Keywords

Introduction

Menopause and Skeletal Muscle Mass

Menopause is widely associated with profound changes in body composition. Evidence suggests that women increase in body fatness with age, and that this change may be accelerated with the onset of menopause. Indeed, fat mass and lean mass appear to be stable in the premenopausal years, whereas a linear decline in lean mass is noted in postmenopausal women, along with an increase in fat mass. Moreover, the loss of lean mass (and by extrapolation skeletal muscle mass) is paralleled by changes in characteristics of muscle tissue. For instance, postmenopausal women have been reported to have twice the amount of non-contractile muscle tissue, such as intramuscular fat, compared to younger women [1]. Various mechanisms have been put forth to explain the change in total skeletal muscle mass. This is primarily due to an imbalance between muscle protein synthesis and muscle protein breakdown, and the increase of catabolic factors such as oxidative stress and inflammation, but other factors such as decline in hormonal levels, decreased resting metabolic rate, a loss of neuromuscular function, and apoptosis are thought to be implicated in this inevitable process. Controllable factors such as physical activity and diet are also involved. Although these factors are not specific to menopause, it appears that they are exacerbated by changes in this status. Nevertheless, the combination of these factors directly promotes the emergence of “sarcopenia” with advancing age in women.

The term sarcopenia is derived from the Greek words sarx (flesh) and penia (loss) and was created by Rosenberg in 1989 to refer to the age-related loss in skeletal muscle mass and size with normal aging [2]. Sarcopenia is determined by two factors: the initial amount of skeletal muscle mass and the rate at which it declines with age. Results from longitudinal studies indicate that muscle mass and size decrease by approximately 6 % per decade past the age of 50 years. Therefore, an 85-year-old woman will have a skeletal muscle mass that is three-quarters of what it was when she was 45 years old. Unfortunately, it appears that skeletal muscle mass loss is inevitable. However, it is important to note that there are considerable interindividual differences in both peak skeletal muscle mass and the rate at which it declines, depending on the lifestyle of the individual.

Rather than defining sarcopenia as a process that all aging individuals go through, it was proposed that an operational threshold be used to identify older persons who have low skeletal muscle mass values, qualifying them as sarcopenic [3]. Modeled on the definition of osteoporosis, type I sarcopenia was then defined as height-adjusted skeletal muscle mass of 1–2 standard deviations below the mean of a young adult reference population and type II sarcopenia as an index of 2 standard deviations or more below the same value. Since skeletal muscle mass is not routinely measured or measurable, other indices are then used. Total and appendicular lean mass are the main indices used. Although their definition is not strictly that of skeletal muscle, it is widely accepted that changes in lean mass are representative of changes in muscle mass (since bone mass only represents a small portion of lean body mass). Depending on the studies cited in this chapter, the two terms can be used. Type II sarcopenia is very common in older women with a prevalence from 5 to 13 % in the sixth decade and of 11–50 % in the eighth decade. Furthermore, it was reported that the prevalence of type I and type II sarcopenia was 50 % and 7 % respectively in women aged between 50 and 59 years old. This is a 15 % increment in the prevalence of type I sarcopenia compared to women aged 40–49 years [4], suggesting again a concordance between the increase in the prevalence of sarcopenia increases and significant changes in the hormonal status that occur in women at menopause.

Sarcopenia and Its Consequences

A primary rationale for studying the age-related loss in skeletal muscle mass is the belief that the loss of skeletal muscle mass is indicative of a loss of skeletal muscle strength and function. Thus, in the causal chain, sarcopenia was thought to cause a loss in muscle strength, which in turn would cause functional impairment and physical disability. Most research on the health implication of sarcopenia focused on physical function outcomes, such as the difficulty to perform activities of daily living (self-care tasks) and instrumental activities of daily living (tasks necessary for an individual to live independently in a community). The first evidence, based on cross-sectional studies, suggested that the association between sarcopenia and physical function were moderate to strong in magnitude (Fig. 14.1). However, findings from recent longitudinal studies showed that the effects of sarcopenia on functional impairment and physical disability were overestimated. While it has been postulated that sarcopenia contributes to metabolic and cardiovascular diseases, such as insulin resistance, type II diabetes, dyslipidemia, and hypertension, the literature is also mixed and, in general, does not support this assumption. For instance, it has been reported that sarcopenic postmenopausal women may have more favorable lipoprotein profiles than those without sarcopenia [5] and results of the Cardiovascular Health Study showed that sarcopenia was not a risk factor for the development of cardiovascular disease over an 8-year follow-up period [6]. However, there is ­evidence that accelerated loss of skeletal muscle mass might be a risk factor for early mortality in older persons. Indeed, it appears that individuals with sarcopenia are twice likely to contract infection during a hospital stay than older patients with a normal skeletal muscle mass [7], suggesting a decreased immunity in these individuals.

