ArticlePDF Available

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


Abstract and Figures

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.
Content may be subject to copyright.
A Natural Product Telomerase Activator
as Part of a Health Maintenance Program:
Metabolic and Cardiovascular Response
Calvin B. Harley,
Weimin Liu,
Peter L. Flom,
and Joseph M. Raffaele
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.
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.
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
that short telomeres are associated with disease, including
cardiovascular disease, cancer, human immunodeficiency
virus/acquired immunodeficiency syndrome (HIV/AIDS),
and Down syndrome.
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.
Telomerase, the enzyme that synthesizes telomeric
can slow or even reverse telomere shortening in
normal human cells in culture
and contribute to slowing
or reversal of degenerative, age-related disease in ani-
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.
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).
Consultant to TA Sciences, Murphys, California.
TA Sciences, Inc., New York, New York.
New York, New York.
PhysioAge Systems, LLC, New York, New York.
Volume 16, Number 5, 2013
ª Mary Ann Liebert, Inc.
DOI: 10.1089/rej.2013.1430
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-
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.
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
These changes included significant declines in se-
nescent cytotoxic (CD8
) 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.
A recent study
on the association between telomere length and experimen-
tally induced upper respiratory track viral infection in heal-
thy adults
underscored the predictive value of short
telomeres for viral infections and clinical illness, especially
when telomere length was measured in CD8
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.
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.
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).
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
Serum Insulin
DHEA Sulfate
(Total) (mg/dL)
Cholesterol (LDL)
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
NA 0.33 0.025 - 2.6 - 0.29 - 0.37
NA 0.08 0.002 0.06 0.01 0.02
p value NA
0.32 0.16
Serum Folate
D-25-OH total (ng/mL)
Vitamin B12
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
0.108 0.000 0.05 0.065 0.007 0.036
p value
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).
Slope (m) of the linear regression line of test value versus age of subjects.
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.
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
, 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.
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).
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
T cells using unstructured
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
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,
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
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
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.
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.
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.
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,
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.
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.
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.
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
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,
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
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.
Time on product (months
Fasting glucose (mg/dl)
840 12
Time on product (months)
Fasting Insulin (mIU/dL)
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
840 12
Time on product (months)
LDL Cholesterol (mg/dL)
480 12
Time on product (months)
Systolic BP (mm Hg)
FIG. 1. (Continued).
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.
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.
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
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.
The reduction in senescent sup-
pressor cells that we previously reported
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
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
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,
that TA-65 had positive effects when given to aged telo-
merase-positive but not telomerase-negative mice,
that TA-65 is an active molecule that should be investigated
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
Bone mineral density (g/cm
) 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.
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
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
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.
1. Harley CB, Liu W, Blasco M, Vera E, Andrews WH, Briggs
LA, Raffaele JM. A natural product telomerase activator as
part of a health maintenance program. Rejuvenation Res
2. Lin J, Epel E, Blackburn E. Telomeres and lifestyle factors:
Roles in cellular aging. Mutat Res 2012;730:85–89.
3. Kropski JA, Lawson WE, Young LR, Blackwell TS. Genetic
studies provide clues on the pathogenesis of idiopathic
pulmonary fibrosis. Disease Models Mech 2013;6:9–17.
4. Aubert G, Baerlocher GM, Vulto I, Poon SS, Lansdorp PM.
Collapse of telomere homeostasis in hematopoietic cells
caused by heterozygous mutations in telomerase genes.
PLoS Genet 2012;8:e1002696.
5. Harley CB, Futcher AB, Greider CW. Telomeres shorten
during ageing of human fibroblasts. Nature 1990;345:458–
6. Allsopp RC, Vaziri H, Patterson C, Goldstein S, Younglai
EV, Futcher AB, Greider CW, Harley CB. Telomere length
predicts replicative capacity of human fibroblasts. Proc Natl
Acad Sci USA 1992;89:10114–10118.
7. Vaziri H, Dragowska W, Allsopp RC, Thomas TE, Harley
CB, Lansdorp PM. Evidence for a mitotic clock in human
hematopoietic stem cells: Loss of telomeric DNA with age.
Proc Natl Acad Sci USA 1994;91:9857–9860.
8. Vaziri H, Schachter F, Uchida I, Wei L, Zhu X, Effros R,
Cohen D, Harley CB. Loss of telomeric DNA during aging of
normal and trisomy 21 human lymphocytes. Am J Hum
Genet 1993;52:661–667.
9. Counter CM, Avilion AA, LeFeuvre CE, Stewart NG, Grei-
der CW, Harley CB, Bacchetti S. Telomere shortening asso-
ciated with chromosome instability is arrested in immortal
cells which express telomerase activity. EMBO J 1992;11:
10. Counter CM, Hirte HW, Bacchetti S, Harley CB. Telomerase
activity in human ovarian carcinoma. Proc Natl Acad Sci
USA 1994;91:2900–2904.
