Introduction

One of
the main causes for elderly to enter a nursing home is due to disabilities that
make it more difficult for them to take care of themselves. It has been
calculated by Goates et al(1) that per year the cost of hospitalizations caused
both directly, and indirectly by sarcopenia in the United States of America is
$18.4 billion. Sarcopenia is the increasing loss of muscle mass with ageing. It
has been estimated that sarcopenia is the leading cause for 2% to 5% of the
decrease in mobility in elderly people above the age of 70(2). After the age of 70 years, there is a decrease in
muscle mass of 10% to 15% per decade, where the damage caused by sarcopenia can
be measured through strength and physical performance. There are various
negative consequences due to the development of sarcopenia, including an increase
of insulin resistance and a decrease in the Vo2-Max. Other syndromes related to
sarcopenia include frailty, hyperplasia and atrophy(3). At the moment, the only treatment available for this
disease is exercising with the method of resistance training and endurance
training(4, 5). This procedure helps to prevent and reverse the
sarcopenia. Nevertheless, the treatment is not favored by the elderly(2), probably due the general loss of mobility caused by
ageing, making it more difficult to perform the trainings. Therefore, there is
still a growing need for research on sarcopenia that could lead to more
available pharmaceutical options to relieve the symptoms, as well as cure the
disease. A promising treatment with testosterone administration has already
shown that muscle mass could be increased to counter sarcopenia(6). Treatment of sarcopenia could lead to a decrease of
elderly needing to be institutionalized into a nursing home, and decrease the
cost to take care of the elderly (7). Additionally, as sarcopenia influences various other
syndromes, it is a significant area of research that should be investigated, as
it will effect a large population.           

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Consequently, this review is to investigate and gather insight on the ageing
disease sarcopenia. The main subjects that will be discussed in relation to
sarcopenia are the pathogenesis of the disease, the link of sarcopenia to the
hallmarks of ageing, the role of genetics in the disease, the effects of lifestyle
on sarcopenia and possible treatments and interventions.

Method

Articles
that were reviews as well as experimental studies were looked at to gain a
better understanding on sarcopenia. The Maastricht University ‘LibSearch’ was
used as a search tool, where key phrases such as ‘sarcopenia’, ‘hallmarks of
ageing’, ‘muscle loss’, ‘sarcopenia exercise’, ‘pathogenesis sarcopenia’,
‘sarcopenia testosterone’, ‘sarcopenia insulin’ and ‘hallmarks of cancer’ were
entered.

Pathogenesis of the disease

The European
Working Group On Sarcopenia in older people defined sarcopenia as “a syndrome
characterised by a progressive and generalised loss of skeletal muscle mass and
strength with a risk of adverse outcomes such as disability, poor quality of
life and death” (8).The changes in muscle mass are multifactorial
processes. Firstly, an imbalance between the protein production and their
degradation occurs. Indeed, skeletal muscle in older populations have shown an
amino acid anabolic resistance leading to a decrease in both type I myofibers
(slow contractions) and type II myofibers (rapid contractions), starting
earlier in type II (9, 10). As a consequence an atrophy (a decrease in size) and
hypoplasia (a decrease in numbers), of the muscle fibres (9, 10). Furthermore, insulin also plays a role in inhibition
of protein catabolism. In a dose-dependent way, insulin inhibits proteolysis(11). With ageing, the sensitivity to insulin decreases
and the responsiveness to inhibition is lower in elderly, than in younger
people (11). However, the underlying mechanism is currently under
investigation. Both features have been shown in a research where protein
nutrition with insulin clamping and an increase of exercise were investigated (10, 11). Secondly, a decreasing innervation of the muscle
fibres occurring in older people also plays a role in the muscle mass loss (9). It has been suggested that ageing leads to a
decrease in axonal sprouting and a diminished capacity of the remaining axonal
tree to reinnervate the muscle fibres (12, 13). This lack of reinnervation can result in a
degeneration of muscle fibres which leads to an inevitable hypoplasia of the
muscle (13). Thirdly, an increased presence of reactive oxygen
species (ROS) in the ageing tissues could lead to damage to the structure due
to the oxidative stress(9). However, two types of oxidation have to be
considered. The reversible type is the oxidation of thiol proteins. This type
of oxidation may play a major role in modulating many proteins but it is still
under investigation (9, 14). The irreversible type is more dramatic. The
oxidation of proteins leads to a build-up of a pigment in tissue, known as
lipofuscin, and it is a marker of ageing for tissues(9, 15). ROS also play a role in the degradation of axons, as
mentioned earlier, by destroying the Schwann cells surrounding the axons(12).

