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This is a compilation of the research I have done for Hubby. His legs are getting weaker and weaker and he now has trouble getting out of a chair or walking without a cane.

Since I switched to Firefox I have been inundated with ads. One is by a Dr Gundry who sells high priced supplements. One is Muscle Defense from ApexLabs. I am not interested in the supplement but he did have interesting information.

It seems as we get older, our bodies no longer use proteins to make muscle. Or at least not as easily. So here is what I have found.

First Question: Is there actually the problem Gundry stated?

Anabolic Resistance of Muscle Protein Turnover Comes in Various Shapes and Sizes

Abstract

Anabolic resistance is defined by a blunted stimulation of muscle protein synthesis rates (MPS) to common anabolic stimuli in skeletal muscle tissue such as dietary protein and exercise. Generally, MPS is the target of most exercise and feeding interventions as muscle protein breakdown rates seem to be less responsive to these stimuli. Ultimately, the blunted responsiveness of MPS to dietary protein and exercise underpins the loss of the amount and quality of skeletal muscle mass leading to decrements in physical performance in these populations. The increase of both habitual physical activity (including structured exercise that targets general fitness characteristics) and protein dense food ingestion are frontline strategies utilized to support muscle mass, performance, and health. In this paper, we discuss anabolic resistance as a common denominator underpinning muscle mass loss with aging, obesity, and other disease states. Namely, we discuss the fact that anabolic resistance exists as a dimmer switch, capable of varying from higher to lower levels of resistance, to the main anabolic stimuli of feeding and exercise depending on the population. Moreover, we review the evidence on whether increased physical activity and targeted exercise can be leveraged to restore the sensitivity of skeletal muscle tissue to dietary amino acids regardless of the population.

Protein Requirements and Recommendations for Older People: A Review

Abstract

Declines in skeletal muscle mass and strength are major contributors to increased mortality, morbidity and reduced quality of life in older people. Recommended Dietary Allowances/Intakes have failed to adequately consider the protein requirements of the elderly with respect to function. The aim of this paper was to review definitions of optimal protein status and the evidence base for optimal dietary protein. Current recommended protein intakes for older people do not account for the compensatory loss of muscle mass that occurs on lower protein intakes. Older people have lower rates of protein synthesis and whole-body proteolysis in response to an anabolic stimulus (food or resistance exercise). Recommendations for the level of adequate dietary intake of protein for older people should be informed by evidence derived from functional outcomes. Randomized controlled trials report a clear benefit of increased dietary protein on lean mass gain and leg strength, particularly when combined with resistance exercise. There is good consistent evidence (level III-2 to IV) that consumption of 1.0 to 1.3 g/kg/day dietary protein combined with twice-weekly progressive resistance exercise reduces age-related muscle mass loss. Older people appear to require 1.0 to 1.3 g/kg/day dietary protein to optimize physical function, particularly whilst undertaking resistance exercise recommendations.

Evidence-Based Recommendations for Optimal Dietary Protein Intake in Older People: A Position Paper From the PROT-AGE Study Group

Abstract

New evidence shows that older adults need more dietary protein than do younger adults to support good health, promote recovery from illness, and maintain functionality. Older people need to make up for age-related changes in protein metabolism, such as high splanchnic extraction and declining anabolic responses to ingested protein. They also need more protein to offset inflammatory and catabolic conditions associated with chronic and acute diseases that occur commonly with aging. With the goal of developing updated, evidence-based recommendations for optimal protein intake by older people, the European Union Geriatric Medicine Society (EUGMS), in cooperation with other scientific organizations, appointed an international study group to review dietary protein needs with aging (PROT-AGE Study Group). To help older people (>65 years) maintain and regain lean body mass and function, the PROT-AGE study group recommends average daily intake at least in the range of 1.0 to 1.2 g protein per kilogram of body weight per day. Both endurance- and resistance-type exercises are recommended at individualized levels that are safe and tolerated, and higher protein intake (ie, ≥1.2 g/kg body weight/d) is advised for those who are exercising and otherwise active. Most older adults who have acute or chronic diseases need even more dietary protein (ie, 1.2–1.5 g/kg body weight/d). Older people with severe kidney disease (ie, estimated GFR <30 mL/min/1.73m2), but who are not on dialysis, are an exception to this rule; these individuals may need to limit protein intake. Protein quality, timing of ingestion, and intake of other nutritional supplements may be relevant, but evidence is not yet sufficient to support specific recommendations. Older people are vulnerable to losses in physical function capacity, and such losses predict loss of independence, falls, and even mortality. Thus, future studies aimed at pinpointing optimal protein intake in specific populations of older people need to include measures of physical function.