Fig. 14.1
figure 00141

Prevalence of functional impairment and physical disability in sarcopenic women aged 60 years and over. *Significantly greater than non-sarcopenia (p  <  0.05). Figure adapted from Janssen et al. [4]

Full size image

Two main strategies are used to prevent or counteract sarcopenia; exercise and nutritional ­interventions. To this point, numerous resistance training studies have successfully shown gains in skeletal muscle mass in postmenopausal women. Physical activity, particularly resistance training, currently represents the cornerstone of prevention and treatment of sarcopenia. A recent ­meta-analysis revealed that after an average of 20.5 weeks of resistance training, aging men and women experienced an average increase in lean mass of 1.1 kg. These findings bear clinical significance, given the exaggerated rate of skeletal muscle atrophy that occurs among sedentary individuals after the age of 50 years [8]. Alone or in combination with physical activity, the nutritional factor also appears to be crucial to efficiently treat sarcopenia. In this chapter, we try to summarize the state of knowledge concerning the association between diet and sarcopenia, as well as the debates in this field. We then address the issue of protein intake (total, creatinine, and essential amino acids (EAAs)), vitamin D, and isoflavone, three nutrients that appear to play key roles. We also present exercise and dietary recommendations for the elderly and touch upon different types of diets ­(vegetarian vs. omnivore).

Protein

Dietary Protein Needs of Elderly People

Over the last 20 years, scientific evidence has provided new information on the role and impact of nutritional status on functional capacity and health of the aging population. Studies have pointed to protein as a key nutrient for the elderly. Proteins are essential parts of the organism and participate in virtually every intracellular process. The current adult Recommended Dietary Allowance (RDA) for protein is 0.8 g/kg//day [9]. Most individuals do not consider the RDA for protein when preparing meals or selecting foods to eat. In fact, most adults do not know what the RDA is, or how to calculate their daily protein intake even if they were trying to meet the RDA. For instance, 32–41 % of women older than 50 years ingested less than the RDA [10]. The RDA is nonetheless of great importance, because national and international policies regarding food programs are based on this value as the target level of protein that should be eaten. It was also recommended that protein constitute between 10 and 35 % of the daily energy intake, but virtually no older persons ingest the highest acceptable macronutrient distribution of 35 %. Accordingly, in the Health, Aging and Body Composition Study, even persons in the highest quintile of protein intake lost appendicular lean mass than, indicating that their intake of protein failed to counteract the loss of lean mass [11]. It is however interesting to note that for an increase of 0.1 g/kg of daily protein intake, the drop in skeletal muscle mass would be reduced by 0.62 kg [12]. Nevertheless, there is evidence that this recommendation may not be suitable for elderly people. In a study that examined the long-term consequences of consumption of the protein RDA, Campbell et al. [13] showed that over a 14-week period, the subjects (men and women aged 55–77 years) demonstrated a significant reduction in the cross-sectional area of the thigh skeletal muscle. These data suggest that the protein RDA for elderly people is not adequate, even while consuming a weight maintenance diet.

The etiology of this increased need for dietary protein is not well understood. Because of metabolic changes, older persons may produce less muscle protein than younger persons from the same amount of dietary protein. However, larger amounts of protein may produce responses similar to those of younger persons [14]. A protein intake of 1 g/kg//day seems to be the minimal amount required to maintain skeletal muscle mass in elderly women. For these reasons, expert recommendations for optimal protein intake in the elderly range from 1.0 to 2.0 g/kg//day or higher. These conclusions are reinforced by results demonstrating that older individuals whose consumption levels approach the RDA are at greater risk for disease than those consuming more than the RDA [15]. In addition, it is recommended that the amount of protein ingested should be spread equally throughout the day (e.g., equivalent amounts at breakfast, lunch, and dinner).

High protein diets are accused of constituting a favorable environment for kidney stones and renal diseases (through the increase of acid and calcium excretion [16]). In healthy subjects, no damaging effect of high protein diets on kidneys has been found in either observational or interventional studies, and it seems that high protein diets might be deleterious only in patients with preexisting metabolic renal dysfunction [16]. However, since aging is accompanied by a decrease in renal activity and in water consumption, potential damage is never totally excluded.

Essential Amino Acids

Proteins contained in food are broken down by the digestive juices in stomach and intestine into basic units called amino acids (AA). The quality of a protein is relative to its capacity to deliver AAs to the individual. AAs are the building blocks of protein in the body, and thus are critical elements of the diet. They can be reused to make the proteins body needs to maintain skeletal muscles, bones, blood, and body organs. A shortfall of any one of these AAs would be a limiting factor in protein synthesis. Of the 22 standard AAs, nine are called EAAs because they cannot be synthesized by the organism, and therefore must be supplied in the diet.

