Journals of Gerontology: Biological Sciences

cite as: J Gerontol A Biol Sci Med Sci, 2017, Vol. 00, No. 00, 1–9
doi:10.1093/gerona/glx082
Advance Access publication May 16, 2017

Special Issue: Caloric Restriction and Restrictive Diets: Interventions that Target the
Biology of Aging: Review in Depth

Telomeres, Nutrition, and Longevity: Can We Really

Navigate Our Aging?
Nikolina Škrobot  Vidaček,1 Lucia  Nanić,1 Sanda  Ravlić,1 Mary  Sopta,1 Marko  Gerić,2
Goran Gajski,2 Vera Garaj-Vrhovac,2 and Ivica Rubelj1
Department of Molecular Biology, Ruđer Bošković Institute, Zagreb, Croatia. 2Mutagenesis Unit, Institute for Medical Research and
1

Occupational Health, Zagreb, Croatia.

Address correspondence to: Ivica Rubelj, PhD, Laboratory for Molecular and Cellular Biology, Division of Molecular Biology, RBI, Bijenička cesta
54, 10 000 Zagreb, Croatia. E-mail: rubelj@irb.hr

Received: November 28, 2016; Editorial Decision Date: April 20, 2017

Decision Editor: Rozalyn Anderson, PhD

Abstract
Telomeres are dynamic chromosome-end structures that serve as guardians of genome stability. They are known to be one of the major determinants
of aging and longevity in higher mammals. Studies have demonstrated a direct correlation between telomere length and life expectancy, stress, DNA
damage, and onset of aging-related diseases. This review discusses the most important factors that influence our telomeres. Various genetic and
environmental factors such as diet, physical activity, obesity, and stress are known to influence health and longevity as well as telomere dynamics.
Individuals currently have the opportunity to modulate the dynamics of their aging and health span, monitor these processes, and even make future
projections by following their telomere dynamics. As telomeres react to positive as well as negative health factors, we should be able to directly
influence our telomere metabolism, slow their deterioration, and diminish our aging and perhaps extend our life and health span.

Keywords: Telomeres—Human aging—Longevity—Dietary restriction

In recent years, evidence has accumulated revealing the molecular
mechanisms of aging. Among the primary hallmarks of aging that
have been described thus far (1), telomere length has garnered much
attention in the past two decades. Telomeres are specialized struc-
tures found at the ends of chromosomes and in addition to being
the primary gatekeepers of genome stability, they play major role in
senescence and aging (2). Telomeres are dynamic structures in that
they shorten with each cell division (3). Since even a single too short
telomere is detected as DNA damage which induces permanent cell
cycle arrest, sooner or later all cycling somatic cells will permanently
stop dividing and enter senescence, whether in vitro or in vivo (4).
Indeed, numerous studies point to the accumulation of senescent cells
as the main cause of aging and aging-related diseases observed in vari-
ous organisms (5–7). The strongest evidence for a telomere ­controlled
mechanism of aging comes from experiments where ectopic expres-
sion of telomerase in normal cells or transgenic animals prevents
senescence and postpones or even reverses aging (8–10).
In addition to measuring telomere length at the cellular level,
telomere shortening can be followed at the population level as
© The Author 2017. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved.
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well. In various population studies, telomere length is measured
in peripheral leukocytes that correlates well with telomere length
in other body tissues (11). Average telomere length has been used
as a reliable biomarker for prediction of health span and longevity
both in humans and animals, with the exception of the oldest old
subpopulation (12). Therefore, besides measuring average telomere
length, it is important to follow changes in telomere length during
time as well as proportion of short telomeres in overall sample (13).
Several methodologies have been routinely used for telomere length
measurement, including Q-PCR which measures the average length
of bulk telomeres, while Southern blotting and Q-PNA-FISH-based
methods measure telomere length distributions. The latter methods
provide a measure of the shortest telomere fraction which is more
relevant for cell survival and as such is a better predictive factor for
morbidity and mortality in humans (13).
Of particular interest is the fact that environmental and lifestyle
factors influence telomere metabolism and their effects on health
and longevity (14,15). Therefore, in this review, we explore the rela-
tionship between telomeres, genome integrity, aging, and lifestyle in
1
2 Journals of Gerontology: BIOLOGICAL SCIENCES, 2017, Vol. 00, No. 00

light of recent findings in primates (16,17) and humans (14,15) that

open up new perspectives on how to combat aging and aging-related
diseases. Telomere molecular metabolism underlies the observa-
tions of the U.S. Centers for Diseases Control and Prevention (CDC,
2009) and the World Health Organization (WHO, 2005) that aging-
related diseases, such as cancer, type 2-diabetes, and coronary heart
disease, could be reduced between 40% and 80% just by changing
one’s lifestyle. This means primarily implementing an antiaging diet
and moderate but regular physical activity.

