IntroductionOne ofthe main causes for elderly to enter a nursing home is due to disabilities thatmake it more difficult for them to take care of themselves. It has beencalculated by Goates et al(1) that per year the cost of hospitalizations causedboth 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. Ithas been estimated that sarcopenia is the leading cause for 2% to 5% of thedecrease in mobility in elderly people above the age of 70(2).

After the age of 70 years, there is a decrease inmuscle mass of 10% to 15% per decade, where the damage caused by sarcopenia canbe measured through strength and physical performance. There are variousnegative consequences due to the development of sarcopenia, including an increaseof insulin resistance and a decrease in the Vo2-Max. Other syndromes related tosarcopenia include frailty, hyperplasia and atrophy(3). At the moment, the only treatment available for thisdisease is exercising with the method of resistance training and endurancetraining(4, 5). This procedure helps to prevent and reverse thesarcopenia. Nevertheless, the treatment is not favored by the elderly(2), probably due the general loss of mobility caused byageing, making it more difficult to perform the trainings.

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Therefore, there isstill a growing need for research on sarcopenia that could lead to moreavailable pharmaceutical options to relieve the symptoms, as well as cure thedisease. A promising treatment with testosterone administration has alreadyshown that muscle mass could be increased to counter sarcopenia(6). Treatment of sarcopenia could lead to a decrease ofelderly needing to be institutionalized into a nursing home, and decrease thecost to take care of the elderly (7). Additionally, as sarcopenia influences various othersyndromes, it is a significant area of research that should be investigated, asit will effect a large population.            Consequently, this review is to investigate and gather insight on the ageingdisease sarcopenia. The main subjects that will be discussed in relation tosarcopenia are the pathogenesis of the disease, the link of sarcopenia to thehallmarks of ageing, the role of genetics in the disease, the effects of lifestyleon sarcopenia and possible treatments and interventions. MethodArticlesthat were reviews as well as experimental studies were looked at to gain abetter understanding on sarcopenia.

The Maastricht University ‘LibSearch’ wasused as a search tool, where key phrases such as ‘sarcopenia’, ‘hallmarks ofageing’, ‘muscle loss’, ‘sarcopenia exercise’, ‘pathogenesis sarcopenia’,‘sarcopenia testosterone’, ‘sarcopenia insulin’ and ‘hallmarks of cancer’ wereentered.Pathogenesis of the diseaseThe EuropeanWorking Group On Sarcopenia in older people defined sarcopenia as “a syndromecharacterised by a progressive and generalised loss of skeletal muscle mass andstrength with a risk of adverse outcomes such as disability, poor quality oflife and death” (8).The changes in muscle mass are multifactorialprocesses. Firstly, an imbalance between the protein production and theirdegradation occurs.

Indeed, skeletal muscle in older populations have shown anamino acid anabolic resistance leading to a decrease in both type I myofibers(slow contractions) and type II myofibers (rapid contractions), startingearlier in type II (9, 10). As a consequence an atrophy (a decrease in size) andhypoplasia (a decrease in numbers), of the muscle fibres (9, 10). Furthermore, insulin also plays a role in inhibitionof protein catabolism. In a dose-dependent way, insulin inhibits proteolysis(11). With ageing, the sensitivity to insulin decreasesand the responsiveness to inhibition is lower in elderly, than in youngerpeople (11).

However, the underlying mechanism is currently underinvestigation. Both features have been shown in a research where proteinnutrition with insulin clamping and an increase of exercise were investigated (10, 11). Secondly, a decreasing innervation of the musclefibres occurring in older people also plays a role in the muscle mass loss (9). It has been suggested that ageing leads to adecrease in axonal sprouting and a diminished capacity of the remaining axonaltree to reinnervate the muscle fibres (12, 13). This lack of reinnervation can result in adegeneration of muscle fibres which leads to an inevitable hypoplasia of themuscle (13). Thirdly, an increased presence of reactive oxygenspecies (ROS) in the ageing tissues could lead to damage to the structure dueto the oxidative stress(9).

