Prevent Sarcopenia in the Aging Process: Comparison
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Please note this is a comparison between Version 3 by Antonio Cicchella and Version 2 by Rita Xu.

Sarcopenia is one of the main issues associated with the process of aging. Characterized by muscle mass loss, it is triggered by several conditions, including sedentary habits and negative net protein balance.

  • protein
  • aging
  • metabolism
  • nutrition

1. Introduction

The number of older adults has increased over the last decades. According to the World Health Organization (WHO) [1], until 2025, a 38% increase of individuals over 65 years old is expected, suggesting that a better understanding of that population and strategies to avoid age-related problems to achieve healthy aging are needed.
One of the main problems observed in older adults is related to a relative loss of muscle mass, defined as sarcopenia, which increases risk related to falls, reduces physical capacity, and enhances problems associated with disabilities [2]. Sarcopenia is a multifactorial process associated with several risk factors (i.e., inflammatory cytokines, negative net protein balance, sedentarism, and vitamin D deficiency). Dietary protein intake, insulin resistance, and physical inactivity play a vital role in developing this condition [3].
Over the years, it has been established that an insufficient dietary protein intake is associated with loss of muscle mass in older adults due to lower muscle protein synthesis (MPS) [4]. Therefore, the previous recommendation for protein intake (0.66–0.80 g/kg/day) could be underestimated to sustain the protein net balance across the day, considering problems associated with anabolic resistance [5]. Recent studies suggest that older adults need to ingest 1.0–1.3 g/kg/day of protein to sustain their muscle mass and functionality, indicating that these higher doses represent 40% less muscle mass loss when compared to the lower doses previously recommended [5][6]. Besides the minimum amount of protein intake required to optimize the MPS in older adults, other topics related to optimal doses of protein per/meal have been discussed over the decade. It has been suggested that older adults present the capacity to support and synthesize more protein (>20 g) at each meal [7], supporting the importance of the doses and quality of the protein ingested by older adults.
Moreover, MPS can be stimulated by physical activities, leading to significant increases during aerobic (AT) and resistance training (RT) protocols [8][9]. However, considering associated problems with anabolic resistance of older adults, the increased MPS provided by the RT is insufficient to sustain a positive protein net balance across the day, suggesting that the combination of AT/RT and increases in protein intake may be a better approach to preventing sarcopenia [10].