Free Radical Effects on Telomeres

The biology of genome stability and telomeres includes many inter-
actions between these two factors. Short and dysfunctional telom-
eres are the initiating point for cell senescence, cell death, and DNA
instability (18). The effect of aging on the level of DNA damage in
human cells has been assessed in many studies (19,20). Over time,
genome damage accumulates probably due to lower DNA repair
capacity, lower chromosome segregation, and cell cycle checkpoint
efficacy (21). Unhealthy factors, which include endogenous geno-
toxins, inadequate nutrition, and other unfavourable lifestyle fac-
tors, are also responsible for both an increase in baseline genome
damage and accelerated telomere shortening. Most of these fac-
tors have an indirect mechanism of action through free radical
formation and oxidative stress. This points to a conclusion that
since reactive oxygen species (ROS) are predominantly responsible
for age-related damage at the cellular and tissue levels (22,23), a
reduction in calorie intake would lead to a reduction in energy
metabolism and ROS production. Consequently, this would result
in diminished cell and tissue damage. Indeed, ROS strongly influ-
ences replicative senescence and aging through accelerated tel-
omere shortening caused primarily by accumulation of nicks in the
G-rich strand (24).
Under physiological conditions, mitochondria are the main
source of ROS and it has been demonstrated that senescence of
human cells is related to dysfunctional mitochondria and shorter tel-
omeres (25) (Figure 1). Overproduction of ROS results in oxidative
stress which can lead to oxidation of biomolecules including lipids,
proteins, and DNA over time. Such loss of DNA structure or its
information content typically cannot be replaced (26). Obviously,
there is a valid reason why chronic oxidative stress is perceived as
one of the leading causes of many metabolic and neurodegenerative
diseases and chronic inflammation. Inflammation causes accelerated
white blood cell turnover and additional telomere attrition resulting
in accelerated aging (27,28).
Furthermore, mitochondrial and telomere mechanisms of aging
have been united and a direct molecular connection between telomere
attrition and mitochondrial dysfunction has been established (29). It
has been shown that p53 activation induced by telomere shortening,
in addition to halting the cell cycle, downregulates the expression of
PGC1α and β which leads to reduction of mitochondrial biogenesis
and function. Dysfunctional mitochondria demonstrate metabolic
changes, such that they exhibit defective ATP generation, increased
ROS production, and decreased levels of ROS-detoxifying enzymes
which cause additional damage both to mitochondrial and genomic
DNA, including telomeres (29) (Figure 1).
Besides p53 protein, sirtuin family of NAD-dependent protein
deacetylases and ADP-ribosyltransferases plays an important role
in control of mitochondrial function. SIRT1 modulates mitochon-
drial biogenesis through deacetylation and activation of PGC-1α
while SIRT3 deacetylates mitochondrial enzymes involved in energy
Figure 1.  Influence of endogenous and exogenous factors on aging. Aging is
a plastic phenomenon that can be either positively or negatively influenced
by various endogenous or exogenous factors. Accumulating evidence points
to telomeres and mitochondria as the main factors in cellular aging control
that consequently dictate the aging process at the organismal level. Recently,
these two aspects have been connected in that critically short telomeres
trigger the DNA damage response which results in an increase in p53 protein.
In addition to activating mechanisms of cell cycle arrest through activation
of p21, increasing levels of p53 also results in the repression of PGC1α and
β, the main promotors of mitochondrial biogenesis, causing compromised
mitochondrial function. Dysfunctional mitochondria release even more
reactive oxygen species (ROS) into the cytoplasm causing further damage
to the cell and accelerating the onset of senescence. External factors such as
irradiation, pollution, environmental stress as well as unhealthy habits like
smoking, alcohol consumption, unhealthy food, lack of exercise, obesity, etc.
can contribute to increased ROS production and other negative effects of
aging. On the other hand, cellular defence mechanisms like ROS scavenging
enzymes, antioxidants such as vitamins, flavonoids and carotenoids can
diminish ROS production and preserve our telomeres, reduce mitochondrial
damage and extend our health span. Positive lifestyle habits such as regular
moderate exercise, relaxation and healthy diet can similarly improve our
aging profile.
metabolism linked to some of the beneficial effects of calorie restric-
tion (1).
Also, mitochondria can contribute to aging independently of
ROS, through numerous types of mitochondrial dysfunctions like
impaired mitochondrial biogenesis, decreased mitophagy and fission
fusion ratios, mutations and deletions in mtDNA or perturbations
on electron transport chain. All this can cause reduced efficiency of
mitochondrial bioenergetics (1).
Nevertheless, it should be emphasized that ROS are normal
intermediaries of biochemical reactions which serve as important
