Maybe you want better aging, then get your doctor to write up protocols in what to do. Without a protocol this would be just guesswork. And with your rehab you already had tons of guesswork called guidelines.
telomeres (15 posts to november 2012)
I have an easy question, but no-one to ask it of. How much coffee do I need on a daily basis to increase my telomere length? I'm already doing 12 cups a day for Parkinsons and dementia prevention. Give me a number and I'll add that to it. And I do whole milk.
How coffee protects against Parkinson’s Aug. 2014
Coffee May Lower Your Risk of Dementia Feb. 2013
And this: Coffee's Phenylindanes Fight Alzheimer's Plaque
This also: Two Compounds in Coffee May Team Up to Fight Parkinson's
The latest here:
Physical Activity and Nutrition: Two Promising Strategies for Telomere Maintenance?
This article has been cited by other articles in PMC.
Abstract
As
the world demographic structure is getting older, highlighting
strategies to counteract age-related diseases is a major public health
concern. Telomeres are nucleoprotein structures that serve as guardians
of genome stability by ensuring protection against both cell death and
senescence. A hallmark of biological aging, telomere health is
determined throughout the lifespan by a combination of both genetic and
non-genetic influences. This review summarizes data from recently
published studies looking at the effect of lifestyle variables such as
nutrition and physical activity on telomere dynamics.
Keywords: aging, exercise, diet, telomerase, TERRA, telomere length, senescence
1. Introduction
The
proportion of the world population aged 60 years and over is increasing
rapidly and is projected to rise above 20% in 2050, which will exceed
the number of children in the world [1,2].
Indeed, most countries are seeing their demographic structure getting
older. The aging of the population has major implications socially and
economically as aging is characterized by a progressive loss of
physiological integrity, leading to impaired function and autonomy [3].
This functional decline is the greatest risk factor for conditions that
limit health span, i.e., quality of life at old age, and for the
majority of chronic diseases such as type 2 diabetes, Alzheimer’s
disease, and various cancers [4,5]. Notably, senescence has become the greatest risk factor for death in developed countries [6].
With the increasing longevity, the maintenance of health and autonomy
at old age becomes crucial. Today more than ever, highlighting
strategies to counteract age-related disorders is a major public health
concern.
Geroscience is an area that
aims to explain the biological mechanisms of aging. Aging research has
experienced an unprecedented advance over recent years, particularly
with the discovery that the rate of aging is controlled, at least to
some extent, by genetic pathways and biochemical processes conserved in
evolution such as genomic instability, telomere attrition, epigenetic
alterations, loss of proteostasis, deregulated nutrient sensing,
mitochondrial dysfunction, cellular senescence, stem cell exhaustion,
and altered intercellular communication [3]. Recent findings have revealed the importance of the regulation of telomere length and integrity during the aging process [7], as well as potential interventions to improve the health span such as physical activity and healthy diet [8]. Telomere attrition is associated with decreased life expectancy and increased risk of chronic disease [9] and has been described as one of the most important biological hallmarks of aging due to a key role in cellular senescence [3].
During the past decade, telomeres have evolved from a simple capsule
hiding the ends of chromosomes to complex nucleoprotein structures with
an active role in the protection of the genome and in the regulation of
cellular senescence [10,11]. While previous reviews specifically focused on the regulation of telomere length by either nutrition [12] or exercise [13,14],
the present review will give a broader view looking at the impact of
lifestyle variables on human telomere dynamics with emphasis on diet and
physical activity.
2. Telomeres
Mammalian
telomeres consist of repetitive DNA G- and C-rich sequences
(5′-TTAGGG-3′/3′-CCCTAA-5′) with the 3′ end of the G-strand extending
beyond the 5′ end [15].
The double-stranded telomeric DNA is bound by the six-subunit shelterin
complex: telomeric repeat factor 1 (TRF1), telomere repeat factor 2
(TRF2) and protection of telomere 1 (POT1) directly recognize TTAGGG
repeats and they are interconnected with TRF1- and TRF2-interacting
nuclear protein 2 (TIN2), POT1 and TIN2-interacting protein (TPP1) and
repressor/activator protein 1 (RAP1) [16].
The Shelterin complex facilitates the formation of a lariat-like
structure with a T- and a D-loop, allowing the telomere end to be hidden
(Figure 1).