2. Sarcopenia

Sarcopenia comes from the combination of two Greek words: sarx (flesh) and penia (loss) and was initially described by Evans and Campbell. Later, it was used by Irwin Rosenberg, who defined this condition as age-related muscle wasting. Sarcopenia is currently recognized as a critical geriatric problem and an important condition to predict frailty in the elderly [3] and minimize the impact on physical activity [11]. In addition, sarcopenia is associated with increased mortality risk in frail older adults.
On 18 November 2009, researchers and geriatricians defined sarcopenia as “the loss of skeletal muscle function and mass associated with age”. It is a complex syndrome associated with muscle mass loss alone or in conjunction with increased adipose tissue. Its causes are multifactorial and include disuse, altered endocrine function, chronic diseases, inflammation, insulin resistance, and nutritional deficiencies. Although cachexia can be a component of sarcopenia, these conditions are distinct [3].
The European consensus on sarcopenia recommends the inclusion of the factors that cause the decrease in skeletal muscle mass and consequent decrease in its function (strength or performance) for the diagnosis of this syndrome. The justification for using the two factors mentioned above is that muscle strength is not dependent on muscle volume, and that strength and muscle mass ratio is not linear. Therefore, defining sarcopenia only by decreasing muscle mass could have limited clinical value [2].
Like any other complex syndrome, sarcopenia's onset mechanisms and progression are varied and related to the (in)balance of protein synthesis and degradation, neuromuscular integrity, and muscle fat content. Such progression is due to factors such as age advancement, inadequate nutrition, disuse, and endocrine dysfunction [2]. Although the incidence of sarcopenia is higher in the elderly, adults can also develop this syndrome, which can be associated with other diseases such as osteoporosis. Thus, sarcopenia can be considered primary if related to advanced age and with no other evident cause or associated disease. In contrast, secondary sarcopenia can be linked to three other factors: lack of motor activity (long periods in bed, sedentary lifestyle, and others), disease, or inadequate nutrition, caused by inadequate energy and/or protein intake, malabsorption of nutrients, gastrointestinal diseases, and the use of drugs that produce anorectic side effects [12].
The sedentary lifestyle related to the aging process tends to damage mitochondrial function and insulin resistance. This situation is almost always present in metabolic diseases, sarcopenia, and obesity, resulting in increased risk of mortality in the elderly [13]. Currently, the COVID-19 pandemic has led thousands of people worldwide to measures of distancing and social isolation implemented by governments. As a result of these actions, there is a reduction in physical activity, interruption of routine eating habits, stress, and altered sleep patterns, which offer an environment conducive to sarcopenia installation [14]. Like any other complex syndrome, sarcopenia’s appearance and progression depend on various mechanisms related to the balance of protein synthesis and degradation, neuromuscular integrity, and muscle fat content. Such mechanisms include age progression, inadequate nutrition, disuse, and endocrine dysfunction [12]. The lower levels of anabolic hormones (such as testosterone, insulin-like growth factor (IGF-1), and estrogens) that regulate MPS are noticed throughout the aging process [15].
Sarcopenia is associated with changes in skeletal muscle physiology and cellular mechanisms. These changes can be observed at the metabolic, cellular, vascular, and inflammatory levels [16]. Metabolic alterations in the anabolic pathway (mTOR), an important regulator and signaler of muscle cell growth, can often impair the sarcopenic muscle [17][18][19]. The concomitant loss and atrophy of muscle fibers, specifically the loss of type II fibers, is classically one of the most evident signs of sarcopenia [16]. Myofibrillar protein synthesis is also impaired by the inability of satellite cells to react positively to growth factors and cytokines (myokines), which are essential to stimulate the production of these contractile proteins [17][19].