Muscle protein metabolism alternates between periods of net catabolism in the postabsorptive state and net anabolism in the postprandial states. Although muscle protein anabolism decreases with aging, it can nonetheless be directly stimulated by increased AAs availability. In fact, over 80 % of the stimulatory effect on protein synthesis observed after a meal may be attributed to AAs [17]. Specifically, ­hyperaminoacidemia acutely stimulates muscle protein synthesis by increasing the AA transport into muscle. Muscle protein synthesis is an energy-consuming process and if additional energy (from extra food intake or supplements) had any influence on muscle protein synthesis, such an effect should have been positive rather than negative. Insulin is also a potent anabolic stimulus for muscle protein, and a number of studies [14] have reported that hyperinsulinemia can increase muscle protein synthesis, particularly when AAs availability is increased. However, such an anabolic effect of insulin is absent in older subjects [14], suggesting that muscle protein synthesis is resistant to the anabolic action of insulin or that a higher insulin level is required to obtain similar results in older. This also suggests that age-associated insulin resistance of muscle proteins pays a role in the reduced muscle anabolic response to feeding, and in the development of sarcopenia. Evidence indicate that the anabolic response of skeletal muscle proteins to mixed feeding decreases with age despite the fact that AAs alone can normally stimulate protein ­synthesis in older muscle.

Among the EAAs, leucine has been recognized to have a crucial role in enhancing the insulin sensitivity of protein synthesis, bringing about a stimulation of muscle protein synthesis [18]. Furthermore, besides the insulin dependent stimulation, leucine may have a direct effect on protein metabolism [19] by partly inhibiting muscle protein breakdown. Aged skeletal muscle may be less sensitive to the stimulatory effect of AAs at low physiologic concentrations, but this impairment may be overcome by the provision of a larger amount of leucine [18]. For instance, no differences exist in protein balance in the elderly relative to the young postabsorptive or following administration of either 30 g of beef protein or 15 g of EAAs. However, when given half this amount of EAAs (6.7 g), the overall protein synthetic response is blunted in the elderly relative to the young [20]. Furthermore, the anabolic stimulus afforded by a nutritional supplement is influenced by the type and composition of the AA–protein mixture ingested. It appears that the anabolic response to an AA supplementation given to elderly subjects is blunted by the ingestion of carbohydrate, whereas in a young population, this combination elicits an anabolic response greater than achieved by AA ­supplementation alone [21]. This compromised interaction between carbohydrates and AAs may also partly explain why some dietary supplements fail to produce beneficial anabolic effects in the elderly.

In conclusion, to achieve the highest anabolic efficiency, it is not only important to deliver the nutrients that are absolutely necessary for the stimulation of muscle protein metabolism, but it is also crucial to provide them in sufficient quantity (a dose of 15 g/day of EAA appears effective in stimulating protein synthesis). Particularly, leucine may play a key role in the formulation of any AA/protein supplement for reversing attenuated response of muscle protein synthesis in the elderly. Furthermore, a supplementation of leucine may have a sparing effect on muscle glycogen degradation during endurance exercise and result in an increased deposition of lean mass and an increase in strength during intensive resistance exercise training [22].

It is however important to note that a role for leucine as an enhancer of insulin sensitivity also implies the possibility that prolonged very high intakes of leucine may lead to insulin resistance. In addition, some AAs (methionine, cystein, and histidine) are thought to result in toxic effects at high doses. Evidence exists that they can cause tissue damage and increase homocysteine and/or cholesterol levels and so may be associated with chronic diseases if taken over long periods of time. Nonetheless, the data relevant to humans are very limited, so unanticipated adverse consequences of consuming large amounts cannot be completely ruled out [23]. Dietary supplements should then be consumed with caution.

Animal and Vegetal Protein Intake

Proteins can be separated in two broad categories; animal and vegetal proteins. These two types of proteins do not necessarily have the same properties. For instance, proteins from vegetal sources tend to have a relatively low “biological value”, in comparison to protein from eggs, meat, or milk [24]. Biological value is a measure of the proportion of absorbed protein from a food which becomes ­incorporated into the proteins of the organism’s body. It summarizes how readily the broken down protein can be used in protein synthesis in the cells of the organism. However, the biological value does not take into account how readily the protein can be digested and absorbed. Nevertheless, vegetal proteins are “complete” in that they contain at least trace amounts of all of the AAs that are essential in human nutrition. Content of all EAAs in selected items of vegetal commodities (legumes, nuts, oil seeds, grains) is 62–81 % in comparison to reference animal proteins [24]. On the other hand, vegetal proteins are richer in nonessential AAs (111–129 %) compared with animal proteins.

The main limiting AAs in vegetal proteins are methionine, lysine, and tryptophan [25]. These AAs are not specifically critical to the process of protein synthesis, but since all acidic AAs are required to complete the process, a shortfall of any one of the AAs would be a limiting factor [24]. This may explain why 20 % of adults vegans are thought to have a hypoproteinemia. Evidence also shows differences in the bioavailability of these proteins. For an equivalent protein intake, vegetal proteins from cereals and legumes may be less digested and absorbed than animal proteins. A decrease in the amount or bioavailability of EAAs could alter their ability to be used for growth. Finally, it appears that elderly women experience a greater inhibition of protein degradation and a higher net protein balance when consuming a diet high in animal protein as compared to those consuming a diet high in vegetal protein. It is then not surprising that a strong positive association has been repeatedly observed between animal protein intake and skeletal muscle mass or skeletal muscle mass index in postmenopausal women [26] (Fig. 14.2), while the relationship between vegetal protein intakes or total protein intake and skeletal muscle mass or skeletal muscle mass index may be weaker or nonexistent.