This conformation represses the DNA damage response (DDR) at telomeres,
thereby preventing the activation of the ataxia telangectasia mutated
(ATM) and RAD3-related (ATR) kinases that induce cell cycle arrest in
response to DNA double-strand breaks and other types of DNA damage [10,17].
Telomeric DNA with the Shelterin complex facilitating the formation of D- and T-loop.
Many
types of human cells lack telomerase, the enzyme responsible for
telomere synthesis by adding nucleotides to the chromosome ends [18]. Telomerase consists of two core components; the catalytic subunit, telomerase reverse transcriptase (TERT) [19] and a RNA template (TERC) [20].
Hence, because of the “end-replication problem”, i.e., DNA polymerase
incapacity to maintain telomere length during cell divisions, somatic
cells display gradual telomere shortening with age [21].
Critical loss of telomeric DNA or unprotected telomeres leads to
insufficient chromosomes end protection and to the activation of the DNA
damage response [17].
Damage at telomeres can also happen independently of cell division,
notably in response to the accumulation of oxidative lesions, smoking
behavior, or obesity [22].
While telomere shortening is considered as a protection against tumor
development, loss of telomere function induces cellular senescence and
impairs tissue turnover leading to the aging of the whole organism. The
process of telomere attrition is not constant and differs between people
[23,24],
which can be explained by the impact of inflammation and oxidative
stress on telomere shortening, which differs from one individual to the
other [9]. Globally, telomere health is determined throughout the lifespan by a combination of both genetic and non-genetic factors.
3. Telomere Regulation by Nutrition
Lifestyle
factors such as an unhealthy diet, physical inactivity, or smoking
habits have been related to shorter leukocyte telomere length, a
biomarker of the “biological age” of cells, as opposed to the
“chronological age” [25]. Some studies have reported an association between diet [26,27,28,29,30] or consumption of specific foods [31]
and leukocyte telomere length. To note, the rates of telomere
shortening are similar in leukocytes and somatic cells, so that telomere
length in leukocytes is now accepted to be representative of global
telomere length in somatic cells [32].
3.1. Consumption of Specific Foods
Telomere
length is positively associated with the consumption of legumes, nuts,
seaweed, fruits, and 100% fruit juice, dairy products(Your doctor has a question to answer, other research says this: For each 1 percentage point increase in milk fat consumed (e.g., 1% to
2%), adults had more than 4 years of additional biological aging. ), and coffee,
whereas it is inversely associated with consumption of alcohol, red
meat, or processed meat [27,28,33,34]. Telomere attrition may represent a mechanism by which large sugar intake accelerates cardiometabolic disease [35].
Several studies suggest that reducing sugary beverage consumption could
be associated with extended telomere length, independently of other
characteristics such as age, sex, or body mass index [26,27,28].
Those results indicate that leukocyte telomere length maintenance may
be sensitive to the metabolic effects of high sugar consumption over
time [26].
Leung et al. examined the associations between the consumption of
sugar-sweetened beverages (including soda, soft drinks, fruit-flavored
drinks, sports drinks, and energy drinks), diet soda, fruit juice, and
leukocyte telomere length in 5309 adults aged 20–65 years from the
United States without any history of diabetes or cardiovascular disease [28].
After adjustment for sociodemographic and health-related
characteristics, the consumption of sugar-sweetened beverages was
associated with shorter telomeres, whereas the consumption of 100% fruit
juice was associated with a higher telomere length. No significant
association was observed between consumption of diet soda and telomere
length [28].
As cross-sectional study may not be the most appropriate study design
to assess telomere length, more recently, the same group conducted a
longitudinal study to evaluate the associations between sugary foods and
beverages and leukocyte telomere length in 65 overweight and obese
pregnant women aged between 18 and 45 years. From ≤16 weeks gestation to
9 months postpartum, dietary intake was monitored using 24-h diet
recalls and leukocyte telomere length was measured by real-time
quantitative polymerase chain reaction (qPCR). From the baseline to 9
months post-partum, a low consumption of sugar-sweetened beverages was
associated with longer leukocyte telomere length but no association was
found between sugary foods and leukocyte telomere length [26].
People who regularly eat beans and whole grains are frequently spotlighted for increased longevity [36].