However, two types of oxidation have to beconsidered. The reversible type is the oxidation of thiol proteins. This typeof oxidation may play a major role in modulating many proteins but it is stillunder investigation (9, 14). The irreversible type is more dramatic. Theoxidation of proteins leads to a build-up of a pigment in tissue, known aslipofuscin, and it is a marker of ageing for tissues(9, 15).

ROS also play a role in the degradation of axons, asmentioned earlier, by destroying the Schwann cells surrounding the axons(12).Relationship with(ab)normal development      The studied disease does not have adevelopmental aspect linked to it. Sarcopenia is linked to normal ageing, andthe normal hallmarks of ageing (8, 9). Later on, the influence of certain lifestyle characteristicson the development of sarcopenia will be discussed.Influence of Genetics    Muscle mass and muscle strength, two ofthe most acknowledged and studied risk phenotypes for sarcopenia, have beenreported to have a strong genetic determination. The heritability (h2)of muscle strength phenotypes ranges from 30 to 85%, depending on theconditions of the strength measure such as velocity, contraction angle and type(16), while muscle mass has an h2 ranging from45 to 90%(17). An 80% heritability of lean body mass was reportedby Bouchard et al(18).

The identification of genetic factorsimportant to skeletal muscle strength is extremely hard. There are multiplestrength variables, including different musclegroups, contraction types and measurement instruments, that are commonlymeasured in different studies. Additionally, genes contribute to differentaspects of strength that might not be taken into account in differentmeasurement types. When a gene is found to be important in multiple strengthmeasurements, the likelihood that the gene is important to muscle strengthimproves greatly(19).

Only one study has specifically investigated genesin relation to skeletal muscle strength and mass phenotypes targetingsarcopenia. The influence of Vitamin D Receptor (VDR) sequence variants onmuscle strength and mass, was analyzed. VDR has a key regulatory role in calciumhomeostasis and skeletal muscle function(20). VDR FokI genotype was shown to be significantlyassociated with lean mass and sarcopenia (20). There is little evidence of the association betweenVitamin D and sarcopenia. Research has shown that Vitamin D supplementation for2 years increased type II muscle fiber diameter (21).

Type II muscle fibers, which are declined insarcopenia, have a critical role in this fast reaction. Vitamin D is consideredto reduce the risk of falling by combined effects on bone and muscle (22).    Angiotensin converting enzyme (ACE) alleles play a role in the efficiency ofmuscle contraction. A deficiency in the alpha-actin 3 (ACTN3) gene, which isresponsible for anchoring the actin filaments to the 2-disk in fast twitchfibers, is associated with reduced power (10, 23, 24). ACE inhibitors are known to improve endothelialfunction, increase muscle glucose uptake, increase potassium levels andmodulate other hormonal systems including IGF-1, all of which could contributeto improved skeletal muscle function (25).

Despite the findings in this field of research, thegenetic influences of skeletal muscle traits remain largely unknown and thegenetic aspects of sarcopenia are even less clear (19). Finally, there are several different aspects otherthan genetic factors that contribute to sarcopenia-related traits anddevelopmental and environmental factors should not be forgotten in furtherprevention and treatment research (19).Mitochondrialdysfunction is one of the hallmarks of ageing and is particularly relevant intissues with a high oxidative capacity such as skeletal muscle (26). Mitochondrial dysfunction and reduced oxidativecapacity in skeletal muscle have been found to be in relationship with thepathogenesis of sarcopenia(27).

Many studies report the association between ageingand decreased mitochondrial function and content in skeletal muscle. A study byBroksey et al(28) has reported that physical fitness is correlated withmitochondrial density in skeletal muscle. Furthermore, Broksey et al(28) as well as Gram et al(29) confirm that in response to physical activity, ageingdoes not independently prevent mitochondrial biogenesis and it is more likelythat a decrease in mitochondrial function recognized in elderly is due todecreased exercise.

In addition, an increase in mitochondrial reactive oxygenspecies (ROS) and apoptosis induction could be a primary cause for sarcopenia(30). The percentage of apoptosis is more likely toincrease with age, being more outstanding in type II fibers (31). The activation of apoptotic signaling occurringafter mitochondrial dysfunction most likely contributes to sarcopenia(32). The activation of apoptosis signaling is believed tobe 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 increasein plasma levels and cell capability to produce proinflammatory cytokines and areduction of anti-inflammatory cytokines characterize ageing(34, 35).