Fig. 14.2
figure 00142

Partial correlation between animal protein intake and skeletal muscle mass index. Correlation was controlled for sex hormone-binding globulin and plant protein intake. Figure adapted from Aubertin-leheudre et al. [26]

Full size image

This could suggest that diet (omnivore, ovo-lacto vegetarian, or vegan) directly impacts muscle mass. An omnivorous diet includes both plant and animal foods. It is the most common diet among humans in Western countries. Vegetarianism is the voluntary abstinence from eating meat, including seafood. Ovo-lacto-vegetarians supplement their diet with dairy (lactose) products and eggs (ovo). Veganism is a type of vegetarian diet that excludes meat, eggs, dairy products, and all other animal-derived ingredients. Recent estimates suggest that approximately 2.5 % of American adults and 4 % of Canadian adults report following a vegetarian diet [27].

The literature is consistent in reporting that vegetarians’ protein intakes are lower than those of omnivores [28]. One would then expect that vegans or vegetarians have a lower skeletal muscle mass compared with omnivores. However, to date, the literature is too poor in this regard to state on the effect of diet on the development of sarcopenia. Some observed that vegetarians have a lower skeletal muscle mass than omnivores while others did not. In fact, eating various vegetal foods in combination can provide a protein of higher biological value, without the need to intentionally combine different foods for this purpose necessarily. However, as a preventive measure, because animal proteins are higher in EAAs, the elderly are suggested to consume a diet rich in lean source of meat-based and milk products in order to achieve sufficiently high doses. In premenopausal women, diet- and exercise-induced weight loss with higher protein and increased dairy product intakes promotes lean mass maintenance and fat loss [29]. Between minimum benefits and potential adverse effects, a dietary protein intake of 1.1–1.5 g/kg/day may be appropriate to prevent an excessive loss of skeletal muscle mass in postmenopausal women.

Creatine

Creatine is naturally produced or synthesized half in the human body from certain AAs (glycine, arginine, and methionine), the other half comes from food (mainly from meat and fish). Approximately 95 % of creatine contained in the human body is stored in skeletal muscle [30]. In skeletal muscle, a fraction of the total creatine binds to phosphate. The reaction is catalyzed by creatine kinase, and results in phosphocreatine (PCr). PCr then binds to adenosine biphosphate (ADP), to convert it back to adenosine triphosphate (ATP), an important source of energy. An increase in PCr from creatine supplementation should theoretically increase PCr resynthesis during muscle contraction leading to greater exercise training intensity and subsequently skeletal muscle mass. Indeed, creatine supplementation during exercise training has been shown to be effective in increasing skeletal muscle mass, but also appears to slow the loss of skeletal muscle mass and strength during immobilization in young adults [31]. Increasingly, there is research showing a positive effect from creatine supplementation (5–20 g/day for 5 days–6 months) on muscle accretion in postmenopausal women [32]. Based on these results, a low supplementation (5 g/day) over a long period (6 months) appears to more effective that an important supplementation (20 g/day) for a very short duration (5 days). Interestingly, this increase in skeletal muscle mass was paralleled by an increase in muscle strength, which is significant in terms of maintenance of functional capacity. While the mechanistic actions remain to be determined, it has been theorized that creatine has the ability to regulate osmosis within the working cell and could potentially elevate intracellular osmolarity. The anabolic signal induced by cellular hydration may increase the expression of myogenic transcription factors which augment the up-regulation of muscle specific-genes (such as myosin heavy chain), thereby facilitating an increase in skeletal muscle hypertrophy and strength [32]. Furthermore, the timing of creatine supplementation appears to be crucial for creating an anabolic environment for muscle growth. Creatine ingestion in close proximity to resistance training sessions (before and after exercise) may be more beneficial than ingesting creatine at other times of the day [32]. Postmenopausal women, but also the elderly in ­general, may thus be recommended to consume creatine (5 g/day for at least 6 months) or food products containing creatine (red meat or sea food), particularly in close proximity to resistance training sessions, which may enhance functional capacity through increased muscle mass and strength. However, in spite of these studies, there is a need for long-term studies on the effects of creatine on sarcopenia and aging muscle biology.

Vitamin D

Definition and Mechanism of Action of vitamin D

Vitamin D is both a fat-soluble vitamin and a prohormone which has the distinction of being synthesized by the epidermis when exposed to sunlight. In fact, up to 80 % of vitamin D is produced following ultraviolet B light exposure, the other 20 %being provided by food [33]. 10–15 min of sunshine three times weekly may be enough to produce the body’s requirement of vitamin D. Vitamin D can be found in dairy products (Cheese, butter, cream, fortified milk), fatty fish (such as tuna, salmon, and mackerel), oysters, fortified breakfast cereals, margarine, and soy milk. Vitamin D consists of a set of substances sometimes called provitamin D. These include the provitamin ergocalciferol (D2; plant form) and cholecalciferol (D3; animal form). The body partly transforms these compounds in calcitriol, which generates the majority of the health benefits. Vitamin D can accumulate in fat and liver where it is placed in reserve. Depending on the needs of the body, it can be put back in circulation and metabolized.