IGF-1 is a classic pathway for skeletal muscle anabolism that also suffers different adjustments in the sarcopenic muscle. Through animal models that suppressed the expression of insulin receptor substrate (IRS-1), the results showed increased longevity in animals that had this anabolic pathway suppressed. The current explanation for this phenomenon is that reductions in IGF-1 perceived with aging may be an attempt to increase the Silent Information Regulator 1 (SIRT-1) proteins. These proteins are essential for cell survival, especially by combating catabolic cytokines (e.g., tumor necrosis factor-alpha (TNFα)) that are constantly elevated in the circulation and skeletal muscle in the aging process. Therefore, in addition to playing an essential role in myoblast survival, SIRT-1 can also participate in the adequate differentiation, hypertrophy, and atrophy arrest in in vivo processes during stressful stimuli contained in chronic inflammation or disuse [20].
Older men also have decreased testosterone, which is one of the critical factors for decreasing muscle mass in this population. Long-term hormone replacement therapies increase muscle mass and muscle strength in the elderly. Testosterone regulates protein synthesis via the androgen receptor, and its administration has been used to increase this anabolic signaling in response to strength training in older adults. However, testosterone administration in those individuals may be unable to entirely reduce muscle wasting if not combined with nutritional strategies and strength training [21][22][23].
Another condition that is harmful to the sarcopenic muscle is the infiltration of fat (in and/or between) the muscle fibers. Changes in the differentiation of satellite cells into adipocytes explain this phenomenon’s pathophysiology. Adipocyte infiltration, known as lipotoxicity, will promote the release of toxic adipokines that affect muscle cell function [24].
Sarcopenia’s vascular mechanism is explained by a capillary density reduction, associated with low blood perfusion in the musculature, increased oxidative stress, and mitochondrial dysfunction. These modifications are associated with reduced peroxisome proliferator-activated receptor-gamma 1-alpha (PGC1α) coactivator expression, which is involved in type I muscle fibers formation. Together, they participate in mitochondrial activation genes and fatty acid-binding proteins muscle factors involved in the use of fatty acids for energy production in the mitochondria [17]. Finally, sarcopenia is associated with inflammation demonstrated by increased serum C-reactive protein (CRP) levels, interleukin-6 (IL-6), and TNFα. Elevated levels of these inflammatory markers have been associated with reduced muscle mass and strength in rodents [16]. In addition, in vitro studies have shown that TNFα inhibits myogenesis and increases nuclear factor kappa beta (NF-κβ), which is essential in skeletal muscle atrophy [25][26].
Anabolic resistance is also part of the sarcopenia process. It is a diminished response to the stimulating effects of protein synthesis from strength exercise and protein intake in the elderly population [14]. For example, it has been reported that older adults compared to young adults (mean 71 years vs. 22 years) require twice the need for protein intake (0.60 vs. 0.25 g/kg/weight) to stimulate MPS. An essential factor to be considered in anabolic resistance is the reduction of skeletal muscle capillarization, an issue that can hinder the hypertrophic effect of strength training. This issue was demonstrated by researchers who submitted older adults to participate in a strength training program for 12 weeks. At the end of the program, the elderly with reduced muscle capillarization did not present the same level of hypertrophy as those elderly with increased capillarization [27].