Boressen et al. (2016) tried to determine the feasibility of increasing
navy beans or rice bran intake in colorectal cancer survivors to
increase dietary fiber. The authors hypothesized that an increased
amount of dietary fiber could positively regulate telomere length.
Twenty-nine volunteers participated to a randomized-controlled trial
with foods that included cooked navy beans powder (35 g/day),
heat-stabilized rice bran (30 g/day), or no additional ingredient. The
amount of navy beans powder or heat-stabilized rice bran consumed
represented 4–9% of daily caloric intake. Over the intervention period
of 4 weeks, no major gastrointestinal issues were reported and the
dietary fiber amounts increased in the navy beans and rice bran groups
at weeks 2 and 4 compared to baseline and the control group. At
baseline, peripheral blood mononuclear cell (PBMC) telomere length was
positively correlated with high density lipoprotein (HDL)-cholesterol
and negatively correlated with lipopolysaccharide and age. Although a
higher consumption of navy beans (35 g/day) or rice bran (30 g/day),
known to contain fiber, iron, zinc, thiamin, niacin, vitamin B6, folate,
and alpha-tocopherol, did not influence PBMC telomere length after the
short intervention period of 4 weeks [31],
the effect of a fiber-enriched diet on telomere length should be
investigated in a healthy population over a longer period of time. This
may be highly relevant in the context of colorectal cancer known to be
associated with dysfunctional telomeres [37].
3.2. Diet Composition
While
it is important to be aware of the effects of individual foods, it is
even more critical to assess the role of cumulative nutrients contained
in specific diets on telomere length, which better reflects reality. In
2015, Lee et al. compared the influence of the dietary pattern on
leukocyte telomere length [27].
Dietary data were collected from a semi-quantitative food frequency
questionnaire at baseline and leukocyte telomere length was assessed
using qPCR 10 years later. A total of 1958 middle-aged and older Korean
adults (40–69 years at baseline) were included in the study. The authors
identified two major dietary patterns: “the prudent dietary pattern”
was characterized by a high intake of whole grains, fish and seafood,
legumes, vegetables, and seaweed, whereas the “western dietary pattern”
included a high intake of refined grain, red meat or processed meat, and
sweetened carbonated beverages. Using a multiple linear regression
model adjusted for age, sex, body mass index, and other potential
confounding variables, the “prudent dietary pattern” was found to be
positively associated with leukocyte telomere length while an inverse
trend was found in the “western dietary pattern”. These results suggest
that diet in the remote past, that is, 10 years earlier, may affect the
degree of biological aging in middle-aged and older adults [27].
One
of the best models of healthy eating is the Mediterranean diet which is
characterized by a high intake of vegetables, legumes, nuts, fruits,
and cereals (mainly unrefined); a moderate to high intake of fish; a low
intake of saturated lipids but high intake of unsaturated lipids,
particularly olive oil; a regular but moderate intake of alcohol,
specifically wine [38]. This diet has been shown to prevent age-associated telomere shortening [29,30,39] and has been associated with reduced mortality risk in older people [40].
The possible mechanisms for the protective effect of the Mediterranean
diet on telomeres will be discussed in the next section. In 4676 healthy
women (42–70 years), the higher scores on the Mediterranean diet,
evaluated by food frequency questionnaires, were associated with longer
leukocyte telomere length [30]. In the same study, no association between prudent or western dietary patterns and telomere length was observed [30],
while a prudent diet was previously found to be positively and a
western diet negatively associated with leukocyte telomere length in
1958 middle-aged and older women and men [27].
Similarly, in 217 men and women aged 71–87 years, a greater adherence
to a Mediterranean diet was associated with longer leukocyte telomere
length and higher PBMC telomerase activity [29].
However, a recent study in 679 Australian men and women (57–68 years)
found no association between diet quality and whole blood telomere
length, including the Mediterranean diet. In this study, the authors
assessed the dietary intake by using a 111-item food frequency
questionnaire, which assessed self-reported intake of foods and
beverages over the last 6 months, and the diet quality by three indices:
the Dietary Guideline Index (DGI), the Recommended Food Score (RFS),
and the Mediterranean Diet Score (MDS) [41].