Relationship with
(ab)normal development     
The studied disease does not have a
developmental aspect linked to it. Sarcopenia is linked to normal ageing, and
the normal hallmarks of ageing (8, 9). Later on, the influence of certain lifestyle characteristics
on the development of sarcopenia will be discussed.

Influence of Genetics   
Muscle mass and muscle strength, two of
the most acknowledged and studied risk phenotypes for sarcopenia, have been
reported to have a strong genetic determination. The heritability (h2)
of muscle strength phenotypes ranges from 30 to 85%, depending on the
conditions of the strength measure such as velocity, contraction angle and type
(16), while muscle mass has an h2 ranging from
45 to 90%(17). An 80% heritability of lean body mass was reported
by Bouchard et al(18).
The identification of genetic factors
important to skeletal muscle strength is extremely hard. There are multiple
strength variables, including different muscle
groups, contraction types and measurement instruments, that are commonly
measured in different studies. Additionally, genes contribute to different
aspects of strength that might not be taken into account in different
measurement types. When a gene is found to be important in multiple strength
measurements, the likelihood that the gene is important to muscle strength
improves greatly(19). Only one study has specifically investigated genes
in relation to skeletal muscle strength and mass phenotypes targeting
sarcopenia. The influence of Vitamin D Receptor (VDR) sequence variants on
muscle strength and mass, was analyzed. VDR has a key regulatory role in calcium
homeostasis and skeletal muscle function(20). VDR FokI genotype was shown to be significantly
associated with lean mass and sarcopenia (20). There is little evidence of the association between
Vitamin D and sarcopenia. Research has shown that Vitamin D supplementation for
2 years increased type II muscle fiber diameter (21). Type II muscle fibers, which are declined in
sarcopenia, have a critical role in this fast reaction. Vitamin D is considered
to reduce the risk of falling by combined effects on bone and muscle (22).   
Angiotensin converting enzyme (ACE) alleles play a role in the efficiency of
muscle contraction. A deficiency in the alpha-actin 3 (ACTN3) gene, which is
responsible for anchoring the actin filaments to the 2-disk in fast twitch
fibers, is associated with reduced power (10, 23, 24). ACE inhibitors are known to improve endothelial
function, increase muscle glucose uptake, increase potassium levels and
modulate other hormonal systems including IGF-1, all of which could contribute
to improved skeletal muscle function (25). Despite the findings in this field of research, the
genetic influences of skeletal muscle traits remain largely unknown and the
genetic aspects of sarcopenia are even less clear (19). Finally, there are several different aspects other
than genetic factors that contribute to sarcopenia-related traits and
developmental and environmental factors should not be forgotten in further
prevention and treatment research (19).

Mitochondrial
dysfunction is one of the hallmarks of ageing and is particularly relevant in
tissues with a high oxidative capacity such as skeletal muscle (26). Mitochondrial dysfunction and reduced oxidative
capacity in skeletal muscle have been found to be in relationship with the
pathogenesis of sarcopenia(27). Many studies report the association between ageing
and decreased mitochondrial function and content in skeletal muscle. A study by
Broksey et al(28) has reported that physical fitness is correlated with
mitochondrial density in skeletal muscle. Furthermore, Broksey et al(28) as well as Gram et al(29) confirm that in response to physical activity, ageing
does not independently prevent mitochondrial biogenesis and it is more likely
that a decrease in mitochondrial function recognized in elderly is due to
decreased exercise. In addition, an increase in mitochondrial reactive oxygen
species (ROS) and apoptosis induction could be a primary cause for sarcopenia(30). The percentage of apoptosis is more likely to
increase with age, being more outstanding in type II fibers (31). The activation of apoptotic signaling occurring
after mitochondrial dysfunction most likely contributes to sarcopenia(32). The activation of apoptosis signaling is believed to
be the final common pathway of sarcopenia (33). 
Another hallmark of the ageing process is low-grade chronic inflammation (34). Many different studies show that a general increase
in plasma levels and cell capability to produce proinflammatory cytokines and a
reduction of anti-inflammatory cytokines characterize ageing(34, 35). High levels of interleukin IL-6, tumor necrosis
factor alpha (TNF-?), white
blood cells (WBC) and C-reactive protein (CRP) have been associated with
physical performance in the sense of poor function and mobility status (36, 37). These markers could explain the relationship between
an increase of inflammatory cytokines and a decline in physical activity and
mobility (38). Schaap et al.(39) reported that among all the inflammatory markers
(IL-6, CRP, and TNF-?), TNF-? and its soluble receptor showed the strongest
associations with muscle mass and strength decrease. Additionally, Frost et al.(40) proved that high levels of TNF-? can increase muscle catabolism. They show that TNF-? can decrease transcription and translation of
myofibrillar proteins via the inhibition mammalian target of rapamycin (mTOR)
signaling pathway. In line with this, recent evidence shows that inflammation
might be a factor in the generation of mitochondrial dysfunction (41).