3. Muscle Protein Metabolism and Anabolic Resistance of Aging

Skeletal muscle mass is regulated by a tightly and dynamic process involving MPS and muscle protein breakdown (MPB). Skeletal muscle proteins are continuously being turned over since MPS and MPB simultaneously occur throughout the day. When the rate of MPS exceeds MPB, a positive net muscle protein balance occurs, meaning that new proteins are being incorporated into muscle tissue, resulting in muscle hypertrophy in the long term. On the other hand, when the rate of MPB exceeds MPS, a negative net muscle protein balance occurs with a loss of muscle proteins, which in the long term may induce muscle atrophy. Finally, when there is a balance between MPS and MPB throughout the day, there is a neutral muscle protein balance and the maintenance of skeletal muscle mass in the long term [28]. In this sense, during postabsorptive conditions, the rate of MPB generally exceeds those of MPS, resulting in periods of net muscle loss. However, after consuming a meal containing proteins, an MPS increase and MPB suppression generate a positive protein balance. Thus, in healthy and young individuals who consume sufficient daily amounts of protein (around 0.8 g/kg/body weight), the fluctuations between periods of negative and positive net muscle protein balance (which are the results of postabsorptive and postprandial periods, respectively) are generally equivalent. Therefore, the skeletal muscle mass remains stable [29].
Protein ingestion and resistance exercise are the two most potent anabolic factors capable of stimulating MPS and promoting positive muscle protein balance [8]. However, older individuals seem resistant to these external stimuli [30]. Data regarding the effects of resistance exercise [31] and protein ingestion [32] suggest that older people are less sensitive to the anabolic effects of exercise and protein/essential amino acids (EAAs) ingestion. This condition, called “anabolic resistance” of aging, is characterized by a blunted stimulation of MPS to protein ingestion and resistance exercise [10]. The reduced effects of protein consumption on MPS may contribute to a chronic state of negative muscle protein balance, with rates of MPB being constantly higher than MPS, which has been pointed out as a primary contributor to muscle loss in aging [10]. This condition was clearly demonstrated in a study conducted by Wall et al. (2015) [30], which pooled together data from six studies performed in the same laboratory with similar designs. This analysis found a significant reduction in the synthetic muscle protein response to ingesting 20 g of casein protein compared with young counterparts. Importantly, although there is a reduction in the sensitivity of skeletal muscle to nutrient ingestion in older people, basal MPS seems to be similar both in the young and older populations [30][33]. Moreover, skeletal muscle protein metabolism analysis revealed that the rate of MPB, both at rest and after a resistance exercise session, seems to be comparable between the young and elderly [34]. Therefore, the reduction of MPS to external anabolic factors characterizes the anabolic resistance of aging and may be partly responsible for the progression of sarcopenia in the latter stages of life.
The possible contributors to the onset of anabolic resistance are still unclear. However, factors such as reduced capillarity and/or vasodilation capacity, attenuated muscle uptake, reduced ribosomal protein content or activity, chronic low-grade inflammation, obesity, and physical inactivity may play a role in the decreased muscle sensitivity to protein and amino acids ingestion [35]. This section highlights the roles of physical inactivity, inflammation, and obesity as aggravating anabolic resistance factors, which can be modifiable through lifestyle changes. We also briefly discuss the possible role of gut microbiota in the genesis of anabolic resistance. 