It has been well-established that vitamin D plays an essential role in the regulation of calcium and phosphate homeostasis and in bone development and maintenance. Over the last two decades, however, there has been increasing evidence that vitamin D plays an important role in many other tissues including skeletal muscle. The identification of vitamin D receptors (VDR) on muscle cells provided further support for a direct effect of vitamin D on skeletal muscle tissue [34]. It has been suggested that the VDR in ­skeletal muscle tissue is a nuclear receptor that binds 1,25-dihydroxyvitamin D (1,25(OH)2D) with high affinity and elicits its actions to regulate protein synthesis. This may be confirm by results showing an association between 1,25(OH)2D and skeletal muscle mass [35] (Fig. 14.3).

Fig. 14.3
figure 00143

Effect of a 6 months supplementation of isoflavone or placebo on muscle mass index. *Significantly different from baseline values (p  <  0.05). Figure adapted from Aubertin-leheudre et al. [62]

Full size image

The mechanisms by which vitamin D and its metabolic pathways may affect muscle function are quite complex [36]. A physiologic explanation for the beneficial effect of vitamin D on muscle strength is that 1,25(OH)2D, the active vitamin D metabolite, binds to a vitamin D-specific nuclear receptor in muscle tissue, which leads to enhanced transcription of a range of proteins, including those involved in calcium metabolism, a critical modulator of skeletal muscle function. 1,25(OH)2D may affect skeletal muscle function through both calcium-related protein transcription and total body calcium levels. However, it has been suggested that 1,25(OH)2D also has a transcription-enhancing role on proteins other than those involved directly in calcium metabolism. Briefly, 1,25(OH)2D may promote IGFP-3 expression, a component which bind IGF-1 with high affinity and specificity, limiting its clearance. This mechanism is of importance since IGF-1 has been recognized as a potential means for addressing sarcopenia. Accordingly, IGF-1 is known to induce proliferation, differentiation, and hypertrophy of skeletal muscle.

While the vast majority of food components (proteins, carbohydrates, vitamin A, etc.) standards are defined in terms of quantity to absorb daily, the fact that vitamin D is mainly synthesized by the body invalidates this approach. Then, to determine whether an individual is in the standard or not, we refer to a concentration (measured in the blood, in nmol/L) rather than a quantity provided by food.

The consensus threshold for defining vitamin D deficiency is currently set at 25 nmol/L, and the threshold selected by the World Health Organization to define vitamin D insufficiency is 50 nmol/L. However, more recently, it has been suggested that the most advantageous target concentration of 25(OH)D begins at 75 nmol/L and that the optimum concentrations are between 90 and 100 nmol/L [37]. If 75–100 nmol/L were the target range of a revised RDA, the new RDA should meet the requirements of 97 % of the population.

It is currently estimated that at least 1 billion people through the world have a vitamin D deficiency [33]. More precisely, Vitamin D insufficiency and deficiency may be particularly prevalent in people who live at higher latitudes where the winters are prolonged. Thus, at latitudes above 40° (e.g., Europe or the USA), 40–90 % of community dwelling elderly have a hypovitaminosis D. Even if all adults can be affected by hypovitaminosis D, those most at risk are the elderly, especially if they live in institutions or are hospitalized. Also, over 50 % of women taking treatment for osteoporosis have been reported to be deficient [38].

Aging and Vitamin D

This high prevalence of hypovitaminosis D in the elderly is due to different mechanisms directly associated with aging, foremost among them the decreased skin synthesis. Hypovitaminosis D may also be the consequence of the altered metabolism of vitamin D (renal and hepatic insufficiency), inadequate food intake, reduction in bioavailability (malabsorption, obesity with sequestration of vitamin D in the fat), increased catabolism (anticonvulsants, glucocorticoids, immunosuppressants) and urinary losses of vitamin D. Furthermore, this decreased vitamin D synthesis/intake with aging is paralleled by a diminished Vitamin D receptor expression in muscle tissue [39]. Over time, this may impair protein synthesis in muscle cells, resulting in a decrease in muscle fibers (mostly type II fibers), and eventually sarcopenia. Also, vitamin D and its metabolites are transported in blood by an α-globulin called Vitamin D-Binding Protein whose synthesis is increased in the presence of estrogen. The decrease in estrogen production at menopause therefore directly impairs the transport of vitamin D. It is however interesting to note that, in men, this relationship may also depend on VDR polymorphisms [40]. These results suggest that the VDR locus may contribute to interindividual variation in skeletal muscle mass and susceptibility to sarcopenia. A few studies showed associations of allelic variants at the VDR locus with muscle strength in postmenopausal women [41]. To date, no study has established a relationship between VDR polymorphism and skeletal muscle mass in postmenopausal women. However, it appears that such a relationship does not exist in young women [42].