Influences
of lifestyle on sarcopenia     
One of the major factors affecting the
presence and severeness of sarcopenia is the level of physical activity. As
people get older, they will get ill more often, this will provoke a situation
in which the older people have to stay in bed and will not be able to move
enough. Also, older people will not be working anymore, thus have a decreased
physical activity. Another reason that older people will be less active is that
their muscles and bones will lose strength, causing a positive feedback loop:
The muscles and bones will get weaker; the older person will move less; less
activity in the muscles; even more decreased performance.

Diet is
very closely related to sarcopenia as well as physical activity. Older people
will gradually eat less, this development is called the ‘anorexia of ageing’.
The loss of sense of taste and smell, poor oral health, dementia and
age-related changes in the loss of appetite are several examples of factors
influencing this development. A decrease in neuropeptide Y prevalence is found
to be one of the causes for these characteristics of the decrease in caloric
intake. Neuropeptide Y is also related to leptin and ghrelin; the
‘hunger-hormone’ (42). Next to that, the decrease in functioning of the
Central Nervous System (CNS) over time is a cause for this, as explained before(12).

 

Possible treatments and
interventions

Exercising
can either be a way of treatment for sarcopenia, or a way of prevention.
Exercising is known to be increasing the strength of the muscles, the muscle
mass and therefore, the physical performance of the subject (43). Resistance training is the type of exercise that is
mostly efficient as a real treatment for sarcopenia. Next to that, endurance
training is also thought to be effective against sarcopenia (5). For these studies, the researchers had the subjects
adhere to a certain program which included 3 training days a week (with a day
of rest between every training-day) for 3 to 4 months (4, 5). What actually changes by exercising that has a
positive influence on sarcopenia, is the protein synthesis in the muscles (4). There is an increase in protein synthesis, increase
in muscle strength and muscle hypertrophy (44, 45). The studies by Mayhew et al (44) and Williamsom et al (45) define muscle hypertrophy as an increase in cross
sectional area of the muscle. Another aspect of sarcopenia is the decreased autophagy
of the cells (46, 47). Autophagy is the regulated destruction of several
cell components and is linked to sarcopenia (48). Exercising will counter this defect of the cell and
could reverse the decreased autophagy tremendously. Additionally, the muscle
fatigue will decrease and the strength will increase because of this reversal.                
Other researchers have looked into the relationship between the functioning of
the mitochondria and sarcopenia. A study by Short et al (49) showed that subjects who had followed a relatively
intense training program (16 weeks, 4 trainings a week, 80% of maximal heart
rate for 40 minutes), had an increased Vo2-Max, an increased activity of
mitochondrial enzymes and an increase in mRNA levels of mitochondrial genes.
These findings prove that with such a way of exercising, the biogenesis of
mitochondria and the mitochondrial function can be improved during ageing.    
Unfortunately, a large part of the elderly who are a victim of sarcopenia,
are not able to exercise as described already. Replaced joints, cardiovascular
diseases, broken bones or disorders influencing the respiration, are all
examples why older people may not be able to exercise well enough anymore. Lack
of motivation might play a major part as well. Fortunately, administration of
testosterone was found to be effective in the treatment of sarcopenia. Levels
of testosterone decrease with age, and so does the performance of the muscles (6). In experimental studies, it was concluded that
testosterone administration to males aged 65 years, or older, increased muscle
mass, strength and physical performance (6, 50). A randomized controlled trial by Travison, et al (51) found that there was an increase in muscle strength
and physical function in community-dwelling men. However, during the trial
several cardiovascular incidents happened with the men who received the
testosterone, instead of  the placebo, which caused the organizers to stop
the trial immediately. Currently there are a lot of trials going on with
different concentrations of testosterone to avoid these adverse effects. Borst
and Yarrow (52) are currently seeing if there is a different response
with a different administration of the testosterone; injection instead of oral
treatment.

Conclusion
In this review paper several aspects of sarcopenia
were discussed including the pathogenesis, the influence of genetics and
lifestyle, and various possible treatments. Currently there are many
experimental studies going on with different pharmaceutical treatments, like
GH, beta-Hydroxy beta-methylbutyric
acid and Bimagrumab(53). A treatment for sarcopenia should be developed since it is such a large
problem in our society