11. Counter CM, Botelho FM, Wang P, Harley CB, Bac-
chetti S. Stabilization of short telomeres and telomerase
activity accompany immortalization of Epstein-Barr
virus-transformed human B lymphocytes. J Virol 1994;
12. Perera SA, Maser RS, Xia H, McNamara K, Protopopov A,
Chen L, Hezel AF, Kim CF, Bronson RT, Castrillon DH, et al.
Telomere dysfunction promotes genome instability and
metastatic potential in a K-ras p53 mouse model of lung
cancer. Carcinogenesis 2008;29:747–753.
13. Artandi SE, DePinho RA. Telomeres and telomerase in
cancer. Carcinogenesis 2010;31:9–18.
14. Sahin E, Depinho RA. Linking functional decline of telo-
meres, mitochondria and stem cells during ageing. Nature
15. de Lange T. How telomeres solve the end-protection prob-
lem. Science 2009;326:948–952.
16. Ridker PM, MacFadyen J, Cressman M, Glynn RJ. Efficacy of
rosuvastatin among men and women with moderate chronic
kidney disease and elevated high-sensitivity C-reactive
protein: A secondary analysis from the JUPITER ( Justifica-
tion for the Use of Statins in Prevention-an Intervention Trial
Evaluating Rosuvastatin) trial. J Am Coll Cardiol 2010;55:
17. Blackburn EH, Greider CW, Szostak JW. Telomeres and
telomerase: The path from maize, Tetrahymena and
yeast to human cancer and aging. Nat Med 2006;12:
18. Bodnar AG, Ouellette M, Frolkis M, Holt SE, Chiu CP, Morin
GB, Harley CB, Shay JW, Lichtsteiner S, Wright WE. Ex-
tension of life-span by introduction of telomerase into nor-
mal human cells. Science 1998;279:349–352.
19. Jiang XR, Jimenez G, Chang E, Frolkis M, Kusler B, Sage, M,
Beeche M, Bodnar AG, Wahl GM, Tlsty TD, et al. Telomerase
expression in human somatic cells does not induce changes
associated with a transformed phenotype. Nat Genet 1999;
20. Jaskelioff M, Muller FL, Paik JH, Thomas E, Jiang S, Adams
AC, Sahin E, Kost-Alimova M, Protopopov A, Cadinanos J,
et al. Telomerase reactivation reverses tissue degeneration in
aged telomerase-deficient mice. Nature 2011;469:102–106.
21. Bernardes de Jesus B, Vera E, Schneeberger K, Tejera
AM, Ayuso E, Bosch F, Blasco MA. Telomerase gene
therapy in a dult and old mice delays aging and increases
longevity without increasing cancer. EMBO Mol Med
22. Bernardes de Jesus BB, Schneeberger K, Vera E, Tejera, A,
Harley CB, Blasco MA. The telomerase activator TA-65
elongates short telomeres and increases health span of
adult/old mice without increasing cancer incidence. Aging
Cell 2011;10:604–621.
23. Svenson U, Nordfjall K, Baird D, Roger L, Osterman P,
Hellenius ML, Roos G. Blood cell telomere length is a dy-
namic feature. PloS One 2011;6:e21485.
24. Epel ES, Merkin SS, Cawthon R, Blackburn EH, Adler NE,
Pletcher MJ, Seeman TE. The rate of leukocyte telomere
shortening predicts mortality from cardiovascular disease in
elderly men. Aging 2009;1:81–88.
25. Jacobs TL, Epel ES, Lin J, Blackburn EH, Wolkowitz OM,
Bridwell DA, Zanesco AP, Aichele SR, Sahdra BK, MacLean
KA, et al. Intensive meditation training, immune cell telo-
merase activity, and psychological mediators. Psychoneur-
oendocrinology 2011;36:664–681.
26. Farzaneh-Far R, Lin J, Epel ES, Harris WS, Blackburn EH,
Whooley MA. Association of marine omega-3 fatty acid
levels with telomeric aging in patients with coronary heart
disease. JAMA 2010;303:250–257.
27. Kiecolt-Glaser JK, Epel ES, Belury MA, Andridge R, Lin J,
Glaser R, Malarkey WB, Hwang BS, Blackburn E. Omega-3
fatty acids, oxidative stress, and leukocyte telomere length:
A randomized controlled trial. Brain Behav Immun 2013;
28. Ho RT, Chan JS, Wang CW, Lau BW, So KF, Yuen LP,
Sham JS, Chan CL. A randomized controlled trial of qi-
gong exercise on fatigue symptoms, functioning, and
telomerase activity in persons with chronic fatigue or
chronic fatigue syndrome. Ann Behav Med 2012;44:160–
29. Wolkowitz OM, Mellon SH, Epel ES, Lin J, Reus VI, Rosser
R, Burke H, Compagnone M, Nelson JC, Dhabhar FS, et al.