Whole blood telomere length did not differ by age, smoking status, BMI,
or physical activity but women had longer telomeres than men [41].
The discrepant results between studies could be explained by the use of
different questionnaires to assess the diet quality and/or the
populations studied. Longitudinal studies may be more suitable to
determine the potential positive influence of diet on telomere health.
Of note, in animal models, calorie restriction has been shown to have a positive effect on telomere length [42]
and to globally delay the onset of aging and age-related disease such
as diabetes, cardiovascular diseases, various neurological disorders,
cancer, and obesity [43,44], possibly via a reduction in oxidative stress [45,46].
In humans, the data are less convincing, probably because decreasing
the caloric intake by a third or a half is very challenging in that
population, certainly in the long-term.
Having
presented which foods and diets were potentially beneficial for
telomere health in general, the next section will attempt to summarize
the mechanisms involved in those effects.
3.3. Mechanisms
Unhealthy dietary habits have been linked to an inflammatory state, contributing to progressive telomere attrition [47].
As unhealthy dietary habits increase the production of reactive oxygen
species (ROS), it is possible that the impact on telomere erosion goes
through an increased oxidation of telomeric DNA. Supporting this, is the
observation that, because of their high content in guanine residues,
telomeric sequences are highly prone to oxidation into 8-oxoG, at least
in in vitro experiments [48].
When present at telomeres, 8-oxoG residues are likely decreasing the
affinity of shelterin proteins for telomeric DNA and are, as well,
disrupting the G-quadruplex structures of telomeres that play important
roles at telomeres, like the regulation of telomerase activity [49].
Altogether, it is therefore possible that nutrients regulate telomere
health by regulating oxidative stress and systemic inflammation [50].
Globally, it can be hypothesized that any antioxidant or
anti-inflammatory diet could be protective for telomeres by slowing down
telomeric shortening and delay the aging process. The intake of
nutrients having antioxidant and anti-inflammatory properties, such as
vitamin C or E, polyphenols, curcumin, or omega-3 fatty acid, has been
associated with longer telomeres, at least in mouse [51].
The positive effects of the Mediterranean diet on telomeres may be due to its antioxidant and anti-inflammatory potential [52,53].
To understand whether the Mediterranean diet could prevent endothelial
cellular senescence by regulating oxidative stress, the serum of 20
elderly subjects (age > 65 years; 10 men and 10 women) was collected
before and after having randomly followed each of the 3 following diets
for 4 weeks: a Mediterranean diet, a saturated fatty acid diet and a low
fat and high carbohydrate diet [54].
Human endothelial cells incubated with the serum collected after
ingestion of the Mediterranean diet produced lower intracellular ROS,
unavoidable byproducts of aerobic metabolism, and the percentage of
cells with telomere shortening was lower compared to baseline and the
two other intervention diets. The authors postulated that those findings
were possibly due to nutrients with antioxidant capacities included in
the Mediterranean diet [54].
In 2015, a direct association was found between the pro-inflammatory
capacity of the diet and telomere shortening in a population at high
risk of cardiovascular disease. The diets with the higher
pro-inflammatory scores were associated with a higher risk of having
shorter telomeres and a two-fold risk of accelerated telomere shortening
after a five-year follow-up period [47].
At a molecular level, exposure of human leukemic cells to the
pro-inflammatory factor tumor necrosis factor alpha (TNFα) induced a
senescence state, which was featured by prolonged growth arrest,
increased beta-galactosidase activity, cyclin-dependent kinase inhibitor
1 (p21) activation, decreased telomerase activity, telomeric
disturbances such as shortening, losses, and fusions, as well as
additional chromosomal aberrations [55].
Those results indicate that TNFα alters telomere maintenance. Moreover,
subjects with higher adherence to Mediterranean diet had lower
plasmatic level of C-reactive protein (CRP), interleukin 6 (IL-6), TNFα,
and nitrotyrosine, all markers of inflammation and/or oxidative stress [29]. As high levels of oxidative stress [56] and inflammation [57]
are known to increase telomere attrition rate, the Mediterranean diet
may protect telomere maintenance by downregulating both processes.
While
a healthy diet may have an overall positive influence on telomeres, it
seems that the benefit may be reduced in some individuals with specific
genetic background [58]. For example, the rs1800629 polymorphism at the TNFα
gene has been shown to interact with the Mediterranean diet to modify
triglyceride metabolism and inflammation status in patients suffering
from the metabolic syndrome [58].
