week, all doses were individualized based on each volunteer's particular responses. Thereafter, blood was collected one week prior to trial months 2, 3, 4, 6, and 9 to enable further dose adjustments at those time points (to maximize IGF-1 and minimize insulin), and additional blood samples were obtained at 12 months to conclude the treatment monitoring period.
"Although, on average, trial volunteer epigenetic ages (EAs) were lower than their chronological ages (As) at baseline [(EA-A)0 < 0, Table 1], epigenetic age was nevertheless significantly decreased by treatment based on the results of all four epigenetic clocks (Figure 5a-d), with a mean change in EA-A after 12 months of about 2.5 years”
There may be both immunological and non-immunological mechanisms of epigenetic aging reversal. GH, DHEA, and metformin have unique effects that are in opposition to aging, and it is possible that the specific combination of these agents activates a broad enough range of therapeutic pathways to account for the previously unpredictable reversal of epigenetic aging, even independently of the immunological markers we have measured.
Treatment safety and side effects
A primary concern in this study was whether increased levels of a mitogen (IGF-1) might exacerbate cancerous or precancerous foci in the prostate. Both of these changes should be detectable by measuring PSA or percent free PSA levels. However, PSA, percent free PSA, and the ratio of PSA to percent free PSA, an overall index of prostate cancer risk, improved significantly by day 15 of treatment and remained favorably altered to the end of 12 months (Figure 1a-c). A brief spike in PSA at 6 months in two volunteers was rapidly reversed and, after volunteer consultation, was interpreted as reflecting sexual activity close to the time of PSA testing. No change in testosterone levels was observed.
Another significant concern was whether augmenting immune activity might exacerbate age-related inflammation. However, CRP declined with treatment, the decline reaching statistical significance by 9-12 months (Figure 1d). The pro-inflammatory cytokine, IL-6, did not change (Figure 1e).
No remarkable changes were noted in serum albumin, lipids, hemoglobin, hematocrit, platelet count, electrolytes, and hepatic enzymes (Figure 1f). Insulin levels were in general adequately controlled by co-administration of DHEA and metformin (Figure 1g) (although one outlier increased mean insulin at 12 months), and glucose levels did not change (Figure 1h). Finally, estimated glomerular filtration rates (eGFR), which are relevant to the potential for lactic acidosis with metformin as well as to treatment efficacy, showed a statistically significant improvement after 9-12 months (with a trend toward improvement at 18 months as well) (Figure 1i). Side effects were mild, typical of rhGH administration, and did not require dosing modification except in two cases. Side effects included arthralgias (2 cases), anxiety (1 case), carpal tunnel syndrome (1 case), fluid retention (1 case), mild gynecomastia (1 case), and muscle soreness (1 case). One trial volunteer was removed from the study after approximately one month due to self-reported bradycardia, which preceded the trial, and belated admission of a strong familial history of cancer.

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