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A Natural Product Telomerase Activator as Part of a Health Maintenance Program: Metabolic and Cardiovascular Response

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Short average telomere length is associated with low telomerase activity and certain degenerative diseases. Studies in animals and with human cells confirm a causal mechanism for cell or tissue dysfunction triggered by critically short telomeres, suggesting telomerase activation may be an approach to health maintenance. We previously reported on positive immune remodeling in humans taking a commercial health maintenance program, PattonProtocol-1, composed of TA-65® (a natural product-derived telomerase activator) and other dietary supplements (1). In over a 5 year period and an estimated 7000 person-years of use, no adverse events or effects have been attributed to TA-65 by physicians licensed to sell the product. Here we report on changes in metabolic markers measured at baseline (n=97-107 subjects) and every 3-6 months (n=27-59 subjects) during the first 12 months of study. Rates of change per year from baseline determined by mixed effects ANOVA were -3.72 mg/dL for fasting glucose (p=.02), -1.32 mIU/mL for insulin (p=0.01), -13.2 and -11.8 mg/dL for total- and LDL-cholesterol (p=0.002, p=0.002, respectively), -17.3 and -4.2 mm Hg for systolic and diastolic blood pressure (p=0.007 and 0.001, respectively), and -3.6 umole/L homocysteine (p=0.001). In a subset of individuals with bone mineral density (BMD) measured at baseline and 12 months, density increased 2.0% in the spine (p=0.003). We conclude that in addition to apparent positive immune remodeling, PattonProtocol-1 may improve markers of metabolic, bone and cardiovascular health.
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A Natural Product Telomerase Activator
as Part of a Health Maintenance Program:
Metabolic and Cardiovascular Response
Calvin B. Harley,
1
Weimin Liu,
2
Peter L. Flom,
3
and Joseph M. Raffaele
4
Abstract
A short average telomere length is associated with low telomerase activity and certain degenerative diseases.
Studies in animals and with human cells confirm a causal mechanism for cell or tissue dysfunction triggered by
critically short telomeres, suggesting that telomerase activation may be an approach to health maintenance.
Previously, we reported on positive immune remodeling in humans taking a commercial health maintenance
program, PattonProtocol-1, composed of TA-65
(a natural product–derived telomerase activator) and other
dietary supplements. In over a 5-year period and an estimated 7000 person-years of use, no adverse events or
effects have been attributed to TA-65 by physicians licensed to sell the product. Here we report on changes
in metabolic markers measured at baseline (n = 97–107 subjects) and every 3–6 months (n = 27–59 subjects)
during the first 12 months of study. Rates of change per year from baseline determined by a multi-level model
were - 3.72 mg/dL for fasting glucose ( p = 0.02), - 1.32 mIU/mL for insulin ( p = 0.01), - 13.2 and - 11.8 mg/dL
for total cholesterol and low-density lipoprotein cholesterol (LDL-C) ( p = 0.002, p = 0.002, respectively), - 17.3
and - 4.2 mmHg for systolic and diastolic blood pressure ( p = 0.007 and 0.001, respectively), and - 3.6 lmole/L
homocysteine ( p = 0.001). In a subset of individuals with bone mineral density (BMD) measured at baseline and
12 months, density increased 2.0% in the spine ( p = 0.003). We conclude that in addition to apparent positive
immune remodeling, PattonProtocol-1 may improve markers of metabolic, bone, and cardiovascular health.
Introduction
T
elomeres, the structures that protect the ends of
our chromosomes, are fascinating components of our
genome. They are complex, dynamic structures composed of
DNA, RNA, and protein that play a key role in aging and
age-related disease, including cancer.
1–4
At a biochemical
level, telomeres protect chromosome ends from degradation
or recombination events and facilitate faithful segregation of
chromosomes during cell division. Early work over 20 years
ago showed that the average length of human telomeres in
normal somatic (non-tumor, non-germ line) cells is a mea-
sure of the remaining replicative capacity of those cells
5,6
and
that short telomeres are associated with disease, including
cardiovascular disease, cancer, human immunodeficiency
virus/acquired immunodeficiency syndrome (HIV/AIDS),
and Down syndrome.