At baseline, the patients with the GG alleles had higher fasting and
postprandial triglyceride and higher sensitivity C-reactive protein
plasma levels than the patients with the GA or AA alleles. However,
those differences between the polymorphisms observed at baseline
disappeared after having followed a Mediterranean diet for 12 months,
suggesting that the GG carriers were highly sensitive to this specific
diet. Globally, understanding the role of gene–diet interactions may be
an efficient strategy for personalized treatment of specific pathologies
such as metabolic syndrome.
While
some molecular mechanisms have already been highlighted, further
research is needed to better understand how different diets and specific
foods regulate biological aging in order to develop efficient
nutritional strategies according to specific populations.
4. Telomere Regulation by Physical Activity
This
section will deliberately present a positive view regarding the effects
of physical activity on telomere dynamics, but it should be kept in
mind that about half of the studies dealing with that topic found no
association between physical activity and telomere length [13].
Obviously, further investigation will be needed to determine why the
different findings are such discrepant from one study to the other. In
addition, new analytical tools need to be developed to measure telomere
length more accurately as well as new biomarkers for assessing
biological aging [13].
4.1. Dose-Response
The beneficial effect of physical activity on telomere length has been reviewed and discussed by Denham et al. [59].
However, there is currently no clear consensus on the optimal exercise
dose to exert the most beneficial response on telomere health. The
effect of 9 different modes of physical activity, and thereby intensity
levels, on leukocytes telomere length has been tested in US adults
(20–84 years, N = 6503) [60].
The only mode of physical activity displaying an association with
leukocyte telomere length was running, the most intense mode in that
study. Another study used the data of a subgroup of the previously
mentioned cohort (N = 5883) and found a strong positive
association between the weekly amount of physical activity and telomere
length in leukocytes [61].
However, a recent study indicated that moderate amounts of exercise are
sufficient to protect telomere health, while higher amounts may not
elicit additional benefits [62].
In 2010, telomere length was measured in skeletal muscle of 18
experienced middle-aged endurance runners versus 19 sedentary subjects [63].
No difference between groups was found. However, telomere length in the
muscle of endurance athletes was inversely related to the number of
years they spent running and the hours of spent training, which
indicated that high level of chronic endurance could accelerate telomere
attrition and thereby biological aging. More recently, leukocyte
telomere length was determined in 61 young elite athletes and 64 healthy
inactive controls [64].
Even with their high intensity and training volume, the young elite
athlete had longer telomeres than their inactive peers. Finally,
leukocyte telomere length was 11% higher in ultra-marathon runners
compared to 56 healthy subjects, matched for age [65].
Altogether, these results suggest that high amounts of exercise may not
reverse the beneficial impact of exercise on telomere length but
further investigation is needed to see whether tissue-specific
differences exist.
In humans, Diman et al. showed that a high intensity cycling exercise (75% VO2 peak) boosted the transcription of skeletal muscle telomeres more than a moderate intensity exercise (50% VO2 peak) of the same duration [66].
More details on the molecular mechanisms of this observation will be
reported in a following section. In conclusion, due to the paucity of
data, it remains unclear which of the intensity or the volume of each
training session or the combination of both is crucial to induce the
beneficial effects exercise has on telomere maintenance.
4.2. Physical Activity and Telomerase Activity
While physical activity has been associated with longer telomere length and protection against age-related telomere attrition [65,67,68,69,70,71,72],
the mechanisms by which physical activity exerts its positive effects
on telomeres are still largely unknown. As TERT, the catalytic subunit
of the telomerase complex, is considered as the limiting factor for
telomerase activity in human somatic cells, an increase in telomerase
activity after exercise could promote telomere elongation. Chilton et
al. were the first to look at the regulation of telomerase after one
acute bout of exercise [73].
To that end, they investigated the acute exercise-induced response on
telomeric-associated genes and microRNAs (miRNAs), i.e., small noncoding
RNA molecules functioning in RNA silencing and post-transcriptionally
regulating gene expression by base pairing with messenger RNA (mRNA).