Resting leukocyte telomerase activity is elevated in major
depression and predicts treatment response. Mol Psychiatry
30. Lavretsky H, Epel ES, Siddarth P, Nazarian N, Cyr NS,
Khalsa DS, Lin J, Blackburn E, Irwin MR. A pilot study of
yogic meditation for family dementia caregivers with de-
pressive symptoms: Effects on mental health, cognition,
and telomerase activity. Int J Geriatr Psychiatry 2013;28:
31. Epel E. How ‘reversible’ is telomeric aging? Cancer Prev
Res 2012;5:1163–1168.
32. Fauce SR, Jamieson BD, Chin AC, Mitsuyasu RT, Parish ST,
Ng HL, Kitchen CM, Yang OO, Harley CB, Effros RB. Tel-
omerase-based pharmacologic enhancement of antiviral
function of human CD8 + T lymphocytes. J Immunol 2008;
33. Yung LY, Lam WS, Ho MK, Hu Y, Ip FC, Pang H, Chin AC,
Harley CB, Ip NY, Wong YH. Astragaloside IV and cy-
cloastragenol stimulate the phosphorylation of extracellular
signal-regulated protein kinase in multiple cell types. Planta
Medica 2012;78:115–121.
34. Zhu J, Lee S, Ho MK, Hu Y, Pang H, Ip FC, Chin AC, Harley
CB, Ip NY, Wong YH. In vitro intestinal absorption and first-
pass intestinal and hepatic metabolism of cycloastragenol, a
potent small molecule telomerase activator. Drug Metab
Pharmacokinet 2010;25:477–486.
35. Cohen S, Janicki-Deverts D, Turner RB, Casselbrant ML,
Li-Korotky HS, Epel ES, Doyle WJ. Association b etween
telomere length and experimentally induced upper respi-
ratory viral infection in healthy adults. JA MA 2013;309:
36. Sehl ME, Yates FE. Kinetics of human aging: I. Rates of
senescence between ages 30 and 70 years in healthy
people. J Gerontol A Biol Sci Med Sci 2001;56:B198–
37. Sahin E, Colla S, Liesa M, Moslehi J, Muller FL, Guo M,
Cooper M, Kotton D, Fabian AJ, Walkey C, et al. Telomere
dysfunction induces metabolic and mitochondrial compro-
mise. Nature 2011;470:359–365.
38. Haendeler J, Drose S, Buchner N, Jakob S, Altschmied J, Goy
C, Spyridopoulos I, Zeiher AM, Brandt U, Dimmeler S.
Mitochondrial telomerase reverse transcriptase binds to and
protects mitochondrial DNA and function from damage.
Arterioscler Thromb Vasc Biol 2009;29:929–935.
39. Rentoukas E, Tsarouhas K, Kaplanis I, Korou E, Nikolaou M,
Marathonitis G, Kokkinou S, Haliassos A, Mamalaki A,
Kouretas D, et al. Connection between telomerase activity in
PBMC and markers of inflammation and endothelial dys-
function in patients with metabolic syndrome. PloS One
40. Berns MA, de Vries JH, Katan MB. Determinants of the in-
crease of serum cholesterol with age: a longitudinal study.
Int J Epidemiol 1988;17:789–796.
41. Volpato S, Zuliani G, Guralnik JM, Palmieri E, Fellin R. The
inverse association between age and cholesterol level among
older patients: The role of poor health status. Gerontology
42. Kelley GA, Kelley KS, Roberts S, Haskell W. Comparison of
aerobic exercise, diet or both on lipids and lipoproteins in
adults: A meta-analysis of randomized controlled trials. Clin
Nutr 2012;31:156–167.
43. Ornish D, Lin J, Daubenmier J, Weidner G, Epel E, Kemp C,
Magbanua MJ, Marlin R, Yglecias L, Carroll PR, et al. In-
creased telomerase activity and comprehensive lifestyle
changes: a pilot study. The Lancet Oncol 2008;9:1048–1057.
44. Franklin SS., Gustin WT, Wong ND, Larson MG, Weber MA,
Kannel WB, Levy D. Hemodynamic patterns of age-related
changes in blood pressure. The Framingham Heart Study.
Circulation 1997;96:308–315.
45. Benetos A, Gardner JP, Kimura M, Labat C, Nzietchueng R,
Dousset B, Zannad F, Lacolley P, Aviv A. Aldosterone and
telomere length in white blood cells. J Gerontol A, Biol Sci
Med Sci 2005;60:1593–1596.
46. Graham IM, O’Callaghan P. Vitamins, homocysteine and
cardiovascular risk. Cardiovasc Drugs Ther 2002;16:383–389.
47. Ulrich CM, Potter JD. Folate supplementation: Too much of
a good thing? Cancer Epidemiol Biomarkers Prev 2006;15:
48. Sauer J, Mason JB, Choi SW. Too much folate: A risk factor
for cancer and cardiovascular disease? Curr Opin Clin Nutr
Metabol Care 2009;12:30–36.