6–11
Telomere length in general be-
comes shorter with each cell division, until one or more
telomeres become critically short, triggering cell senescence,
loss of normal cell function, genomic instability, and possibly
cell death or tumor initiation.
12–16
Telomerase, the enzyme that synthesizes telomeric
DNA,
17
can slow or even reverse telomere shortening in
normal human cells in culture
18,19
and contribute to slowing
or reversal of degenerative, age-related disease in ani-
mals.
14,20–22
In almost all large-scale cross-sectional studies in
humans, telomere length is inversely correlated with chro-
nological age; but with the recent interest in longitudinal
tracking of telomere length in humans, evidence for possible
telomere lengthening within an individual is emerging.
23–31
Because telomere length can vary within different cell line-
ages, average telomere length is a function of the distribution
of different cell types and their telomere lengths at any given
time. Thus, for complex tissues, one cannot easily distinguish
between true telomere length changes versus a shift over
time in subsets of cells in the sampled tissue(s).
1
Consultant to TA Sciences, Murphys, California.
2
TA Sciences, Inc., New York, New York.
3
New York, New York.
4
PhysioAge Systems, LLC, New York, New York.
REJUVENATION RESEARCH
Volume 16, Number 5, 2013
ª Mary Ann Liebert, Inc.
DOI: 10.1089/rej.2013.1430
386
In the late 1990s, we (Harley and colleagues at Geron
Corporation and the Hong Kong University of Science and
Technology) conducted a screening program for telomerase
activators, which led to the discovery that certain small-
molecule components of Huang Xi, a traditional Chinese
medicine reputed to maintain health, were activators of tel-
omerase.
1,22,32–34
Definitive pharmacodynamic studies and
randomized, placebo-controlled studies with these molecules
in humans have not been completed, but the majority of
studies to date have suggested that they modestly activate
telomerase and/or help maintain telomere length in vitro and
in vivo, and that they have positive functional effects on
human cells. In addition, a number of recent studies have
suggested that telomerase activation in mice with shortened
telomeres and signs of engrained age-related disease can be
rescued in part through telomerase activation without signs
of increased global cancer risk.
14,20–22
Thus, telomerase acti-
vation is gaining support as a potential treatment or pre-
vention of degenerative diseases using drugs and for health
maintenance using dietary supplements.
In our first analysis of PattonProtocol-1, a commercial
health maintenance program composed of TA-65
(a natural
product–derived telomerase activator), other dietary sup-
plements, and physician counseling, we reported positive
immune remodeling over a 1-year period relative to baseline
values.
1
These changes included significant declines in se-
nescent cytotoxic (CD8
+
/CD28
-
) T cells, particularly in cy-
tomegalovirus (CMV)- seropositive subjects. In addition, we
found that TA-65 alone increased telomerase in human cells
in culture. In aged mice with shortened telomeres, TA-65
reduced the percentage of cells with short telomeres and
improved the structure of multiple tissues.
22
A recent study
on the association between telomere length and experimen-
tally induced upper respiratory track viral infection in heal-
thy adults
35
underscored the predictive value of short
telomeres for viral infections and clinical illness, especially
when telomere length was measured in CD8
+
/CD28
-
cells.
Here we report on observed changes from baseline in
metabolic and cardiovascular markers, including bone min-
eral density, from the same set of subjects consuming TA-65
for a 1-year period.
Methods
PattonProtocol-1
PattonProtocol-1 was launched in January, 2007, by TA
Sciences (New York, NY) as a commercial age-management
product composed of a natural product-derived telomerase
activator (TA-65
, described below), a dietary supplement
pack, laboratory testing, and physician counseling. Further
details are found in Harley et al.