physiological regulators of intracellular signaling pathways (30).
Depending on the circumstances, they can be either harmful or ben-
eficial to living systems (31). Beneficial effects of ROS occur at low/
moderate concentrations and involve physiological roles in cellular
responses to anoxia, defense against infectious agents, or induction
of a mitogenic response (30). In contrast, a significant increase in
oxidative stress induces premature senescence in many human cell
types (32). Thus, the delicate balance between the beneficial and
Journals of Gerontology: BIOLOGICAL SCIENCES, 2017, Vol. 00, No. 00
harmful effects of free radicals is a very important aspect of human
aging (33) as proposed in the gradual ROS response hypothesis (23).
Nutrients and Food Groups That Protect
Telomeres
As mentioned earlier, oxidative stress has a great impact on telomere
shortening. It is expected that an excess of oxidants can be offset
with antioxidants, substances capable of donating electrons, and
neutralizing free radicals in the cell (34). Therefore, experiments
were performed examining the effect of the most common antioxi-
dant compounds found in food such as vitamins, minerals, polyphe-
nols, and omega-3 fatty acids in prevention of telomere shortening
and possibly slowing down the aging process (35) (Figure 1).
Vitamins and Minerals
Although in vitro experiments have shown positive results with
antioxidants regarding telomere metabolism (36), similar results
with in vivo experiments are considered more relevant because
more complex biological factors might influence telomere shorten-
ing. Vitamins and minerals have particularly garnered the spotlight
recently because of their widespread use among the general popula-
tion and the potential for increasing commercial value. Vitamins C,
D, E, folate, and β-carotene and the minerals zinc and magnesium
have shown positive effects in protection against oxidative stress and
inflammation which leads to telomere protection and are positively
associated with telomere length in humans (37).
Naturally Occurring Polyphenols
Polyphenols are naturally occurring chemicals that have also shown
positive effects on telomere length and organismal aging. Study con-
ducted on a Belgian population demonstrated antioxidant properties
of theaflavins, polyphenols found in green and black tea, as well
as its negative association with biomarkers of inflammation (38).
Consequently, polyphenols may have a positive influence on tel-
omere length. However, in western society’s tea drinking is gener-
ally associated with a healthier lifestyle which could have influenced,
these observed levels of inflammation markers compared to the gen-
eral population. Elderly Chinese who are habitual tea drinkers have
longer telomeres which correspond to an average increase of 5 years
in life span as compared to their counterparts who do not drink tea
as frequently (39). This association was observed only in men but
not in women. A  particular weakness of this study is that it does
not include young or middle-aged male subjects and as both studies
are cross-sectional in nature a strict causal relationship cannot be
established.
Another significant naturally occurring polyphenol related to tel-
omere length is resveratrol which activates SIRT1, an intracellular
regulatory protein that regulates important metabolic and physio-
logical processes (40). It is commonly found in the skin of red grapes
and has antioxidant and anti-inflammatory properties as well as a
positive effect on general health in mammals (40,41). Resveratrol
delays senescence at the cellular level, increases telomere length
and telomerase activity in rodents but does not extend life span in
healthy rodents or in a rodent model of premature aging (42,43).
However, synthetic small molecules, sirtuin agonists SRT2104 and
SRT1720, extend both mean and maximal life span of mice fed a
standard diet (44,45). In humans, resveratrol has been reported
to decrease oxidative stress and attenuate inflammation, reduce
the risk of cardiovascular diseases and diabetes (46). These are all
3
aging-related pathologies so it has yet to be established whether
resveratrol can slow the aging process by lowering the incidence of
chronic diseases in humans. To achieve this goal, it is necessary to
establish the optimal dosage of resveratrol administration because of
its very low bioavailability in humans. Furthermore, resveratrol and
its metabolites accumulate in human cells in a tissue-specific manner
which greatly depends on the dosage. Different dietary factors, for
example, high-fat meals consumed by some individuals may influ-
ence plasma resveratrol concentrations which may differ consider-
ably within population (46).
Fats
Omega-3 fatty acids have been recognized over the last decade as
important molecules for well-being and in particular helpful for the
cardiovascular system. It has been shown that there is a negative cor-
relation between the blood level of marine omega-3 fatty acids (doc-
osahexaenoic and eicosapentaenoic acids) in patients with coronary
heart disease and the rate of their telomere attrition over a 5-year
period (47). A recent randomized controlled 4 months trial showed
that it is not omega-3 itself, but rather the ratio between omega-