49. Dawson-Hughes B, Harris SS, Krall EA, Dallal GE. Effect of
calcium and vitamin D supplementation on bone density in
men and women 65 years of age or older. N Engl J Med
50. Graham LS, Tintut Y, Parhami F, Kitchen CM, Ivanov Y,
Tetradis S, Effros RB. Bone density and hyperlipidemia: The
T-lymphocyte connection. J Bone Min Res 2010;25:2460–
51. Bernardes de Jesus B, Schneeberger K, Vera E, Tejera A,
Harley CB, Blasco MA. The telomerase activator TA-65
elongates short telomeres and increases health span of
adult/old mice without increasing cancer incidence. Aging
Cell 2011;10:604–621.
Address correspondence to:
Calvin B. Harley
1177 Sandalwood Drive
Murphys, CA 95247
Received: March 19, 2013
Accepted: June 29, 2013
... The first method uses specific drugs. The plant-derived astragalosides stimulate telomerase expression [170,171]. However, astragalosides are expensive and with limited effectiveness [172]. ...
Full-text available
The interpretation of aging as an adaptive and programmed phenomenon implies the existence of specific genetically determined and regulated aging-causing mechanisms. This interpretation is in contrast to the explanation of aging as the gradual accumulation of the effects of harmful factors that are only partially countered by natural selection. The subtelomere–telomere theory of aging offers what is required by the interpretation of aging as a programmed phenomenon. The experimentally documented mechanisms that are part of the subtelomere–telomere theory are the repression of subtelomeric sequences (TERRA sequences) consequent to the sliding of a telomeric hood over subtelomere in proportion to telomere shortening, epigenetic modifications caused by the repression of the subtelomeric sequences, cell senescence and gradual cell senescence (which are not synonyms, as discussed in the text), progressive decline of stem cells, and effects of these phenomena over the whole organism. Evidence against the interpretation of cell senescence and telomerase restrictions as defense mechanisms against cancer is reported. Consequently, the fears that telomerase activation or senescent cell elimination are potentially oncogenic factors should be eliminated as preconceived ideas or limited on the basis of any available evidence. In the context of the mechanisms described under the subtelomere–telomere theory, three types of strategies that could be used to modify and counter the mechanisms of aging can be deduced, namely telomerase activation, senescent cell elimination, and restoration of stem cell numbers to that existing in young individuals. The limits and the potential effectiveness of these methods, already the subject of active research, are briefly discussed.
... A randomized, double-blind, placebo-controlled clinical study involving 117 relatively healthy cytomegalovirus-positive individuals (aged 53 to 87 years) showed that TA-65 can lengthen telomeres in a telomerase-dependent manner [27]. Another study, involving 7000 person-years over a 5-year period, found that TA-65 improves some metabolic, bone and cardiovascular health markers, without any adverse events, suggesting that it improves overall health by reducing mobility and mortality risks [61]. ...
Full-text available
Globally, better health care access and social conditions ensured a significant increase in the life expectancy of the population. There is, however, a clear increase in the incidence of age-related diseases which, besides affecting the social and economic sustainability of countries and regions around the globe, leads to a decrease in the individual’s quality of life. There is an urgent need for interventions that can reverse, or at least prevent and delay, the age-associated pathological deterioration. Within this line, this narrative review aims to assess updated evidence that explores the potential therapeutic targets that can mimic or complement the recognized anti-aging effects of physical exercise. We considered pertinent to review the anti-aging effects of the following drugs and supplements: Rapamycin and Rapamycin analogues (Rapalogs); Metformin; 2-deoxy-D-glucose; Somatostatin analogues; Pegvisomant; Trametinib; Spermidine; Fisetin; Quercetin; Navitoclax; TA-65; Resveratrol; Melatonin; Curcumin; Rhodiola rosea and Caffeine. The current scientific evidence on the anti-aging effect of these drugs and supplements is still scarce and no recommendation of their generalized use can be made at this stage. Further studies are warranted to determine which therapies display a geroprotective effect and are capable of emulating the benefits of physical exercise.
... 60,61,62  Telomere Therapy: Various products are available as a natural telomerase activator, 63, but they failed to prolong the lifespan with healthspan . 64 Overactivation of telomerase may increase the risk of cancer and tumour development. 65 Drug Therapy: Resveratrol is a sirtuin stimulant that has been shown to increase animal longevity, however its impacts are unknown. ...