3.1. Decreased Muscle Contraction in Aging (Physically Inactive X Sedentary Behavior)

Currently, the classification of an individual as “sedentary” or “physically inactive” occurs through different criteria, which aim to quantify the contractile muscle stimulus (weekly and/or daily) of the subject observed. People considered “sedentary” are characterized by having sedentary behavior for the most part of the day (such as watching television, working sitting in the offices and/or stores, or spending extended periods lying down during the day), thus presenting a low metabolic demand rate in the muscle tissue (≤1.5 metabolic equivalents) [36][37]. In addition, the term “physically inactive” is used for subjects who perform an insufficient amount of exercise compared to current health recommendations (<150 min of moderate or vigorous physical activity per week, through aerobic exercise, training strength, team sports, and other activities) [36][37]. Considering these terminologies, the effects of reducing muscular metabolic demand (physical inactivity or sedentary lifestyle way) must be interpreted with full attention and together. Notably, a subject can be considered “physically active” but “highly sedentary” as well as “physically inactive” and with almost non-existent sedentary behavior. For each case, associations between these different “lifestyles” (through the motor activities performed) and distinct anthropometric and/or metabolic outcomes are pointed out [38].
In this context, a large study based on a database of 1.9 million individuals pointed out that physical inactivity has a high prevalence in the adult population worldwide (27.5%), with wide variation in its incidence between different countries analyzed (10 to >50% of the population) [39]. In addition, recent (robust and well-defined) studies indicate that the degree of physical activity observed among older adults (≥60 years old) is reduced during the aging process, with a parallel increase in sedentary behavior [40][41][42]. This scenario raises a “state of alert” among researchers worldwide, who aim to understand how the global adult population is aging and the outcomes of a reduced muscle metabolic demand on the quality of life and muscle area/function of older adults.
Globally, the relationship between physical inactivity and the significant incidence of chronic diseases is already well established [43]. On the other hand, there is a 6–10% incidence reduction of diseases such as type 2 diabetes (DM2) and some types of cancer, which occurs by increasing physical exercise in the world population [44]. In addition, well-controlled clinical trials indicate that the practice of lifelong physical training (among former highly active athletes, for example) can preserve muscle tissue’s function and volume in aging when compared to the effects of physical inactivity on muscle tissue of healthy elderly (absence of chronic diseases) and/or young adults [45][46]. Regarding sedentary lifestyle, Seguin et al. [47] pointed out that older women with high levels of sedentary behavior (8–11 h·day−1) have lower muscle functionality when compared to older women of the same age group who presented reduced sedentary behavior in their waking period (<6 h·day−1). Complementarily, Gianoudis et al. [48] indicated that a 60-min increase in the daily sedentary behavior of the elderly (variation of 6–10 h·day−1) was related to a 33% greater risk of presenting a reduction in muscle volume and muscle strength during aging (sarcopenia). These results suggest that aging is not necessarily accompanied by sarcopenia, reinforcing the notion that the absence of exercise and/or sedentary behavior are “key elements” for the progression of sarcopenia/atrophy of the aging muscle tissue.
Regardless of the causes behind the reduction in muscle activity in aging, it is commonly accepted that older individuals have higher rates of both “muscle volume” and “muscle functionality” losses in periods of physical inactivity/disuse when compared to younger individuals [49][50]. Moreover, studies indicate that older subjects present lower muscle volume/functionality recovery (after a period of disuse) than young adults [50][51][52]. Recent findings indicate that physical inactivity/disuse intensifies the muscular anabolic resistance state of the elderly, possibly through the increase of pro-inflammatory markers (TNFα and CRP) and through the reduction of postprandial insulin sensitivity [53][54]. Noteworthily, the current literature indicates an interesting relationship between the increase in pro-inflammatory markers (or the dysregulation between pro- and anti-inflammatory markers) and the accentuated loss of muscle volume/function in the elderly (for more details, see topic “Inflammation, aging, and muscle tissue”). In randomized trials focusing on measuring MPS rates and lean mass gain, this crosstalk between muscle, aging, and “inflammatory balance” needs further investigation.
Aiming to elucidate the impact of different periods (or “models”) of reduced contractile activity in aging, several studies investigated the changes in muscle metabolism under three circumstances, which are typical throughout the aging process: the number of daily steps [29][51][54][55][56], specific muscle groups immobilization [52][57][58][59][60], and/or “bed rest” periods [61][62][63][64][65][66]. These three different models of reduced muscle contractile activity led to the so-called “catabolic crises”: events that favor the transition of older adults to the sarcopenic state, through brief moments of reduction in muscle activity with high catabolism of muscle mass, often difficult to establish “full recovery” for older individuals [67]. Based on this concept, older adults may have one or more of these catabolic crises “triggering” events as the decades go by (by hospital admissions, limb immobilization, and momentary difficulty in locomotion), increasing their risk for muscle atrophy in older-aged subjects.
Among the studies that analyzed the impact of reducing daily steps among participants aged 65–73 years [51][54], it was pointed out that individuals who perform a small number of daily steps (<1000–1500 daily steps, for 14 days) show a ~14–26% MPS decay when compared to subjects who practice ≥6000 steps daily [51][54]. Limb immobilization studies showed that quadriceps immobilization for 14 days led to a 5% decrease in thigh muscle volume among older adults. Other studies showed losses of around 2% in the first five days of immobilization/disuse, combined with an initial loss of muscle strength in the order of 8.3% [60]. On the other hand, bed rest muscle contractile activity reduction models (a more rigorous model of sedentary lifestyle and physical inactivity) showed that only five days of bed rest provides a 4% reduction in the thigh lean mass with a more accentuated reduction in the MyHC I fiber type (−26.3% ± 17.2%) [68]. Relevant losses in muscle functionality are well documented in the elderly during the first ten days of bed rest [63][64][65].
From these initial data, individualized strategies (nutrition, low-intensity exercises, and reduction of sedentary behavior) for the elderly population aiming to recover muscle functionality and/or protection from muscle catabolism should be better investigated during these periods of physical inactivity/disuse. Nutritional strategies might include the appropriate consumption of protein or amino acids. Physical exercise practice should focus on improving specific older people’s limitations/needs. In addition, sedentary behavior seems to be potentially relevant in the context of aging and musculoskeletal changes. In this case, studies indicate that sedentary behavior could be reversed by increasing the number of steps per day (>6000 steps) or engaging in fewer than 6 h·day−1 of sedentary behavior during the individual’s waking time. In the context of aging, this should be better explored in future clinical trials.