3(n-3) and omega-6 (n-6) fatty acids that is important, as telomere
length increases with decreasing n-6:n-3 plasma ratios regarding
baseline telomere length. Telomerase activity was unchanged during
the study in these individuals but there was a significant negative cor-
relation between telomere length and biomarkers of oxidative stress
and inflammation, two factors that affect telomere shortening (48).
So, the individuals with higher endogenous n-6:n-3 polyunsaturated
fatty acid ratios would have greater benefits from simple nutritional
intervention in the form of omega-3 supplementation.
Food Groups
Based on the premise that higher intakes of fresh fruits, vegetables,
legumes, fish, poultry, and whole grains lower markers of inflamma-
tion (49), it can be concluded that antioxidant-rich food may have a
positive influence on telomere length. Indeed, consumption of seeds,
nuts, legumes, seaweeds, and coffee was associated with longer tel-
omeres (50). In addition, dietary fiber intake, specifically from cereals
and whole grains, has a positive effect on telomere length in women
(51). An interesting finding is that colonocyte telomere shortening
in rats fed with red or white meat can be attenuated by the inclu-
sion of resistant starch in the diet suggesting a protective effect of
dietary fiber (52). Furthermore, intake of processed meats was nega-
tively linked to telomere length in a multiethnic study (53) but not
among African American and Hispanic population (50). Because of
their high fat and protein content, heat-generated glycotoxins are
produced that increase cell-oxidant stress and promote inflamma-
tion (54) which has been associated with inflammatory diseases like
type-2 diabetes and atherosclerosis (55). There have been conflict-
ing reports regarding fruit and vegetable consumption and telomere
length. However, there is at least some evidence that they can have a
positive influence on telomere length and further studies are needed
to confirm these results (50,56).
Accumulation of information on the positive effects of various
food compounds on molecular mechanisms that dictate the aging
process and resistance to developing diseases open up the opportu-
nity to make better choices towards healthier nutritional habits that
will prolong our health and life span. To benefit the most from all of
the aforementioned positive effects, the best sources of antioxidants
are from food rather than dietary supplements due to the synergistic
effect of a variety of compounds found in the original plant product.
4 Journals of Gerontology: BIOLOGICAL SCIENCES, 2017, Vol. 00, No. 00
In addition, the exact dosage and side effects for dietary supplements
have yet to be established. Accordingly, it has been shown that some
compounds, like β-carotene, are positively related to lung cancer
incidence in smokers (57).
Dietary Patterns with Effect on Telomere
Length and Aging
An association between telomere length and nutritional status can
be seen since birth because exclusive breastfeeding in the first 4–6
weeks of life is associated with longer telomeres in Latino preschool
children at 4 and 5 years of age (58). Later in life various diets show
beneficial effects on human health. Among those, reduced calorie
intake has raised much attention both among scientists and the gen-
eral public because it is the only nonpharmacological intervention
known to date that slows down the aging process and increases both
average and maximal life span in rodents, fish, fruit flies, worms, and
yeast (59,60).
Calorie Restriction
A longitudinal calorie restriction (CR) studies in rhesus monkeys
(Macaca mulatta) implied that CR can prolong life span in longer-
lived species (61). These investigations raised the hope that CR
might be effective in humans. However, contradictory results were
later published which indicated that, while some health benefits were
observed, CR had no effect on longevity in these monkeys (62). Both
studies demonstrated that CR in tested animals delayed the onset of
several aging associated pathologies such as diabetes, cancer, cardio-
vascular diseases, and brain atrophy (61,62). Another study showed
that CR does not significantly affect telomere length in the skin and
muscle of rhesus monkeys (63). Possible differences in the life span
of CR animals can be explained by differences in dietary composi-
tion, vitamin and mineral supplementation, husbandry, and genetic
background. It was shown that all calories are not the same, and
significantly it is the quality of the source of calories that matters
(62). Meanwhile, the effect of CR on humans has been poorly stud-
ied. The great number of centenarians and the high average life span
of Okinawa women who consumed 15%–20% less calories than
mainland Japanese throughout their lifetime may be living proof
that moderate CR in combination with a well-balanced diet can
have significant effect on human life span (64). CR in the Biosphere
2 experiment due to unexpected food insufficiency showed that
healthy nonobese humans on a low-calorie, nutrient-dense diet
show physiologic, hematologic, hormonal, and biochemical alterna-
tions consistent with caloric restricted rodents and primates (65).
Following the first 6  months of the first randomized human trial,
it was shown that CR had positive physiological and psychologi-