1
All subjects signed a
comprehensive Customer Acknowledgement Form. Baseline
assays (Table 1) indicated that most individuals were within
the normal ranges (data not shown). The consulting physi-
cian prescribed new medications for only 3 subjects. There
was no qualitative change in the overall conclusions whether
these subjects were included or excluded from the analyses.
The number of subjects at 3, 6, 9, and 12 months for most
tests was 43, 59, 27, and 37, respectively. The age and gender
frequencies of the subset at each time-point were similar to
those of the total baseline population (n = 114; 63 12 years,
72% male).
TA-65
TA-65
was exclusively licensed from Geron Corporation
(Menlo Park, CA) to TA Sciences (New York, NY). It is a
single-molecule entity with 95% purity by high-performance
liquid chromatography (HPLC) derived from a proprietary
extract of the dried root of Astragalus membranaceus. All data
Table 1. Cross-Sectional Baseline Values for Metabolic and Cardiovascular
Biomarkers and Relationship to Age
Age
(year)
Glucose
(mg/dL)
Serum Insulin
(lIU/mL)
DHEA Sulfate
(lg/dL)
Cholesterol
(Total) (mg/dL)
Cholesterol (LDL)
(mg/dL)
Mean 62.5 97 7.1 148 188 106
SD 12.5 15 7.0 131 38 34
n 114 107 107 106 105 104
m
a
NA 0.33 0.025 - 2.6 - 0.29 - 0.37
R
2
NA 0.08 0.002 0.06 0.01 0.02
p value NA
0.0046
b
0.64
0.011
0.32 0.16
SBP
(mmHg)
DBP
(mmHg)
Homo-cysteine
(lmol/L)
Serum Folate
(ng/mL)
Vitamin
D-25-OH total (ng/mL)
Vitamin B12
(pg/mL)
Mean 128 77 11 17 40 786
SD 19 10 3.6 5.8 16 409
N 97 97 107 105 107 105
m 0.51 - 0.018 0.066 0.12 0.11 6.1
R
2
0.108 0.000 0.05 0.065 0.007 0.036
p value
0.0010
0.83
0.016 0.0086
0.38 0.053
The mean, standard deviation, and linear regression statistics for test values vs. age are provided for all baseline subjects (n = number).
a
Slope (m) of the linear regression line of test value versus age of subjects.
b
p value for significance of the regression line slope. p values less than 0.05 are shaded.
DHEA, dehydroepiandrosterone; LDL, low-density lipoprotein; SD, standard deviation; NA, not applicable; SBP, systolic blood pressure;
DBP, diastolic blood pressure.
A TELOMERASE ACTIVATOR IN HEALTH MAINTENANCE 387
in this report are from the original TA-65 product. Post 2011,
the purity of the manufactured product has improved from
roughly 95% to > 98%.
Clinical laboratory assays
At baseline and each time point after initiation of the
product, blood samples were drawn from each subject (for
plasma or serum assays) and shipped the same day at am-
bient temperature to appropriate commercial, academic, or
contract laboratories. Assays for standard blood counts,
blood chemistry (including glucose, insulin, hemoglobin
A1c, and serum vitamins), specialized immune subsets
(CD8
+
, CD28
-
, and CD95
-
, both gated on CD8
+
), CMV
antibody titer, and inflammation markers (homocysteine and
cardio C-reactive protein) were all conducted at a standard
clinical laboratory (either Quest Diagnostics, Bio-Reference
Laboratory, or UCLA Clinical Laboratories and Pathology
Services). Data related to the immune markers have been
reported previously.
1
Bone mineral density
Bone mineral density (BMD) was analyzed at baseline and
at 12 months on the first available 31 subjects at PhysioAge
Medical Group (New York, NY) to reach the 12-month time
point. Full anteroposterior (AP) spine L1–L4 and dual
proximal femur (neck, trochanter, and dual mean) bone
density data were generated using a dual-energy X-ray ab-
sorptiometry (DEXA) instrument (GE Healthcare).