Full-text available
A challenge in front of is the rapid aging of the population. Aged population contributes the largest in the spectrum of chronic disorders. Various therapies have been studied to determine their effect on longevity or healthspan.However, ageing experts are focusing about there research on methods that work against by the organic sequence of the ageing procedure in order to postpone it, and the results, as well as the side effects, of these methodologies are unknown.Yoga is a comprehensive practise that promotes health by incorporating dietary, lifestyle, behavioural, but also psychological therapies. Yogic intervention is to restore all the system's homeostasis and function simultaneously at the body, mind, and spirit levels. A search of the literature was made by using keywords such as: " Yoga" OR "asana" OR "pranayama" OR "meditation" OR "mindfulness" OR "reverse aging" OR "telomere" OR "telomerase enzyme" OR "oxidative stress." A total of 17 papers are set in this review for evaluation through PUBMED database search. This review shows that Yogapositively affects length of telomeres and telomerase enzyme activity. Yoga is critical in reversing the ageing process by reducing the signs or symptoms of ageing.
... Telomerase reactivation is, however, contentious as it is also strongly associated with cancer (Akincilar et al., 2016), although mice derived from embryonic stem cells with extremely long telomeres showed better glucose and insulin tolerance and lower cancer risk than controls (Munoz-Lorente et al., 2019), suggesting that transient telomere lengthening strategies may improve health and avoid cancer risk. While transgenic techniques are not yet ready for human use, nutraceutical telomerase reactivators have been developed (Tsoukalas et al., 2019), which appear to reduce fasting glucose levels and slightly increase bone mineral density in the spine (Harley et al., 2013). ...
Full-text available
Bone is a complex organ serving roles in skeletal support and movement, and is a source of blood cells including adaptive and innate immune cells. Structural and functional integrity is maintained through a balance between bone synthesis and bone degradation, dependent in part on mechanical loading but also on signaling and influences of the tissue microenvironment. Bone structure and the extracellular bone milieu change with age, predisposing to osteoporosis and increased fracture risk, and this is exacerbated in patients with diabetes. Such changes can include loss of bone mineral density, deterioration in micro-architecture, as well as decreased bone flexibility, through alteration of proteinaceous bone support structures, and accumulation of senescent cells. Senescence is a state of proliferation arrest accompanied by marked morphological and metabolic changes. It is driven by cellular stress and serves an important acute tumor suppressive mechanism when followed by immune-mediated senescent cell clearance. However, aging and pathological conditions including diabetes are associated with accumulation of senescent cells that generate a pro-inflammatory and tissue-destructive secretome (the SASP). The SASP impinges on the tissue microenvironment with detrimental local and systemic consequences; senescent cells are thought to contribute to the multimorbidity associated with advanced chronological age. Here, we assess factors that promote bone fragility, in the context both of chronological aging and accelerated aging in progeroid syndromes and in diabetes, including senescence-dependent alterations in the bone tissue microenvironment, and glycation changes to the tissue microenvironment that stimulate RAGE signaling, a process that is accelerated in diabetic patients. Finally, we discuss therapeutic interventions targeting RAGE signaling and cell senescence that show promise in improving bone health in older people and those living with diabetes.
... Ingredients of another widely consumed beverage, flavanols, polyphenolic compounds in cocoa, also reduce the risk for CVDs [197,198]. In addition, TA-65, a small molecule from the medicinal plant Astragalus membranaceus used in traditional Chinese medicine, given over a five-year period, reduces fasting glucose, total and LDL-cholesterol, as well as blood pressure, all risk factors for CVDs [199]. It is captivating to speculate that these plant-derived molecules affect different cellular pathways, and thus, might potentially act additively or even synergistically in reducing the risk for CVDs. ...
Full-text available
Cardiovascular diseases (CVDs) contribute to a large part of worldwide mortality. Similarly, two of the major risk factors for these diseases, aging and obesity, are also global problems. Aging, the gradual decline of body functions, is non-modifiable. Obesity, a modifiable risk factor for CVDs, also predisposes to type 2 diabetes mellitus (T2DM). Moreover, it affects not only the vasculature and the heart but also specific fat depots, which themselves have a major impact on the development and progression of CVDs. Common denominators of aging, obesity, and T2DM include oxidative stress, mitochondrial dysfunction, metabolic abnormalities such as altered lipid profiles and glucose metabolism, and inflammation. Several plant substances such as curcumin, the major active compound in turmeric root, have been used for a long time in traditional medicine and for the treatment of CVDs. Newer mechanistic, animal, and human studies provide evidence that curcumin has pleiotropic effects and attenuates numerous parameters which contribute to an increased risk for CVDs in aging as well as in obesity. Thus, curcumin as a nutraceutical could hold promise in the prevention of CVDs, but more standardized clinical trials are required to fully unravel its potential.
... This clear demonstration of protective functions of mitochondrial TERT in myocardial infarction suggests that a therapeutic increase in mitochondrial TERT would be beneficial in cardiovascular diseases. The Telomerase activator TA-65 has already been shown to be safe for humans [160], and it has been demonstrated ex vivo that treatment with this compound leads to increased TERT levels in mitochondria as well as enhanced endothelial cell migration and myofibroblast differentiation of cardiac fibroblasts [159]. TA-65 is currently tested in a clinical trial in patients with acute coronary syndrome [161], which will potentially reveal protective effects in humans. ...