It is therefore quite logical to observe that Vitamin D deficiency has been widely associated with functional disabilities. In an analysis of men and women age 60 and over who participated in the cross-sectional NHANES III survey, individuals with higher serum 25(OH)D levels up to 94 nmol/L were able to walk faster (8-ft walk test) and to get out of a chair faster (sit-to-stand test) than subjects with lower levels, particularly in the subset with 25(OH)D levels under 60 nmol/L [43]. Time of the 8-ft-walk test in subjects in the highest quintile of 25(OH)D was 5.6 % lower than the results in subjects in the lowest quintile of 25(OH)D. Time of the sit-to-stand test in subjects in the highest quintile of 25(OH)D was 3.9 % lower than the results in subjects in the lowest quintile of 25(OH)D. This finding is supported by data from the Longitudinal Aging Study Amsterdam that included 1,351 Dutch men and women aged 65 years and more. In that study [44], a physical performance score (chair stands, a walking test, and a tandem stand) showed the greatest improvement from very low concentrations of serum 25(OH)D up to 50 nmol/L and had less pronounced but continuous improvement at concentrations >50 nmol/L. low 25(OH)D levels (less than 25 nmol/L) were also associated with an increased risk of repeated falling over the subsequent year. Finally, lower serum 25(OH)D levels predicted decreased grip strength and appendicular skeletal muscle mass in elderly men and women over the subsequent 3 years [44]. All these phenomenon being closely linked, a poor vitamin D status may play a role in the risk of developing incapacities through an effect on muscle function (skeletal muscle mass and strength).

Vitamin D Supplements

If standards are based on 25(OH)D blood levels, supplements, however, are expressed in terms of quantity (International Unit, IU) to absorb daily. Oral supplementation is the most effective way to treat vitamin D deficiency. Vitamin D found in supplements and fortified foods comes in two different forms (D3 and D2), the D3 form appearing to have a superior efficacy compared with the D2 form. Studies suggest that 700–1,000 IU vitamin D per day may bring 50 % of younger and older adults up to a concentration of 90–100 nmol/L [37]. The current intake recommendation for older persons (600 IU/day) may bring concentrations in most subjects to 50–60 nmol/L, but not to 90–100 nmol/L. Because of seasonal fluctuations in 25(OH)D concentrations, some persons may be in the target range during the summer months, but not during the winter months, even in sunny latitudes. Several studies even suggest that many older persons will not achieve optimal serum 25(OH)D concentrations during the summer months. However, it is important to note that although vitamin D is relatively rare in food, some foods are particularly rich and can largely achieve doses provided by supplementation. Among the richest foods in vitamin D are pure cod liver oil (1,360 IU for one tablespoon), salmon (360 IU for 100 g), mackerel (345 IU for 100 g), tuna fish (200 IU for 100 g), milk (whole, skimmed or low-fat; 100 IU for 1 cup), or eggs (20 IU for a whole egg).

Intakes of 700–800 IU vitamin D/day (with or without calcium) could prevent approximately one-fourth of all hip and nonvertebral fractures in both ambulatory and institutionalized older persons [45]. Furthermore, because the positive association between 25(OH)D concentrations and bone mineral density in younger adults is consistent with the concept that higher concentrations of serum 25(OH)D may contribute to peak bone mass, maintenance of high 25(OH)D concentrations in younger adulthood could further protect against fractures at older ages [46].

Also, a few studies have examined the effect of vitamin D supplementation on balance and gait performance [37, 47]. Specifically, vitamin D with calcium, compared to calcium alone, improved body sway in ambulatory elderly women with serum 25(OH)D levels less than 50 nmol/L within 8 weeks and improved musculoskeletal function in institutionalized elders with serum 25(OH)D levels less than 50 nmol/L within 12 weeks. A recent meta-analysis showed that the efficacy of supplemental vitamin D for fall prevention depended on dose and achieved 25(OH)D concentrations among individuals aged 60 years and older. No fall reduction was observed for a daily dose of less than 700 IU vitamin D or achieved serum 25(OH)D concentrations below 60 nmol/L. Daily vitamin D doses in the range of 700–1,000 IU or achieved serum concentrations between 60 and 95 nmol/L reduced the risk of falling by 19 %. The benefit was sustained for 12–36 months [48], partly through improved muscle function.

700–1,000 IU per day may thus be recommended to improve muscle function and functional capacity in postmenopausal women. Furthermore, contrary to high doses of vitamin E and C, vitamin D supplements do not seem to increase risks of cancers. However, it is important to note that excessive intake of vitamin D may lead to hypercalcemia, which may cause nausea, vomiting, loss of appetite, and weakness. In case of chronic hypercalcemia, kidney stones as well as deposits of calcium and phosphorus in the organs and soft tissues can be observed.