Statistics
Because data were collected primarily as a hypothesis-
generating exercise and the clients were not participating
in a controlled clinical study, statistical analysis was not
formally defined apriori. Baseline dat a were primarily
analyzed for cross-sectional donor age effects to c ompare
results with the PattonProtocol-1 population. Where sig-
nificance of linear regression lines is reported for cross-
sectional analysis, the F-distribution was used to calculat e
the probability that the observed correlation occurre d by
chance and p values are reported. Modeling of the 1-year
change in valu es us ed a multilevel or mixed model with
random intercepts and slopes. Each person had an indi-
vidual sta rting point and an individual slope for change
over time on treatment. For each dependent v ariable, we
first graphed the data, looking for outliers and for points
that indicated the pr esence of disease. Erroneous dat a
entries were corrected, as were entries indicating either a
failure to follow protocol (e.g., glucose over 125 or insulin
over 20 indicating non-fasting). Systolic blood pressure
(SBP) over 160 or diastolic blood pressure (DBP) over 100
was taken to indicate hypertension. These relatively high
cutoffs for SBP and DBP were chosen so as not to exclude
those individuals with possible metabolic syndrome bu t
not currently carrying a diagnosis of hypertension or on
anti-hypertensive medic ation. Gr aphs were examined for
non-linear trends, and multi-level models were used to
account for dependence in the data. For each dependent
variable, we tested a relative ly full model that included
fixed effects of time, time squared, baseline age, sex, telo-
mere length, and CD8
+
CD28
-
T cells using unstructured
co-variance.Time,age,andsexwerekeptinallmodels.
Other variables were eliminated if the parameter estimate
was close to 0 and the p value above 0.10. The i nitial model
included random effects for intercept, slope, and slope
squared. The ran dom e ffect of slope squared was d eleted if
the fixed effect for time squared was deleted. The resultant
model was tested with three different cova riance struc-
tures, unstructured, compound symmet ry, and auto- re-
gressive, and the choice m ade was based on the Akaike
information criterion (AIC).
Results and Discussion
Key baseline observations
Most subjects for this study were relatively affluent indi-
viduals motivated to maintain personal health, and thus may
not reflect the general population. Table 1 shows mean val-
ues, standard deviations, count, slope, and R
2
from linear
regression on subject age, and the statistical significance of
the slope for the baseline tests investigated in this report. As
expected, this population showed a statistically significant
increase as a function of client age in fasting blood glucose
(0.33 mg/dL/year), SBP (0.51 mmHg/year), and homo-
cysteine (0.066 lmol/L/year), and a significant decrease in
dehydroepiandrosterone (DHEA) sulfate ( - 2.6 lg/dL/
year). The increase in serum folate (0.12 ng/mL per year) was
unexpected but may reflect the relatively greater use of folic
acid–containing multivitamins in older compared to younger
subjects prior to starting the protocol.
As described previously,
1
by cross-sectional analysis,
telomere length declined in a characteristic manner in this
population as a function of client age in both lymphocytes
and granulocytes (55 and 34 bp/year; p = 10
- 15
and 10
- 8
,
respectively).
Changes from baseline while on PattonProtocol-1
The baseline analysis confirmed that test data from TA
Sciences subjects were similar to those reported in other el-
derly groups and provided a benchmark
36
against which we
could plot relative changes with time on the PattonProtocol-1.
As discussed earlier, it is important to note that we cannot
determine the contribution of any single component of the
PattonProtocol-1 to the observed changes. Changes from
baseline that are unusual in comparison to other dietary
supplement studies could be due to TA-65
and its effects on
telomeres, but it is also possible that placebo effects or the
unique combination of ingredients in the TA Sciences dietary
supplement pack also play a role. Medical/lifestyle ques-
tionnaires at baseline and after the 12-month period for each
client were used to record changes in medications, diet or
exercise while on the PattonProtocol-1. No clients reported
significant changes in diet or exercise, but where clients re-
ported a change in drug therapy, the test results that the
physician felt could be significantly impacted by the medi-
cation change were excluded from the analysis. Because this
study did not have a control group, seasonal effects could
also be a factor, but as the 114 clients studied here were
enrolled over a 2.5-year period, it is unlikely that seasonal
effects influenced the observed changes from baseline. With
these caveats in mind, we summarize the most interesting
findings below.