3.2. Inflammation, Aging, and Muscle Tissue

Aging is characterized by physiological changes that induce low-grade chronic inflammation through the constant presence of pro-inflammatory factors/agents. The main changes inherent to aging occur both because of changes in cellular aging/cell renewal processes (senescence process), as well as significant changes in lipid metabolism and/or storage in the muscle tissue [69][70][71]. Notably, these changes induce more significant chronic signaling in the activity of immune cells (infiltrating lymphocytes and macrophages), in addition to a higher production of reactive oxygen species (ROS) and cell damage, providing systemic increases in pro-inflammatory markers throughout the aging process (such as NF-κB, Interleukin-1 [IL-1], IL-6, interleukin-8 [IL-8], CRP, and TNFα) [70][72][73][74].
Higher levels of some of these pro-inflammatory markers are related to unfavorable muscle metabolism and function changes during the aging process (sarcopenia) [75][76][77][78][79][80]. In these cases, some studies showed a higher concentration of inflammatory markers (CRP, IL-6, and TNFα) in the elderly who have a more significant loss of strength/muscle mass, with a simultaneous decrease in their physical capacity [80][81].
In a recent study, Sciorati et al. (2020) [82] clarified the physiological impacts of TNFα production on muscle fibers by monitoring the aging of healthy mice from 12 to 28 months of life (corresponding to 40–90 years of age in humans) under two conditions. In the study, control mice (C57BL/6) showed functional impairment of muscle tissue with parallel muscle atrophy (±20% drop) [82]. In contrast, the rodents that were treated weekly with a pharmacological blocker for TNFα (Etanercept) did not present atrophy and loss of muscle fibers (mainly those of type IIB and IIA), which provided improvements in the muscular function of the mice [82].
Another component correlated to increased pro-inflammatory markers (CRP, IL-6, and TNFα) and the loss of functionality in the elderly’s muscle tissue is myosteatosis. It is defined as changes in fat infiltration, leading to increasing intramyocellular and inter-muscular fat [83][84]. Delmonico et al. (2009) [85] studied changes related to thigh muscles composition, strength, and muscle quality of 1678 elderly (mean age of 73.5 years), pointing to a direct relationship of gains and/or maintenance of body weight with the increase in subcutaneous fat (common condition to sarcopenia). Regarding the fat infiltration in the muscle tissue, an increase in intramuscular fat (16.8–74.6%) and loss of maximum torque strength (13.4–16.1%) were observed regardless of the reduction, maintenance, or increase of individuals’ subcutaneous fat [85]. In addition to these findings, Gueugneau et al. (2015) [86] compared the lipid infiltration into the muscle fibers of 5 young people, 15 healthy elderly, and nine elderly subjects with metabolic syndrome (MS), pointing out higher intramyocellular lipid contents in the elderly (both healthy and with MS). In addition, a more pronounced increase in the atrophy of IIX type and IIA-IIX type muscle fibers was observed among the group of older people with MS compared to the group of healthy elderly subjects [86].
Since both the lipids storage and the plasma level of some pro-inflammatory markers are related to the functionality and muscle volume of the elderly, researchers and health professionals should look more closely this population. During the past two and a half decades, factors such as physical inactivity, insulin resistance, increased plasma levels of IL-6, increased intramuscular fat storage, and adequacy of protein consumption have been identified as “therapeutic targets” in combating sarcopenia during the aging process [87][88].
Current research shows that greater “body adiposity” [89][90][91][92], “scenarios of insulin resistance”, and “sarcopenia” are associated with increased systemic levels of various inflammatory markers (particularly IL-6 and TNFα). These markers, in theory, would be able to stimulate metabolic pathways related to muscle atrophy and reduced muscle fiber regeneration [93][94]. As a result, greater adiposity, MS, DM2, and other chronic diseases associated with aging, promote an even more robust increase in pro-inflammatory markers, which are potentially harmful to protein synthesis and muscle mass gain/maintenance.
From recent discoveries about the imbalance of pro- and anti-inflammatory mediators and their possible impacts on the synthesis and/or maintenance of muscle tissue, contemporary research has studied the effects of dietary training on seniors’ inflammatory markers and muscle tissue. Notably, the consumption of low amounts of protein is related to the increase in pro-inflammatory markers (CRP, IL-6, and TNFα). Therefore, specific adjustments in protein consumption/fractionation are indicated for the elderly population [75][95]. In addition, it is pointed out that muscle contraction induced by physical training can increase the production of a series of anti-inflammatory markers (IL-6, Interleukin-10 [IL-10], and transforming growth factor beta [TGF-β], for example), which are favorable for adaptive processes of the muscle tissue [96][97]. There are also encouraging results pointing to a reduction in some pro-inflammatory markers (TNFα, CRP, IL-1, IL-6, and IL-8) in the elderly population, either through the acute realization of specific training protocols or by greater physical conditioning [54][96][97][98][99][100][101]. For a complete review of exercise protocols (aerobics, and combined and strength exercises), refer to Bruunsgaard, 2005 [99]. For more information about the impact of physical inactivity/sedentary behavior on muscle tissue, the reader should be directed to the section “Effect of physical inactivity/sedentary behavior on muscle tissue in aging”.
In summary, regular physical exercises and adequate dietary protein intake must be essential points of attention in geriatrics studies. In this regard, the current academic literature points out that physical training and protein support are factors of high importance both for the balance of pro- and anti-inflammatory markers (such as the TNFα/IL-10 ratio or the IL-6/IL-8 ratio) and for the synthesis/degradation stimuli balance in the muscle mass of the elderly [97][101][102][103][104].