Blood samples were taken in 22 healthy young males before, immediately
after, and 60 min after a 30-min bout of treadmill running at 80% VO2
peak. In white blood cells, both TERT and sirtuin-6 (SIRT6) mRNA levels
were increased immediately after exercise. Sixty minutes post-exercise,
there was an upregulation of miR-186 and miR-96 expression, two miRNA
controlling the expression of genes involved in telomere homeostasis [73].
In addition, telomeric repeat binding factor 2, interacting protein
(TERF2IP) was identified as a potential binding target for miR-186 and
miR-96 and demonstrated concomitant downregulation with the upregulation
of those 2 miRNA at 60 min post-ex. TERF2IP is part of the shelterin
complex and is recruited to telomeres via interaction with TRF2 [74]. TERF2IP deletion reduces telomere stability and increases telomere recombination [75]. However, TERF2IP/RAP1 has been found to be both a negative [76] and a positive regulator of telomere length [74].
Interestingly, TERF2IP/RAP1 is also known to play additional
telomere-unrelated functions through the binding to extra-telomeric
sites in the genome. Several regulatory functions have been attributed
to the binding of TERF2IP/RAP1 outside telomeres, including the
modulation of the nuclear factor-kappa B (NF-kB)-dependent pathway [77]. Whether the non-telomeric functions of TERF2IP/RAP1 play any role after exercise however warrants further investigation.
A
very recent study tested whether an acute bout of exercise would induce
a different response on telomerase activity in older vs. young
individuals and whether this response would be gender-specific [78].
To test this hypothesis, age- and gender-related differences in
telomerase and shelterin responses at 30, 60, and 90 min after a high
intensity interval cycling exercise were determined in PBMC of 11 young
(22 years) and 8 older (60 years) men and women. A larger increase in
telomerase activity, as assessed by TERT mRNA levels, was found in the
young compared to the older group after exercise [78].
The second main finding of that study was the higher TERT response to
the acute endurance exercise in men compared to women, in whom the
response was negligible, independently of age. Those results showed that
aging is associated with reduced telomerase activation in response to
high-intensity cycling exercise in men [78].
Another study showed that a 30-min treadmill running session was long
enough to increase PBMC telomerase activity in 22 young healthy subjects
including 11 women and 11 men [79].
Altogether, those recent studies confirm that the increasing telomerase
activity after a single bout of exercise could be one of the mechanisms
by which physical activity protects against aging [73,78,79].
Nevertheless,
the increase in telomerase activity seems transient after acute
exercise. The effect of a whole training program on telomerase activity
and telomere length was investigated in 68 female and male caregivers, a
population known to cope with chronic high stress, physical inactivity,
and dealing with a high risk of disease [80].
Half of the subjects followed an endurance training program consisting
in 40 min of aerobic exercise 3–5 times per week, while the other half
remained inactive for 24 weeks. In aerobic trained caregivers, the
leukocyte telomere length was lengthened after training while the
telomere length was slightly shortened in the inactive group, as would
be expected over a six month-period. However, no change in PBMC
telomerase activity after the intervention was observed in either group [80].
Together with the findings from the acute exercise studies, it can be
hypothesized that exercise-induced higher telomerase activity in PBMC
may be a transient mechanism returning to basal level several hours
after a single bout of exercise, though the exact kinetics still needs
to be determined. In addition, telomerase is not active in all cell
types, which implies that other mechanisms contribute to the
exercise-induced beneficial effects on telomere length and integrity in
those cells.
4.3. Physical Activity and Oxidative Stress
It
is well established that moderate and regular physical activity is able
to reduce the effect of aging by alleviating oxidative stress level [81].
Recently, an inverse relationship between the aerobic capacity and
oxidative stress biomarkers in the blood was found in older Mexican
adults [82]. Moreover, several studies indicate that oxidative stress accelerates telomere attrition [83,84,85].
Mechanistically,
exercise transiently upregulates ROS production, which is counteracted
by an antioxidant exercise-induced systemic adaptation response to
protect the cells against oxidative damage [86,87].
This antioxidant response can be explained by the hormesis concept,
namely that low levels of stress stimulate existing cellular and
molecular pathways that improve the capacity of cells and organisms to
withstand subsequent greater stress [88]. The antioxidant response leads to the activation of redox-sensitive transcription factors such as NF-kB, activator-protein 1 (AP-1) [89], and co-factors such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) [81,90].