Full-text available
Mitochondria play a critical role in providing energy, maintaining cellular metabolism, and regulating cell survival and death. To carry out these crucial functions, mitochondria employ more than 1500 proteins, distributed between two membranes and two aqueous compartments. An extensive network of dedicated proteins is engaged in importing and sorting these nuclear-encoded proteins into their designated mitochondrial compartments. Defects in this fundamental system are related to a variety of pathologies, particularly engaging the most energy-demanding tissues. In this review, we summarize the state-of-the-art knowledge about the mitochondrial protein import machinery and describe the known interrelation of its failure with age-related neurodegenerative and cardiovascular diseases.
Aging is well-characterized by the gradual decline of cellular functionality. As redox balance, proteostasis, and telomerase systems have been found to be associated with aging and age-related diseases, targeting these systems with small compounds has been considered a promising therapeutic approach. Cycloastragenol (CA), a small molecule telomerase activator obtained from Astragalus species, has been reported to positively affect several age-related pathophysiologies, but the mechanisms underlying CA activity have yet to be reported. Here, we presented that CA increased NRF2 nuclear localization and activity leading to upregulation of cytoprotective enzymes and attenuation of oxidative stress-induced ROS levels. Furthermore, CA-mediated induction of telomerase activity was found to be regulated by NRF2. CA not only increased the expression of hTERT but also its nuclear localization via upregulating the Hsp90-chaperon complex. In addition to modulating nuclear hTERT levels at unstressed conditions, CA alleviated oxidative stress-induced mitochondrial hTERT levels while increasing nuclear hTERT levels. Concomitantly, H2O2-induced mitochondrial ROS level was found to be significantly decreased by CA administration. Our data also revealed that CA strongly enhanced proteasome activity and assembly. More importantly, the proteasome activator effect of CA is dependent on the induction of telomerase activity, which is mediated by NRF2 system. In conclusion, our results not only revealed the cross-talk among NRF2, telomerase, and proteasome systems but also that CA functions at the intersection of these three major aging-related cellular pathways.
Cycloastragenol (CAG) is a sapogenin of Astragaloside IV (AG-IV), isolated from the dried roots of legumes Astragalus mongolica or Astragalus membranaceus. Cycloastragenol has a steroidal skeleton of tetracyclic triterpene and possess diverse pharmacological activities such as anti-aging, anti-inflammatory, anti-fibrosis, pro-wound healing, liver protection and endothelial protection. In addition, cycloastragenol is the only telomerase activator reported in natural products, which is closely related to MAPK and PI3K/Akt signaling pathways. This review provides a theoretical basis for the development of cycloastragenol into the candidate for the treatment of multi-factorial diseases in clinic, focusing on the extensively biological activities as well as the mechanism of action and structural modification and aiming to attract researchers to conduct in-depth studies on cycloastragenol. Meanwhile, the pharmacokinetics and toxicology studies of CAG are also described for further druggability exploration to provides valuable reference.
Background : With the rising age of the global population, the incidence rate of cardiovascular and cerebrovascular diseases (CCVDs) is increasing, which causes serious public health burden. The efforts for new therapeutic approaches are still being sought since the treatment effects of existing therapies are not quite satisfactory. Chinese traditional medicine proved to be very efficient in the treatment of CCVDs. Well described and established in Chinese medicine, Astragali Radix, has been commonly administered in the prophylaxis and cure of CCVDs for thousands of years. Purpose : This review summarized the action mode and mechanisms of Astragali Radix phytochemicals on CCVDs, hoping to provide valuable information for the future application, development and improvement of Astragali Radix as well as CCVDs treatment. Methods : A plenty of literature on biological active ingredients of Astragali Radix used for CCVDs treatment were retrieved from online electronic PubMed and Web of Science databases. Results : This review highlighted the effects of five main active components in Astragali Radix including astragaloside Ⅳ, cycloastragenol, astragalus polysaccharide, calycosin-7-O-β-D-glucoside, and calycosin on CCVDs. The mechanisms mainly involved anti-oxidative damage, anti-inflammatory, and antiapoptotic through signaling pathways such as PI3K/Akt, Nrf2/HO-1, and TLR4/NF-κB pathway. In addition, the majority active constituents in AR have no obvious toxic side effects. Conclusion : The main active components of Astragali Radix, especially AS-IV, have been extensively summarized. It has been proved that Astragali Radix has obvious therapeutic effects on various CCVDs, including myocardial and cerebral ischemia, hypertension, atherosclerosis, cardiac hypertrophy, chronic heart failure. CAG possesses anti-ischemia activity without toxicity, indicating a worthy of further development. However, high-quality clinical and pharmacokinetic studies are required to validate the current studies.