cal effects including improvement of several markers of aging (64).
This was confirmed by a later study where the effects of CR on dis-
ease risk and human survival suggested potential benefits for aging-
related outcomes (66). Although the effect of CR intervention on life
span in humans remains to be determined unequivocally, evidence
thus far suggests that it can be a successful step to prolonged health
span and healthy aging.
Without strong proof that long-term CR indeed prolongs human
life and the fact that it is very hard for most individuals to practice
calorie restriction in an overfeeding environment, later studies have
focused on compounds, like resveratrol that mimic calorie restriction
metabolism (67). The effects of various forms of dietary restrictions,
including normocaloric diets with planned deficiencies (in particu-
lar macronutrients: proteins or carbohydrates), and time-restricted
feeding (68) have also been used as alternative models for impacting
telomere length and health span. Most of these interventions have
positive effects on overall health and longevity in model organisms
(68,69). It has been shown that short-term dietary restriction has
multiple benefits in mammals including modulation of inflammatory
responses (70), reduction in cell senescence, and decreases in oxida-
tive stress markers in the small intestinal epithelium and liver in mice
(71). Recent work suggests that a fasting-mimicking diet (FMD)
consisting of cycles of short-term FMD followed by a standard ad
libitum diet can produce health benefits in people and extend the
life span of mice (72). The aforementioned evidence suggests that
beneficial effects on health span and life span can be achieved by less
invasive dietary interventions, rather than CR, which do not require
long lasting or overall reduction in calorie intake.
While a positive effect of CR on telomere length and telomerase
activity in rodents has been well documented (73), there have been
very few reports regarding the association of energy intake with
telomere length in humans. A  cross-sectional Multiethnic Study
of Atherosclerosis that encompasses men and women showed a
nonsignificant negative correlation of energy intake with telomere
length (53). The absence of a correlation between energy intake
and telomere length was also found in the Nurses’ Health Study
(51) and in elderly Chinese men (39). In contrast, research con-
ducted on young adults in Jerusalem showed a significant nega-
tive correlation of dietary energy and macronutrient intake with
both baseline and follow-up telomere length in men only (74). It
is important to emphasize that the test subjects in this study were
younger (age 30–43) than in other reports. Recently an article was
published describing the connection of plasma irisin levels and
telomere length. Irisin is a hormone released from skeletal mus-
cles after exercise which may induce CR-like effects by increas-
ing energy cost from adipose tissue. Using telomere length as a
marker of aging, this study showed a significant positive correla-
tion between plasma irisin levels and telomere length (75).
Mediterranean Diet
In the last 15  years, a lot of attention has focused on the
Mediterranean diet, proven to be one of the healthiest diets in the
world (50,76). It respects all the principles of the healthy antiaging
diet mentioned earlier as it is based on the intake of seasonal fruits,
vegetables, nuts and seeds, whole grains, olive oil, fish and low fat
meat, and dairy products as well as moderate intake of alcohol. As
a result, the Mediterranean diet has been linked to low morbidity,
lower occurrence of some chronic, especially cardiovascular diseases
and consequently greater longevity (50,76). The Mediterranean diet
lowers the level of oxidative stress markers and inflammation due
to a high abundance of antioxidant compounds such as omega-3
and resveratrol (48,77). Importantly, it has a direct positive effect
on telomere length (48,78). Additional confirmation of a positive
influence of the Mediterranean diet on telomere length came from a
Nurses’ Health Study which is one of the largest research studies into
the risk factors for major chronic diseases in women. Adherence to a
Mediterranean diet managed to preserve a telomere length that cor-
responded to 4.5 years of aging which is comparable to the effects
of smoking (4.6 years) and physical activity (4.4 years) on the tel-
omere shortening rate (79). The Mediterranean diet also stimulates
telomerase activity in peripheral blood mononuclear cells (50). If
combined with moderate exercise, this diet demonstrates elevated
long-term improvement in endothelial microvascular and cardiores-
piratory functions, important for both better health and increased
life expectancy (80).
Journals of Gerontology: BIOLOGICAL SCIENCES, 2017, Vol. 00, No. 00
Vegetarian Diets
Vegetarians, including vegetarian subgroups, which differ in their
degree of avoidance of meat consumption and based on a degree
of restriction of other animal products (milk, eggs, etc.), have also
been studied for effects on health span and telomere length. Even
though it is perceived as very healthy by the general public, observed
consequences of a vegetarian diet are higher intake of antioxidants