388 HARLEY ET AL.
Observed changes from baseline: Blood sugar,
cholesterol, blood pressure, inflammatory markers,
vitamin levels, and BMD
Fasting glucose and insulin levels both declined with time
in clients on the PattonProtocol-1 (at a rate of - 3.72 mg/dL
and - 1.32 mIU/mL per year, respectively; Table 2). De-
creases of this magnitude for fasting glucose are significant
relative to the mean baseline values and the donor-age de-
pendent change per year in the baseline population (98 mg/dL
and + 0.34 mg/dL per year, respectively, from Table 2). In
the general population, Sehl et al.
36
reports 0.5–1.5 mg/dL
per year increase in fasting glucose. On a relative basis,
PattonProtocol-1 apparently reversed *11 years of mean
increase in fasting glucose. The concomitant reduction in
fasting glucose and insulin is indicative of an improvement
in insulin sensitivity. Shorter leukocyte telomere length has
been associated with insulin resistance, oxidative stress, and
metabolic syndrome.
37–39
It is possible that the combination
of anti-oxidants and increased telomerase activation im-
proved insulin sensitivity in our subjects, although the exact
mechanism is unknown.
Total cholesterol and low-density lipoprotein cholesterol
(LDL-C) also decreased significantly. At 12 months, the
13.2 mg/dL and 11.8 mg/dL decreases in total cholesterol
and LDL-C, respectively, were statistically significant
( p = 0.002 for both) and large compared to the small decrease
associated with client age in this population ( - 0.29 mg/dL
per year and - 0.37 mg/dL per year, respectively). Choles-
terol generally increases with age,
40
possibly due to reduced
clearance of LDL from circulation and reduction in conver-
sion of cholesterol to bile acids, but some studies have sug-
gested a flat profile with aging or even a reduction in total
cholesterol with age attributed to poor health.
41
Because the
baseline average total cholesterol in the PattonProtocol-1
clients was borderline high (mean 188 mg/dL, Table 2), we
consider the declines of * 10 mg/dL in total cholesterol and
LDL-C to be beneficial because it is comparable to what has
been achieved in successful diet and exercise programs.
42
The mechanism of the reduction in cholesterol is unclear, but
given that no subjects reported changes in their exercise or
dietary habits, it is possible that increased telomerase acti-
vation from the PattonProtocol-1 contributed. A small study
demonstrated that increased telomerase activity in periph-
eral blood mononuclear cells (PBMCs) is significantly asso-
ciated with a decrease in LDL-C.
43
SBP and DBP declined 17.8 mmHg and 4.2 mmHg, re-
spectively, over the 1-year period (Table 2). In the baseline
population, DBP was relatively flat but SBP increased
0.51 mmHg/year (Table 2), comparable to that seen in other
studies,
44
suggesting that the PattonProtocol-1 may have
reversed > 30 years of increase in SBP. The decrease in SBP is
comparable to first-line therapy with diuretics, which confer
a significant reduction in cardiovascular events. Using the
Framingham 10-year CVD event calculator, these reductions
would cause a 25% reduction in 10-year risk for males (from
8% to 6%). Mechanisms are difficult to determine given the
observational nature of the study, but telomere attrition has
been associated with higher blood pressure and increased
aldosterone production,
45
which in turn can increase oxida-
tive stress and blood pressure by reducing nitric oxide pro-
duction. If the reduction in percentage of short telomeres and
senescent cytotoxic T cells we reported previously also re-
sulted in decreased inflammatory cytokines (such as tumor
necrosis factor-a (TNF-a) and interleukin-6 (IL-6), this pro-
cess could have been reversed in our cohort and could ex-
plain the reduction in blood pressure. This reversal of
inflammation along with increased telomerase activation
could rescue pre-senescent endothelial cells and increase the
production of nitric oxide, which could reduce SBP. The
supplement packs could also have contributed.