Full-text available
Loss of telomeric DNA during cell proliferation may play a role in ageing and cancer. Since telomeres permit complete replication of eukaryotic chromosomes and protect their ends from recombination, we have measured telomere length, telomerase activity and chromosome rearrangements in human cells before and after transformation with SV40 or Ad5. In all mortal populations, telomeres shortened by approximately 65 bp/generation during the lifespan of the cultures. When transformed cells reached crisis, the length of the telomeric TTAGGG repeats was only approximately 1.5 kbp and many dicentric chromosomes were observed. In immortal cells, telomere length and frequency of dicentric chromosomes stabilized after crisis. Telomerase activity was not detectable in control or extended lifespan populations but was present in immortal populations. These results suggest that chromosomes with short (TTAGGG)n tracts are recombinogenic, critically shortened telomeres may be incompatible with cell proliferation and stabilization of telomere length by telomerase may be required for immortalization.
Full-text available
When human fibroblasts from different donors are grown in vitro, only a small fraction of the variation in their finite replicative capacity is explae by the chronological age of the donor. Because we had previously shown that telomeres, the terminal guanine-rich sequences of chromosomes , shorten throughout the lifespan of cultured cells, we wished to determine whether variation in initial telomere length would account for the unexplained variation in replicative capacity. Analysis of cells from 31 donors (aged 0-93 yr) indicated relatively weak correlations between proliferative ability and donor age (m =-0.2 doubling per yr; r =-0.42; P = 0.02) and between telomeric DNA and donor age (m =-15 base pairs per yr; r =-0.43; P = 0.02). However, there was a stiking correlation, valid over the entire age range of the donors, between replicative capacity and initial telomere length (m = 10 doublngs per kilobase pair; r = 0.76; P = 0.004), indicating that cell strains with shorter telomeres underwent slglcantiy fewer doublings than those with longer telomeres. These observations suggest that telomere length is a biomarker ofsomatic cell aging in humans and are consistent with a causal role for telomere loss in this process. We also found that fibroblasts from Hutchinson-Gilford progeria donors had short telomeres, consistent with their reduced division potential in vitro. In contrast, telomeres from sperm DNA did not decrease with age ofthe donor, suggesting that a mechanism for maintaining telomere length, such as telomerase expression, may be active in germ-line tissue.
Full-text available
Idiopathic pulmonary fibrosis (IPF) is a progressive and often fatal lung disease for which there is no known treatment. Although the traditional paradigm of IPF pathogenesis emphasized chronic inflammation as the primary driver of fibrotic remodeling, more recent insights have challenged this view. Linkage analysis and candidate gene approaches have identified four genes that cause the inherited form of IPF, familial interstitial pneumonia (FIP). These four genes encode two surfactant proteins, surfactant protein C (encoded by SFTPC) and surfactant protein A2 (SFTPA2), and two components of the telomerase complex, telomerase reverse transcriptase (TERT) and the RNA component of telomerase (TERC). In this review, we discuss how investigating these mutations, as well as genetic variants identified in other inherited disorders associated with pulmonary fibrosis, are providing new insights into the pathogenesis of common idiopathic interstitial lung diseases, particularly IPF. Studies in this area have highlighted key roles for epithelial cell injury and dysfunction in the development of lung fibrosis. In addition, genetic approaches have uncovered the importance of several processes - including endoplasmic reticulum stress and the unfolded protein response, DNA-damage and -repair pathways, and cellular senescence - that might provide new therapeutic targets in fibrotic lung diseases.
Full-text available
Chronic fatigue is common in the general population. Complementary therapies are often used by patients with chronic fatigue or chronic fatigue syndrome to manage their symptoms. This study aimed to assess the effect of a 4-month qigong intervention program among patients with chronic fatigue or chronic fatigue syndrome. Sixty-four participants were randomly assigned to either an intervention group or a wait list control group. Outcome measures included fatigue symptoms, physical functioning, mental functioning, and telomerase activity. Fatigue symptoms and mental functioning were significantly improved in the qigong group compared to controls. Telomerase activity increased in the qigong group from 0.102 to 0.178 arbitrary units (p < 0.05). The change was statistically significant when compared to the control group (p < 0.05). Qigong exercise may be used as an alternative and complementary therapy or rehabilitative program for chronic fatigue and chronic fatigue syndrome.