and lower fat intake but at the same time deficiencies in vitamins
B, D, iron, and calcium were also shown (81). Over time, conflict-
ing results were reported regarding general health, antioxidant sta-
tus, and DNA damage observed in vegetarians (82) and so far, no
clear conclusions about beneficial effects can be drawn from these
studies without a thorough multibiomarker meta-analysis. As far
as telomeres are concerned, there is very little data. One case–con-
trol study conducted on an Indian subjects with coronary artery
disease showed trend toward longer telomeres in vegetarians com-
pared with subjects on a mixed diet without a statistical significance
(83). Additional research is needed specifically designed to test this
correlation.
Behevioral and Psychological Factors That
Affect Telomeres and Aging
In recent years, a growing body of literature has emerged showing
a connection between telomere length and various lifestyle factors.
Thus, beside genetics, smoking, obesity, lack of physical activity, and
sleep, stress or depression can increase the rate of telomere short-
ening that directly correlates to increased incidence of cancer and
mortality rate. In contrast, positive correlation of telomere length
with healthy lifestyle is well-documented, suggesting a great impact
of these factors on telomere maintenance and consequently overall
health status (84).
Obesity and Smoking
Smoking and obesity affect an increasing number of people world-
wide. There are opposite results regarding obesity related pheno-
types and telomere length correlation. Multiple studies have shown
that high body mass index (BMI) correlates with short telomere
length, DNA damage, and cancer incidence (85). Individuals with
higher total and abdominal adiposity have shorter telomeres sug-
gesting that obesity may accelerate the aging process (86), and recip-
rocally shorter telomere length may be a risk factor for increased
adiposity (87). It should be emphasized that negative effect of obe-
sity-related phenotypes on telomere length may be more evident in
women than men (88). Valdes and colleagues conducted a scientific
study in which participants were 45 monozygotic and 516 dizygotic
twin pairs of Caucasian women aged 18–76 years. The telomeres of
obese women were 240 bp shorter than those of their slender coun-
terparts (89). In contrast, some other studies did not find a signifi-
cant association between shorter telomere length and obesity (87).
Recently, a systematic review was published assessing the effects of
obesity on telomere length. Sixty-three original studies with a total
of 119,439 subjects that satisfied strict inclusion criteria showed that
despite weak to moderate associations between obesity and telomere
length, there was a trend toward an negative correlation between
those two (90).
Tobacco smoke produces free radicals which cause damage to
lipids, proteins, DNA, and other endogenous cellular structures
including telomeres and increase various inflammation biomarkers
(91). A  negative correlation between active smoking and telomere
length has been indicated in many studies (85,92). In addition, a
5
dose-dependent relation with smoking was established and smoking
one pack of cigarettes a day over a 40-year period was equivalent
to an additional 18% of telomere length lost (eg, 7,4 years of life)
compared with the rate in the overall sample (89). The connection
between passive smoking or smoking cessation and telomere length
has not been investigated adequately. It was shown that prenatal
tobacco exposure greatly affects telomere length in children leading
to a significant health impact (93). Further, longer telomeres were
indicated among former smokers but this phenomenon is limited to
a 3–16-year period after smoking cessation. It should be emphasized
that this finding only implied an association rather than causation.
Clearly, further investigations on biological pathways underlying
these results are needed (92).
Exercise
Correlation between physical activity, sedentary behavior, and tel-
omere length has been extensively studied. Physical activity is a
factor that is positively associated with greater leukocyte telomere
length among healthy individuals and twin volunteers while seden-
tary behavior is negatively correlated with telomere length (88). In
addition, research in patients with coronary heart disease and post-
menopausal women with stage I-III breast cancer indicates a strong
association between physical fitness and telomere length (88). On the
other hand, there are some studies that show no significant associa-
tions between physical activity and telomere length (88). It seems
likely that there is no clear answer yet at this point. After adjustment
for other patient characteristics, including markers of cardiac disease
severity and physical inactivity, participants with low exercise capac-
ity had 94% greater odds of having short telomere length than those
with high exercise capacity. A recent 30-year long study showed that
people who practiced moderate physical activity in midlife had longer
telomeres in old age than participants who had low or high physi-
cal activity (88). These results suggest a dose-related link between
intensity of physical exercise, telomere length, and baseline DNA