The changes we observed could not continue year after
year. To explore whether the slope of observed trends is
constant regardless of the starting level of the dependent
variable, we generated sub-group spline graphs. Figure 1A
shows a graph of fasting glucose levels over time. Levels of
glucose at baseline were divided into three groups: Low
(below 88 mg/dL), high (above 102 mg/dL), and middle (the
middle 50%). Splines were fit to each group. The overall
trend was for those in the highest group to have relatively
large declines, those in the mid-range smaller declines, and
those in the lowest group a slight increase. Figure 1B is
similar for insulin, except here groups were set based on
medical expertise: High (above 10 mg/dL), low (below
5 mg/dL), and middle and patterns were similar to those
for glucose. These patterns suggest an improvement in in-
sulin sensitivity. Insulin resistance is a cardinal element of
the metabolic syndrome and thought to be a result of in-
creased inflammation, which the PattonProtocol-1 might
have reduced. From a clinical standpoint, this pattern of ef-
fectiveness is similar to metformin, a first-line therapy for
pre-diabetes.
Table 2. Multi-Level Analysis of Variance
Dependent variable Intercept Time on program (year) Baseline age (year) Female
Glucose 84.32 ( < 0.001) - 3.72 (0.02) 0.18 (0.01) - 3.03 (0.15)
Insulin 3.94 (0.07) - 1.32 (0.01) 0.04 (0.18) - 1.68 (0.07)
Total cholesterol 196.89 ( < 0.001) - 13.2 (0.002) - 0.23 (0.49) 7.59 (0.44)
LDL-C 123.49 ( < 0.001) - 11.8 (0.002) - 0.32 (0.27) 1.52 (0.86)
SBP 114.62 ( < 0.001) - 17.3 (0.007) 0.23 (0.06) - 10.05 (0.005)
DBP 85.59 ( < 0.001 - 4.2 (0.001) - 0.11 (0.26) - 4.84 (0.08)
Homocysteine 8.97 ( < 0.001) - 3.6 ( < 0.001) 0.04 (0.10) - 0.94 (0.21)
Vitamin B12 382.56 (0.09) 72.4 (0.27) 6.88 (0.04) - 35.90 (0.71)
Vitamin D 27.2 ( < 0.001) 17.6 (0.008) 0.21 (0.06) - 4.83 (0.13)
Shown are the parameter estimates and (p-values) from the model as described in the Methods section.
LDL-C, low-density lipoprotein cholesterol; SBP, systolic blood pressure; DBP, diastolic blood pressure.
A TELOMERASE ACTIVATOR IN HEALTH MAINTENANCE 389
70
80
90
100
110
120
04182
Time on product (months
Fasting glucose (mg/dl)
A
5
10
15
840 12
Time on product (months)
Fasting Insulin (mIU/dL)
B
FIG. 1. Spline graphs based on the multi-level model, representing the change over time (baseline to 12 months) for fasting
glucose (A), serum insulin (B), low-density lipoprotein cholesterol (LDL-C) (C), and systolic blood pressure (D). In each
panel, dots represent subjects on PattonProtocol-1. To avoid over-plotting of symbols, a small amount of random noise (jitter)
was added to each plot. Subjects with low, mid, and high baseline values are colored green, blue, and red, respectively. The
cut-off values for these subgroups are given in the text. The shaded regions around each spline represent the 95% confidence
intervals.
390 HARLEY ET AL.
50
100
150
200
840 12
Time on product (months)
LDL Cholesterol (mg/dL)
C
100
125
150
480 12
Time on product (months)
Systolic BP (mm Hg)
D
FIG. 1. (Continued).