Full-text available
Telomerase activity is readily detectable in extracts from human hematopoietic stem and progenitor cells, but appears unable to maintain telomere length with proliferation in vitro and with age in vivo. We performed a detailed study of the telomere length by flow FISH analysis in leukocytes from 835 healthy individuals and 60 individuals with reduced telomerase activity. Healthy individuals showed a broad range in average telomere length in granulocytes and lymphocytes at any given age. The average telomere length declined with age at a rate that differed between age-specific breakpoints and between cell types. Gender differences between leukocyte telomere lengths were observed for all cell subsets studied; interestingly, this trend could already be detected at birth. Heterozygous carriers for mutations in either the telomerase reverse transcriptase (hTERT) or the telomerase RNA template (hTERC) gene displayed striking and comparable telomere length deficits. Further, non-carrier relatives of such heterozygous individuals had somewhat shorter leukocyte telomere lengths than expected; this difference was most profound for granulocytes. Failure to maintain telomere homeostasis as a result of partial telomerase deficiency is thought to trigger cell senescence or cell death, eventually causing tissue failure syndromes. Our data are consistent with these statements and suggest that the likelihood of similar processes occurring in normal individuals increases with age. Our work highlights the essential role of telomerase in the hematopoietic system and supports the notion that telomerase levels in hematopoietic cells, while limiting and unable to prevent overall telomere shortening, are nevertheless crucial to maintain telomere homeostasis with age.
Full-text available
A major goal in aging research is to improve health during aging. In the case of mice, genetic manipulations that shorten or lengthen telomeres result, respectively, in decreased or increased longevity. Based on this, we have tested the effects of a telomerase gene therapy in adult (1 year of age) and old (2 years of age) mice. Treatment of 1- and 2-year old mice with an adeno associated virus (AAV) of wide tropism expressing mouse TERT had remarkable beneficial effects on health and fitness, including insulin sensitivity, osteoporosis, neuromuscular coordination and several molecular biomarkers of aging. Importantly, telomerase-treated mice did not develop more cancer than their control littermates, suggesting that the known tumorigenic activity of telomerase is severely decreased when expressed in adult or old organisms using AAV vectors. Finally, telomerase-treated mice, both at 1-year and at 2-year of age, had an increase in median lifespan of 24 and 13%, respectively. These beneficial effects were not observed with a catalytically inactive TERT, demonstrating that they require telomerase activity. Together, these results constitute a proof-of-principle of a role of TERT in delaying physiological aging and extending longevity in normal mice through a telomerase-based treatment, and demonstrate the feasibility of anti-aging gene therapy. See accompanying article
A critical question in human health is the malleability of telomere length. Telomere length, sampled at one point during adult life, is predictive of certain types of cancer and other immune and metabolic-related diseases. We now know from basic studies that the telomere/telomerase maintenance system plays a causal role in accelerating biologic aging and promoting disease processes. One can develop short telomeres for a multitude of reasons. Historical factors such as genetics, prenatal conditions, and early adversity, contribute to adult telomere length; however, current stress and lifestyle are also associated. If these modifiable predictors are causal factors in telomere shortening, there is a tremendous opportunity to improve maintenance and possibly even lengthen telomeres with behavioral interventions. This minireview discusses our current understanding of telomere lengthening and questions facing the field. Several small-scale stress reduction/wellness studies show promising findings, suggesting that cell aging can be slowed or reversed in vivo over short periods. Moreover, possible mechanisms are discussed, that take into account actual telomeric lengthening, such as that which occurs through telomerase-mediated elongation, or mechanisms resulting in "pseudo-telomeric lengthening" as might occur from changes in cell type distribution. There is a strong need for more translational clinical to bench research to address mechanistic questions in experimental models. In addition, well-designed intervention research that examines both telomeres and potential mediators of change can further enhance our understanding of malleability, mechanism, and clinical implications of telomere lengthening. Cancer Prev Res; 5(10); 1163-8. ©2012 AACR.
Shorter telomeres have been associated with poor health behaviors, age-related diseases, and early mortality. Telomere length is regulated by the enzyme telomerase, and is linked to exposure to proinflammatory cytokines and oxidative stress. In our recent randomized controlled trial, omega-3 (n-3) polyunsaturated fatty acid (PUFA) supplementation lowered the concentration of serum proinflammatory cytokines. This study assessed whether n-3 PUFA supplementation also affected leukocyte telomere length, telomerase, and oxidative stress. In addition to testing for group differences, changes in the continuous n-6:n-3 PUFA ratio were assessed to account for individual differences in adherence, absorption, and metabolism. The double-blind four-month trial included 106 healthy sedentary overweight middle-aged and older adults who received (1) 2.5g/day n-3 PUFAs, (2) l.25g/day n-3 PUFAs, or (3) placebo capsules that mirrored the proportions of fatty acids in the typical American diet. Supplementation significantly lowered oxidative stress as measured by F2-isoprostanes (p=0.02). The estimated geometric mean log-F2-isoprostanes values were 15% lower in the two supplemented groups compared to placebo. Although group differences for telomerase and telomere length were nonsignificant, changes in the n-6:n-3 PUFA plasma ratios helped clarify the intervention's impact: telomere length increased with decreasing n-6:n-3 ratios, p=0.02. The data suggest that lower n-6:n-3 PUFA ratios can impact cell aging. The triad of inflammation, oxidative stress, and immune cell aging represents important pre-disease mechanisms that may be ameliorated through nutritional interventions. This translational research broadens our understanding of the potential impact of the n-6:n-3 PUFA balance. identifier: NCT00385723.