damage where regular moderate physical activity is most beneficial.
In addition, different forms of physical activity should be performed
at certain ages to obtain the positive effect on telomere maintenance.
It seems likely that in older adults, physical capacity like the ability
to perform activities of daily living, sit-to-stand performance, and
walking distance, rather than exercise, may have a greater impact on
telomere length (88). In contrast, at younger age, intensity of exercise
rather than duration of physical activity may have a beneficial effect
on telomeres (88). Further research is needed to find the optimal
exercise conditions for telomere length maintenance.
Alcohol Consumption
Consumption of alcohol is a custom in many societies in the world
and its ambiguous impact on human health is extensively studied
over the years. In a long-term study over three decades, a negative
relationship of even minor alcohol consumption in midlife and tel-
omere length in old age is described in the Helsinki Businessman
study (50). Differences in telomere length between nonalcohol users
and the group with highest alcohol consumption rate could be rep-
resented as a 10-year difference in biological age. In contrast, the
Copenhagen City Heart Study shows no association between alco-
hol consumption and telomere length measured after 10 years (50).
While Nordic populations usually drink spirits, Mediterranean pop-
ulations characteristically have a regular intake of red wine and beer,
both polyphenol-rich beverages. One study explored the association
between telomere length and alcohol consumption in an Italian pop-
ulation but no effects on telomere length were detected (50).
6 Journals of Gerontology: BIOLOGICAL SCIENCES, 2017, Vol. 00, No. 00
Mental Health
It is well known that better mental health greatly contributes to
physical health as well. Despite some contradictory reports, there are
a large number of results that support a connection between shorter
telomere length and chronically high levels of perceived stress,
especially in caregivers, maternal stress during pregnancy, and the
number of childhood adversities (11). There is also a positive cor-
relation between accelerated telomere shortening and psychological
disorders like depression and high phobic anxiety (11). Also, sleep
deprivation (less than 5 hours) shortens telomeres by 6% compared
with subjects sleeping 7 hours or more (11).
It should be stated that most of these studies are observational
and there were conflicting results for each of the above-mentioned
factors. These inconsistencies are likely due to the biological diversi-
ties in the subjects such as genetic polymorphisms, ethnicity, age, and
sex differences. Furthermore, DNA extraction methods, study par-
ticipant sampling, and methodological differences are a contributing
factor for these discrepancies. Despite these limitations, the studies
reviewed provide insight into the complex connection between tel-
omere length and various lifestyle factors.
Can Dietary and Lifestyle Interventions
Improve Telomere Stability And Modulate the
Aging Process?
Lifestyle
With respect to the accumulating evidence that telomere length
can be modulated by a variety of lifestyle factors, a longitudinal
study has been conducted in order to closely examine the direct
influence of comprehensive lifestyle changes on telomerase activ-
ity and telomere length (14). Comprehensive lifestyle changes
imply a specific diet accompanied by stress management, mod-
erate aerobic exercise, and group support sessions. In the pilot
study that lasted for 3  months, 24 men with biopsy-diagnosed
low risk prostate cancer who chose active surveillance rather than
conventional treatments were provided precooked meals based on
food low on fat and refined carbohydrates, with plenty of fruits,
vegetables, unrefined grains, and legumes supplemented with soy,
fish oil, vitamins E and C, and selenium. Additionally, they were
asked to conduct moderate exercise in the form of walking 30
minutes/d, 6  days/wk. Stress management included gentle yoga
based stretching, breathing, meditation, and relaxation tech-
niques for 1 hour/d, 6  days/wk and psychological support ses-
sions once a week.
The most important result of this study is that strictly follow-
ing lifestyle recommendations for only 3  months was sufficient to
increase telomerase activity in peripheral blood mononuclear cells
(PBMC) of test subjects by almost 30%. This increase in telomerase
activity was correlated with improvements of risk factors for car-
diovascular diseases as well as a decrease in the aging biomarker C
reactive protein (CRP) value (14). Ornish and colleagues conducted
a 5-year follow-up study in order to determine whether the long-
term comprehensive lifestyle changes affect telomere length as well.
Over time assessment of gross telomere shortening showed a reduc-
tion such that the relative telomere length decreased in only ~30% of
subjects in lifestyle intervention group compared to 64% of subjects
in the control group. It is interesting that a dose–response relation
has been established between the lifestyle change adherence score
and degree of change in telomere length. The weakness of this study
is its relatively small sample group; so, these results do not address