A TELOMERASE ACTIVATOR IN HEALTH MAINTENANCE 391
The same pattern is demonstrated by the spline graphs for
LDL-C (Fig. 1C) and SBP (Fig. 1D). The cholesterol groups
were divided by the treatment categories defined by the
National Cholesterol Education Program: Low ( < 100 mg/
dL), middle (100–130), and high > 130), and the SBP groups
were tertiles, where high was above 138 mmHg, low below
120 mmHg, and middle 120–138 mmHg. The moderating
trends show biomarker improvements in those that need it,
with little or no change in those within the normal biomarker
range. The moderating trend for SBP fits with the mecha-
nisms of SBP reduction discussed above in which a dys-
functional endothelium (in those with higher baseline SBP) is
repaired, rather than a direct anti-hypertensive effect, which
could result in hypotension. One might see these moderating
trends as regression to the mean, but the decreasing variance
over time that is evident from all four of the spline graphs
argues against this.
Homocysteine and C- reactive protein (CRP) a re signifi-
cant markers of inflammation and are associated with ar-
terial dysfunction and cardiovascular disease risk.
16,46
We observed significant reductions in both homocysteine
(Table 2) an d CRP (not sho wn) while clients were on
the PattonProtocol-1, but for CRP, a number of individuals
had acute spikes in CRP, possibly related to infections,
which confounded t he analysis. The 3.6-lmol/mL decrease
in homocysteine in clients on the Protocol ( p £ 0.001) is
dramatic compared to the general increase with age
(0.066 lmol/mL per year). It is likely that fo late an d vita-
mins B12 and B6 in the s uppl ement packs played a role in
the d ecline in homocysteine, but a number of ind ividuals
who w ere taking potent supplement packs before initiation
of the protocol also showed reductions in homocysteine,
including some subjects whose folate levels actually de-
creased (data not shown). It is also possible that other
components of the Protocol reduced inflammatory response
and improved health t hrough elongation of short telomeres
and remodeling of the immune system. If reduction in in-
flammation and cardiovascular risk could be achieved
through PattonProtocol-1 without high levels o f fo late
found in some dietary supplement programs, this would be
beneficial because supra-physiological levels of folate could
be detrimental.
47,48
Finally, bone mineral density was measured at baseline
and 12 months in an essentially random subset of individuals
(n = 31). Of the 31 subjects, 26 were either not on hormone
therapy or made no change in hormone therapy during the
1-year period. The remaining five subjects who changed
therapy were excluded from the analysis. Of the 26 analyzed
subjects, one had osteoporosis and four others had varying
degrees of osteopenia. In the overall group, there was a 2.0%
increase in AP spine L1–L4 BMD ( p = 0.003) (Table 3). This is
as large an increase in BMD as seen in a 3-year study of
calcium and vitamin D therapy in comparable subjects
without osteoporosis
49
and certainly contrasts with the ex-
pected *0.5% decrease per year. There were no significant
changes in hip BMD (data not shown). Moreover, because
the average baseline vitamin D levels were well into the
normal range, it is less likely that the approximately 20%
increase in vitamin D contributed significantly to the BMD
increase. A plausible alternative explanation for this im-
provement in BMD could be related to the emerging un-
derstanding of the relationship among hyperlipidemia, T
cells, and bone density.
50
The reduction in senescent sup-
pressor cells that we previously reported
1
combined with the
reduction in LDL-C could decrease the number of activated T
cells in the bone marrow and thereby reduce activated
RankL and other inflammatory cytokines. This would reduce
osteoclast activity and potentially explain the improved bone
density.
Discussion and Conclusions
This study adds to the observations from 2011 that
PattonProtocol-1, containing conventional supplements
plus TA-65, a small-molecule telomerase activator, has a
positive impact on biomarkers of aging or age-related
disease. The initial obse rvational study of r oughly 5 0
subjects on product
1
focused on results from independent
diagnostic laboratory testing of immunological markers
over a 1-year period, while here we focus on similar lab-
oratory testing of metabolic biomarkers and bone mineral
density in the same cohort over the same 1-year period.
We found reductions in fasting blood sugar, insulin, cho-
lesterol, blood pressure, and homocysteine, and increases
in bone mineral density, all considered positive health
changes. These data suggest that PattonProtocol-1 (TA-65
in combination with other supplements and physician
counseling) improves health and may reduce risk of
morbidity and mortality.