Phytoestrogen

Estrogen and Muscle Mass

Estrogens are the primary female sex hormones. Natural estrogens are steroid hormones which ­readily diffuse across the cell membrane. Once inside the cell, they bind to and activate estrogen receptors (ERs) which in turn modulate the expression of many genes. Although it can cause women to retain fluid, and early exposure through early menses can increase a woman’s risk of developing breast cancer, estrogen has its benefits. It can contribute to increase high density lipoprotein and lower the low density lipoprotein. At menopause, women experience a reduction in estrogen. This can lead to ­vaginal dryness, memory problems, hot flashes, fatigue, irritability, and possibly one of the most devastating problems, a decrease in bone mineral density. Furthermore, there is evidence that a decreased estrogen production in women at menopause may be associated with a loss of skeletal muscle mass [49]. The mechanisms by which a decrease in estrogen levels may have a negative effect on skeletal muscle mass are not well understood but it has been suggested that decreases in estrogen concentrations may be associated with increased pro-inflammatory cytokines, such as tumor necrosis factor alpha (TNF-α) or interleukine-6 (IL-6), which might be implicated in the apparition of sarcopenia [50]. Furthermore, estrogen could have a direct effect on skeletal muscle mass since it has been shown that skeletal muscle has ERs on the cell membrane, in the cytoplasm and on the nuclear membrane, implying that estrogen could have a direct influence on protein synthesis, similar to its effects on transcription in bone cells [49].

Estrogens are used as part of some oral contraceptives and in estrogen replacement therapy for postmenopausal women. It is thus not surprising that hormone therapy has been reported to be associated with skeletal muscle mass and has been hypothesized to prevent sarcopenia [51]. The Women’s Health Initiative study randomized a large number (n  =  835) of postmenopausal women to hormone therapy or placebo for 3 years and evaluated changes in lean mass [52]. Women randomized to receive hormone therapy lost 0.04 kg of lean mass, which was significantly less than the 0.44 kg lost by women on placebo, indicating that hormone therapy can have a small beneficial effect on muscle mass. Hormone therapy given over 10 months to postmenopausal women also increased blood ­concentrations of growth hormone and insulin-like growth factor-1, both of which have an anabolic effect on skeletal muscle. Unfortunately, the Women’s Health Initiative also showed that the risks of hormone therapy (estrogen and progesterone) outweigh its benefits. The study found statistically significant increases in rates of breast cancer, coronary heart disease, strokes, and pulmonary emboli. Because of the increased knowledge of these risks, many women are thus seeking alternatives to estrogen or hormone therapy [53].

Phytoestrogens as Alternatives to Hormone and Estrogen Therapies

One such alternative is the class of plant-based compounds termed phytoestrogens. The presumption that phytoestrogens may have beneficial effects on menopausal symptoms arose from the observation that Asian women are thought to suffer from fewer hot flashes than women in Western countries. Phytoestrogens are plant-derived xenoestrogens (environmental hormones that imitate estrogen) functioning as estrogens. Also called “dietary estrogens,” they are a diverse group of naturally occurring nonsteroidal plant compound that, because of their structural similarity with estrogens, have the ­ability to mildly mimic and sometimes act as antagonists of estrogen. Phytoestrogens may have protective action against diverse health disorders, such as prostate, breast, bowel, and other cancers, cardiovascular disease, brain function disorders, and osteoporosis. Evidence also suggests that a sufficiently large quantity of phytoestrogens (70 mg/day for 4 months) may reduce symptoms of menopause [54] while effects are mixed for smaller quantities.

Phystoestrogens cannot be considered as nutrients, given that the lack of these in diet does not produce any characteristic deficiency syndrome, nor do they participate in any essential biological function. The coumestans (an organic compound that is a derivative of coumarin), prenylated flavonoids (a subclass of plant secondary metabolites), and isoflavones are three of the most active in estrogenic effects in this class. In a cohort of 946 healthy US postmenopausal women [55], the intake of phytoestrogens was estimated to be less than 1 mg/day. Median total intake of isoflavones, which main sources were beans and peas, was 154 μg. The estimated daily intake of coumestans was 0.6 μg, with broccoli as the main source and the median total intake of lignans was 578 μg, primarily from fruits.

Rates of absorption and bioavailability of phytoestrogens depend on many factors including the absolute quantity in a foodstuff, processing in food preparation and chemical structure. Concerning the bioavailability of commercial soy isoflavone supplements, overall high levels of absorption but marked qualitative and quantitative differences between types of supplements have been reported. Furthermore, metabolism of dietary components can result in the production of metabolites that are more biologically active than their precursors, which could ultimately influence their effect on host health. For instance, the predominant daidzein (isoflavone compound) metabolites produced by human are dihydrodadzein, equol, and O-desmethylangolensin (O-DMA) and their production appears to be associated with reduced risk of ­certain cancers and other diseases [56]. Interestingly, the prevalence of equol-producer phenotype may be higher (51 % vs. 36 %), and the O-DMA-producer phenotype lower (84 % vs. 92 %), in Korean than in Caucasian women. The prevalence of the combinations of equol- and O-DMA-producer phenotypes also differed between Korean and Caucasian women (41 % and 35 %, respectively) [57]. Nevertheless, little evidence is currently available and larger studies are needed to confirm or refute relationships between daidzein-metabolizing phenotypes and disease risk.