High levels of interleukin IL-6, tumor necrosisfactor alpha (TNF-?), whiteblood cells (WBC) and C-reactive protein (CRP) have been associated withphysical performance in the sense of poor function and mobility status (36, 37). These markers could explain the relationship betweenan increase of inflammatory cytokines and a decline in physical activity andmobility (38). Schaap et al.(39) reported that among all the inflammatory markers(IL-6, CRP, and TNF-?), TNF-? and its soluble receptor showed the strongestassociations 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 ofmyofibrillar proteins via the inhibition mammalian target of rapamycin (mTOR)signaling pathway. In line with this, recent evidence shows that inflammationmight be a factor in the generation of mitochondrial dysfunction (41).

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

Diet isvery closely related to sarcopenia as well as physical activity. Older peoplewill gradually eat less, this development is called the ‘anorexia of ageing’.The loss of sense of taste and smell, poor oral health, dementia andage-related changes in the loss of appetite are several examples of factorsinfluencing this development. A decrease in neuropeptide Y prevalence is foundto be one of the causes for these characteristics of the decrease in caloricintake.

Neuropeptide Y is also related to leptin and ghrelin; the‘hunger-hormone’ (42). Next to that, the decrease in functioning of theCentral Nervous System (CNS) over time is a cause for this, as explained before(12). Possible treatments andinterventionsExercisingcan 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 musclemass and therefore, the physical performance of the subject (43). Resistance training is the type of exercise that ismostly efficient as a real treatment for sarcopenia. Next to that, endurancetraining is also thought to be effective against sarcopenia (5).

For these studies, the researchers had the subjectsadhere to a certain program which included 3 training days a week (with a dayof rest between every training-day) for 3 to 4 months (4, 5). What actually changes by exercising that has apositive influence on sarcopenia, is the protein synthesis in the muscles (4). There is an increase in protein synthesis, increasein 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 crosssectional area of the muscle.

Another aspect of sarcopenia is the decreased autophagyof the cells (46, 47). Autophagy is the regulated destruction of severalcell components and is linked to sarcopenia (48). Exercising will counter this defect of the cell andcould reverse the decreased autophagy tremendously. Additionally, the musclefatigue will decrease and the strength will increase because of this reversal.                 Other researchers have looked into the relationship between the functioning ofthe mitochondria and sarcopenia. A study by Short et al (49) showed that subjects who had followed a relativelyintense training program (16 weeks, 4 trainings a week, 80% of maximal heartrate for 40 minutes), had an increased Vo2-Max, an increased activity ofmitochondrial enzymes and an increase in mRNA levels of mitochondrial genes.These findings prove that with such a way of exercising, the biogenesis ofmitochondria 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, cardiovasculardiseases, broken bones or disorders influencing the respiration, are allexamples why older people may not be able to exercise well enough anymore. Lackof motivation might play a major part as well. Fortunately, administration oftestosterone was found to be effective in the treatment of sarcopenia. Levelsof testosterone decrease with age, and so does the performance of the muscles (6).

In experimental studies, it was concluded thattestosterone administration to males aged 65 years, or older, increased musclemass, strength and physical performance (6, 50). A randomized controlled trial by Travison, et al (51) found that there was an increase in muscle strengthand physical function in community-dwelling men. However, during the trialseveral cardiovascular incidents happened with the men who received thetestosterone, instead of  the placebo, which caused the organizers to stopthe trial immediately. Currently there are a lot of trials going on withdifferent concentrations of testosterone to avoid these adverse effects. Borstand Yarrow (52) are currently seeing if there is a different responsewith a different administration of the testosterone; injection instead of oraltreatment.

ConclusionIn this review paper several aspects of sarcopeniawere discussed including the pathogenesis, the influence of genetics andlifestyle, and various possible treatments. Currently there are manyexperimental studies going on with different pharmaceutical treatments, likeGH, beta-Hydroxy beta-methylbutyricacid and Bimagrumab(53). A treatment for sarcopenia should be developed since it is such a largeproblem in our society