The major limitation of these observational studies is that
they are not randomized, placebo-controlled trials with de-
fined dosing of TA-65. Such a study is in progress, but the
observation that TA-65 was primarily beneficial to CMV-
positive humans who were ‘blind’ to their CMV status,
1
and
that TA-65 had positive effects when given to aged telo-
merase-positive but not telomerase-negative mice,
51
suggests
that TA-65 is an active molecule that should be investigated
further.
Table 3. Bone Mineral Density (L1–L4)
All subjects (n = 26) Males (n = 21) Females (n = 5)
Baseline 1.239 0.186 1.2720 0.171 1.101 0.202
12 Months 1.263 0.202 1.298 0.192 1.118 0.198
Absolute change + 0.025 0.275 + 0.026 0.257 + 0.017 0.283
Relative change 2.0% 2.1% 1.5%
p value
0.0034 0.0070
0.3271
Bone mineral density (g/cm
3
) data are reported for 26 evaluable subjects (individuals who changed hormone therapy during the 12-month
period were excluded). p values less than 0.05 are shaded. Average age of males at baseline was 64.9 12.0 and that of females was 58.3 5.1.
392 HARLEY ET AL.
Because telomerase may extend the life span of relatively
rare pre-malignant cells that otherwise might die due to
critical shortening of telomeres, it is possible that a telo-
merase activator could increase cancer risk in some indi-
viduals. However, prevention of critical shortening of
telomeres in multiple tissues throughout an aging human by
telomerase activation could be a net tumor suppressive
mechanism by reducing genomic instability and maintaining
health of normal tissues. Much larger controlled studies will
be needed to assess the potential risk and benefits of TA-65 in
humans.
Subjects taking TA-65 or any dietary supplement should
consult their doctor and carefully consider the product’s
potential risks and benefits. There had been approximately
260 person-years of TA-65 dosing, mainly in the 5–50 mg/
day range through June, 2010, with no reports of new di-
agnoses of cardiovascular disease or cancer. This represented
age-adjusted incidence rates significantly below the average
US rates for CVD and cancer. As of June, 2013, there are now
an estimated 7000 + person-years of TA-65 exposure at an
average 50-mg TA-65 dose equivalence. Disease and mor-
tality were not formally tracked, but TA Sciences reports few
if any adverse events, and no cases of adverse events being
attributed to TA-65 by the subjects’ doctors. In the overall (all
ages) US population, 7000 person years of life would entail
about 30 new diagnoses each for cancer and CVD, and about
60 deaths, based on data from the Centers for Disease Con-
trol and Prevention. Because of lack of matching demo-
graphics for the study population, as well as lack of exact
disease and mortality data, we cannot make a reliable com-
parison of incidence rates in the study population versus the
general population, but the data to date do not point to in-
creased risk of morbidity or mortality in subjects taking TA-
65. In conclusion, TA-65, a moderate telomerase activator, is
a novel dietary supplement that may enhance one’s health
span.
Acknowledgments
We thank Dr. Russ Kerschmann and Dr. Lennart Olsson
for critical review of the manuscript.
Author Disclosure Statement
C.B.H. is one of the inventors of TA-65, is a paid consul-
tant to TA Sciences, and is the Chief Scientific Officer of
Telome Health, Inc., which has a license arrangement with
TA Sciences. C.B.H. owns stock and stock options in Telome
Health. W.L. is an employee of TA Sciences. J.M.R. offers TA-
65 in his office and is on TA Sciences Scientific Advisory
Board. P.L.F. declares no conflicts of interest.
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Address correspondence to:
Calvin B. Harley
1177 Sandalwood Drive
Murphys, CA 95247
E-mail: charley@telomehealth.com
Received: March 19, 2013
Accepted: June 29, 2013
A TELOMERASE ACTIVATOR IN HEALTH MAINTENANCE 395
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