causality but rather are indicative of an association (15). We should
emphasize that there was no clinical evidence of prostate cancer pro-
gression in these subjects during the test period. Still, one should
keep in mind that lifestyle changes cannot be substituted for conven-
tional treatment in patients with more aggressive forms of cancer.
A recent study that followed 231 healthy women over a short,
1-year period showed that for every major life stress event like ill-
ness, death of a family member or friend, financial, employment or
marital problems that occurred during that time, there was a sig-
nificantly greater decline in telomere length. However, these impacts
were ameliorated by healthy behaviors that included self-reported
physical activity, typical food consumption, and sleep quality (94). It
seems likely that a combination of healthy behaviors has a stronger
influence on telomere length than each factor alone (94). The weak-
ness of this study is that results are limited to postmenopausal and
nonsmoking primarily Caucasian women that are highly educated,
healthy, and have lower levels of stress than the national average.
Meditation
In addition to lifestyle and diet, it is well known that better mental
health greatly contributes to physical health as well. There are a few
studies that directly link meditation and positive psychological change
with telomerase activity showing that mental health is an adjustable
factor associated with telomere length. In a pilot study of yogic medi-
tation for depressed dementia caregivers, 23 subjects in the meditation
group were randomized to practice Kirtan Kriya and 16 subjects in
the relaxation group listened to relaxation music for 12 minutes per
day for eight weeks. Telomerase activity in peripheral blood mononu-
clear cells was measured pre- and postintervention. The meditation
group showed a 43% increase in telomerase activity, accompanied
by improved mental and cognitive functioning and lower levels of
depressive symptoms compared with a relaxation control group. This
increase in telomerase activity can be associated with a lower level
of stress-induced cellular aging (95). In the study by Jacobs and col-
leagues, 60 men and women matched for age, sex, body mass index,
and prior meditation experience were randomly divided into two
groups. Retreat participants meditated for 6 hours daily for 3 months
and the other half served as a wait-list control group A  3-month
retreat of intensive meditation training resulted in 30% higher telom-
erase activity in retreat participants as compared with a control group
(96). Weak points in this study are the absence of a baseline measure
of telomerase activity, relatively small sample size, and the control
condition that did not match the experimental condition such that the
control group was not spared from the stresses of everyday life (96).
However, a recent meta-analytic review based on 190 participants in
four initial randomized control trials indicates a positive correlation
between mindfulness meditation and telomerase activity (97).
Antiaging Intervention Comes of Age
A more direct and so far the only serious attempt to combat aging
through telomerase activation and telomere elongation is the use of
TA-65, a dietary supplement isolated from the Chinese traditional
medicine herb Astragalus membranaceus (98,99). This approach
opens up the possibility of health and life extension, or even reju-
venation, as has been demonstrated in transgenic animals (8–10).
Although some expression of telomerase in normal somatic cells
in culture was detected, the use of TA-65 did not show significant
effects on human subjects during a 1-year trial (98,99). However,
while there was no or just a slight effect on average telomere length,
more important reduction in the proportion of the shortest telomere
Journals of Gerontology: BIOLOGICAL SCIENCES, 2017, Vol. 00, No. 00
fraction (>4  kb or bottom 20%) was demonstrated in most sub-
jects. Since these trials were performed over a relatively short period
of time, it will take years before some positive effects of TA-65 on
health and longevity become more obvious.
Conclusions
We live in an exciting era in which the research field of aging and
senescence is quickly growing because the mechanisms of cell senes-
cence and aging have been largely elucidated. Telomere shorten-
ing has been established as one of the main causes of cellular and
organismal aging in higher mammals (100). Aging is a “disease” that
affects the whole population without exception so finding a “cure”
is the next logical step. But before we discover an effective cure, we
have the opportunity to modulate our aging through comprehen-
sive lifestyle changes. These findings may seem like common sense
but they are based on hard scientific evidence about factors that are
both beneficial or harmful for our health and aging. Armed with this
knowledge, we can now monitor the aging process by measuring our
telomere status through commercially available services and respond
accordingly. Thus, for the first time we really can navigate our aging!
Funding
This work was supported by Zaklada Adris.
Conflict of Interest
The authors declare no conflict of interest.
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