As a metabolic energy deprivation sensor, AMP-activated protein kinase
(AMPK) is activated by exercise and triggers PGC-1α transcription and
activation by allowing its nuclear translocation [91].
Once in the nucleus, PGC-1α induces the transcription of nuclear
respiratory factor 1 (NRF1), an antioxidant factor. By activating the
PGC-1α redox signaling pathway, exercise stimulates mitochondrial
biogenesis and ameliorates the age-related decline in mitochondrial
oxidative capacity [90].
4.4. Physical Activity and Regulation of TERRA
Mature
muscle cells are one example of cells in which telomerase is not active
and despite the absence of telomerase activity, physical activity has
been shown to influence positively telomere length in skeletal muscle [92].
In the search of additional mechanisms, telomeric repeat containing
RNAs, dubbed TERRA, have emerged as particularly interesting targets.
For a long time, telomeres have been considered transcriptionally
silent. Yet it turns out that telomeres are transcribed into TERRA
molecules [93].
Located in the nucleus, TERRA are non-coding RNAs whose transcription
is initiated from subtelomeric promoters. They consist of
subtelomeric-derived sequences and G-rich telomeric repeats [93,94]. Once transcribed, TERRA remain partly associated with telomeres to play crucial functions, including telomere protection [95].
Diman et al. identified NFR1 as an important regulator of human
telomere transcription in cultured cells. In addition to NRF1, PGC-1α as
well as AMPK were found to be important molecular intermediates in the
transcription of telomeres. As AMPK can be activated by high-intensity
or long-lasting endurance exercise, it was tested in vivo whether an
acute endurance exercise bout could upregulate telomere transcription in
human skeletal muscles. Ten healthy young volunteers were submitted to a
cycling endurance exercise of either low or high intensity and three
muscle biopsies were taken before, directly after, and 2 h 30 min after
exercise. Phosphorylation of acetyl-Coa carboxylase (ACC), a bona fide
marker of AMPK activation, was induced after exercise, especially in the
high intensity group. The same pattern of activation was found for the
translocation of PGC-1α to the nucleus and for TERRA induction. As
telomere transcription is activated by NRF1, an antioxidant factor, the
upregulation of TERRA may be part of the antioxidant response that
skeletal muscles set up to counteract exercise-induced ROS production [86].
Moreover, as they consist of a high content in guanine residues prone
to oxidation, TERRA may possibly shield TTAGGG telomeric repeats from
ROS [66].
Together, those results suggest that an acute bout of endurance
exercise is sufficient to induce telomere transcription that, on a
longer term, could possibly provide a mechanism for TERRA renewal and
telomere protection in skeletal muscle.
5. Conclusions
Nowadays,
the aging of the world population has major social and economic
implications. Today more than ever, highlighting strategies to
counteract age-related diseases is a major public health concern. In
this review, we explored data from recently published studies looking at
the influence of lifestyle variables such as nutrition and physical
activity on one of the most important hallmarks of aging: the telomere.
Most
studies indicate an important role of diet on the degree of biological
aging. Indeed, a healthy diet characterized by a high intake of dietary
fiber and unsaturated lipids exerts a protective role on telomere
health, whereas high consumption of sugar and saturated lipids
accelerates telomere attrition. Those effects are likely to be globally
mediated by oxidative stress and inflammation, as antioxidant and
anti-inflammatory properties of nutrients are associated with longer
telomeres. Physical activity may protect telomeres but more research is
needed to establish a consensus on the optimal exercise dose (Figure 2).
The beneficial effects of physical activity on telomeres could be
driven by an increase in telomerase activity following an acute bout of
exercise in PBMC, an alleviation of oxidative stress and a TERRA renewal
in skeletal muscle. Further investigations are needed to study the
other possible mechanisms contributing to the exercise-induced
beneficial effects on telomere length and integrity.
Potential influence of physical activity and nutrition on telomere health.
We
propose that engaging in a healthy diet and regular physical activity
could be both promising strategies to protect telomere maintenance and
improve health span at old age. However, more research on the molecular
based mechanisms is required.
Although dairy has gotten a bad rap, researchers of two recent studies have shown that it actually decreases risk of mortality.