3.3. Digestion, Absorption, and Gut Microbiota

This section highlights the roles of physical inactivity, inflammation, and obesity as aggravating anabolic resistance factors, which can be modifiable through lifestyle changes. We also briefly discuss the possible role of gut microbiota in the genesis of anabolic resistance.
In recent years, knowledge related to gut microbiota and its importance in the host function has been increasing. It is known that gut microbiota suffers many alterations during a person’s life; with aging, an inversion of phyla predominance occurs. For example, proteobacteria phylum (pro-inflammatory bacteria genus) increases overlapping with bacteroid and firmicute phylum (the predominant phylum in a healthy adult), associated with decreasing in health-promoting bacteria (e.g., Bifidobacterium, Faecal-bacterium genera) and short-chain fat acids (SCFA) production. This dysbiosis is associated with increased gut permeability in the elderly [105]. Considering the strong interaction between the gut microbiota and the immune system, studies suggest that with the aging process, gut-microbiota inflammation precedes the low-grade systemic inflammation [105].
There is also a well-known connection between the gut and the muscle tissue, which connects the aging-dysbiosis and sarcopenia process and is related to anabolic resistance. Dysbiosis generates low-grade systemic inflammation (from the increased circulating endotoxins) that culminates in an increase in ROS production, expression of NFKB, inhibition of anabolism, reduction of protein synthesis, and facilitation of insulin resistance [106]. Accordingly, therapeutic targets related to gut microbiota (e.g., probiotics, fermented foods, transplantation) have been appointed as helpful to slow the aging process.
According to Gorissen et al. (2020) [107], protein absorption kinetics is attenuated in the elderly compared to young individuals since older adults have reduced pathways related to carbohydrate metabolism and amino acid synthesis by gut microbiota [108]. Due to the critical relationship between protein adsorption kinetics and anabolic stimulus, probiotics may act on protein absorption kinetics. A study [109] showed that two weeks of probiotic use (5 billion CFU L. paracasei LP-DG® (CNCM I-1572) plus 5 billion CFU L. paracasei LPCifS01 (DSM 26760)) was able to increase methionine, histidine, valine, leucine, isoleucine, tyrosine, total BCAA, and total EAA maximum concentration (Cmax) and area under the curve (AUC) after the consumption of 20 g of pea protein. However, it is important to note that the sample of this study was young and physically active men. Thus, it is possible that in elderly subjects, the results could be different. Additionally, it is unknown if similar results would be found after consuming a higher-quality protein source (meat or milk proteins).
A powerful enterocyte energy source and anti-inflammatory compound is butyrate. Therefore, declines in butyrogenic bacterial species, a characteristic of the aging process, may be viewed as a pivotal contributor to age-related anabolic resistance. Besides, some specific amino acids appear to be dependent on microbial sources (lysine, leucine). For example, aging is associated with a decrease in Prevotella, a microorganism involved in lysine biosynthesis and related to leucine. The gut microbial (Prevotella, Allistiples, and Barnesiella) synthesizes up to 15% of leucine (the most critical amino acid to signal the intracellular anabolic signal). Another point to be considered is the splanchnic amino acids extraction; in older individuals, we can see an increase in leucine oxidation in the gut and/or liver. Studies suggest a heightened rate of leucine oxidation and thus more significant splanchnic sequestration of amino acids associated with aging dysbiosis [110].
Dysregulation of the IGF-1 anabolic signaling cascade and resultant sarcopenia may be caused by dysbiosis of the gut microbiome and depletion of IGF-1-related microbes such as lactobacilli, possibly the L. Plantarum [111]. According to a review by Badal et al. (2020) [108], a greater abundance of L. Plantarum is seen in healthy, long-lived individuals [108]. A study conducted by Hopkins et al. (2001) [112] with healthy elderly subjects and geriatric patients demonstrated a reduced number of Bifidobacterial (other important acid-lactic bacteria genera) [112]. Species diversity was markedly lower in the clostridium difficile associated diarrhea group, characterized by high numbers of facultative anaerobes and low levels of bifidobacteria and bacteroides. According to the authors, the reductions in these organisms may be related to increased disease risk in older adults [112].
Preservation of these good microbial strains with diet strategies, polyphenols, probiotics, prebiotics, and fermented foods should be considered to reduce anabolic resistance in aging [113][114][115].
In addition, studies indicate that physical activity is a viable therapy to counteract age-related gut dysbiosis, improving the bioavailability of nutrients through the action of specific intestinal bacteria (e.g., polyphenols). Additionally, exercise can induce favorable changes in gut microbiota composition (increasing health-promoting bacteria) and metabolite production (increasing SCFA producing taxa and microbial production) [113][114][115].

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