Phytoestrogens and Muscle Mass

Phytoestrogens may exert a beneficial effect on skeletal muscle mass because of their affinity for ERs, which are found on muscle [51]. There are two variants of the estrogen receptor, alpha (ER-α) and beta (ER-β) and many phytoestrogens display somewhat higher affinity for ER-β compared to ER-α. Phytoestrogens may also influence skeletal muscle mass through their effects on reducing inflammation [51]. Indeed, chronic low-grade inflammation is related to decreased skeletal muscle mass and strength with age [58]. Interleukin-6, one of the main inflammatory cytokines, has been associated with a decrease in skeletal muscle mass, strength, and fiber number in older adults. Studies relating phytoestrogens to prevention of inflammation and muscle protein degradation are limited, but one study in rats subjected to intense exercise resulting in muscle damage revealed that a chronic high soy protein diet was effective for reducing activation of pathways involved in muscle protein degradation [59].

In addition to interaction with ERs, phytoestrogens may also modulate the concentration of endogenous estrogens by binding or inactivating some enzymes, and may affect the bioavailability of sex hormones by binding or stimulating the synthesis of sex hormone binding globuline (SHBG) [60]. Plasma SHBG is the major plasma transport protein for biologically active androgens and estrogens, and changes in the blood levels of SHBG widely influence their distribution and access to target tissues and cells.

Finally, emerging evidence shows that some phytoestrogens bind to and transactivate peroxisome proliferator-activated receptors (PPARs) [61], a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes. PPARs play essential roles in the regulation of cellular differentiation, development and metabolism (carbohydrate, lipid, protein).

Isoflavones

Isoflavones belong to a class of phytoestrogens and is the most studied of these. A few studies have ­investigated changes in skeletal muscle mass or lean mass in older individuals with either isolated isoflavones or soy protein, which contains isoflavones. Isoflavones on their own result in a small increase in lean mass; however, it is unclear whether they would result in a significant increase when added to an exercise program. Aubertin-Leheudre et al. investigated the effect of a 70 mg/day of soy isoflavone ­supplementation for 24 weeks on muscle mass in obese-sarcopenic postmenopausal women and observed that isoflavone supplementation was associated with a significant increase in appendicular lean mass (+0.5 kg), but this increase was not enough to reverse sarcopenia [62] (Fig. 14.4). Another study randomized postmenopausal women to receive either isoflavone-rich soy protein (40 g), isoflavone-poor soy protein or whey protein (control) for 24 weeks [63]. It was reported that changes in total lean mass were not different between groups; however, lean mass at the hip increased to a greater extent in the isoflavone-rich group (+3.4 %) than in the isoflavone-poor (+1 %) or control (0 %) groups. Studies of soy protein combined with 12–16 weeks of resistance training in postmenopausal women or older men (age 65 years) did not result in greater increases in strength or muscle mass compared with either placebo or beef protein.

Fig. 14.4
figure 00144

Relationship between 1,25(OH)2D and skeletal muscle mass. *Higher 1,25(OH)2D value was associated with a higher skeletal muscle mass (p  =  0.012). Analyses were adjusted for age, height, physical activity, season, and fat mass. Figure adapted from Marantes et al. [35]

Full size image

Thus, although currently limited, the results obtained with isoflavones are encouraging and deserve some attention to better characterize their effects and determine the optimal dosages. To date, studies indicate that 50 mg/day, for a period of 6 months, is sufficient to have significant endocrine effects, whereas half this dose appears biologically inactive [64].

Conclusion

In conclusion, nutrition clearly appears to play a key role in maintaining skeletal muscle mass, and thus in the prevention and treatment of sarcopenia. In particular, a sufficient protein intake may be the key of a healthy nutrition, even if standards need to be fixed in regard to the needs of an aging population. We have to admit that our understanding of the relationship between nutrition and sarcopenia is still limited, but interesting alternatives to proteins, as well as supplements, emerge in the literature. Among them, vitamin D and isoflavones appear promising, although much research is needed to demonstrate their effectiveness and determine the optimal dosage. Nevertheless, the primary objective of preventing sarcopenia being to limit the functional incapacities associated with this condition, we should keep in mind that an effective therapy to counteract the negative consequences of muscle wasting should improve ­function, not just mass. Data supporting an improvement in muscular function following supplementation are limited, which bring into question the functionality of any lean mass gain. In this regard, effective nutritional intervention would then require to be combined with other interventions aimed to improve muscle function such as physical activity. Indeed, Little and Phillips [65] have highlighted the potential of resistance exercise combined with appropriately timed nutritional supplementation to promote gains in muscle mass and strength. Particularly, a combination of leucine, insulin, or carbohydrate, and contractile activity may have the greatest potential for increasing muscle protein synthesis. Thus, for optimal results, in addition to providing energy to the muscle, it is important to stimulate it.