So yes there is evidence of the problem.

Gundry said he found the KEY protein that ‘unlocks’ the repair and rebuild signal. An amino acid named leucine. Well he is sort of correct but there is a lot more to it. I found an excellent paper and have provided excerpts at the end of this article. It is a very long paper. Before I found that paper I found other information of interest.

Before I go any further into Amino acids and muscle building, I want to point out something that I think the researchers are missing. A Qtreeper handed this information to us.

Exposing The Great Acid Reflux Scam — Why Stomach Acid Is Critical For Health — A Midwestern Doctor

This is the important part for this article.

Why Stomach Acid Is Essential for Your Health

Subtle distortions frequently occur in science, creating a false conception of reality that conveniently allows a profitable industry to exist. For example, stomach acid is largely viewed as unnecessary and thus frequently possible to justify eliminating with acid suppressing medications. In reality, it has numerous vital functions:

Protein Digestion: Amino acids, the building blocks of the body, are obtained from protein. Without sufficient acid, proteins can’t be properly digested, leading to significant nutritional deficiencies, impaired energy levels, mood or cognitive function, and food sensitivities from undigested foreign proteins entering the bloodstream…

Since GERD [Gastroesophageal reflux disease] is so common, that suggests there is also a widespread deficiency in stomach (hydrochloric) acid. Presently, I believe a few factors are responsible:

Aging: Stomach acid production decreases with age, particularly after 60. This decline is linked to various health issues, making amino acid and B-12 supplementation crucial for older adults. The increasing prevalence of GERD with age suggests that doctors often misattribute symptoms to excess acid rather than considering a deficiency…

If the proteins are not being digested, then the amino acids will not be available for muscle building.

How to Get 2.5 gr of Leucine

The Importance of Leucine

Leucine is one of the three branched-chain amino acids (BCAAs) essential for muscle protein synthesis. Unlike other amino acids, the body cannot produce leucine, so getting it from your diet is vital. Understanding the leucine content in foods can help you make informed dietary choices to support your fitness and health objectives.

One reason many people refer to 30 g of protein as the minimum amount per meal is that that’s the amount typically required to get 2.5 g of leucine from most foods. Professor Don Layman’s research emphasises leucine for muscle growth, showing that older adults require at least 2.5 g of leucine to activate muscle protein synthesis, which is vital for muscle building and repair. 

With less than this, the protein you eat is used only to maintain your vital organs, which are a higher priority than your muscles.  While leucine is required to activate muscle protein synthesis, you need all the essential amino acids to build and repair your body, so it’s not as simple as supplementing with leucine. 

How Much Leucine and BCAAs Do You Need?

This article has references to several papers.

….In order to get the most from your time in the weights room, you might want to start thinking about adding more Branched-chain Amino Acids (BCAAs) and Leucine to your diet. But what are they? What will they do for you? Do you even need them? Here’s everything you need to know…

Nine of these are essential for humans to consume in our diets as they can’t be created from other amino acids, and these are known as Essential Amino Acids (EAAs). Three of these are categorised as Branched-chain Amino Acids – so-called because of their structure – and these are leucine, isoleucine and valine.

Different protein-rich foods vary in their protein quality, and you can read more about this in our Guide to Protein Quality, Digestion and Absorption.

3 Amino Acids That Promote Muscle Growth (and the Foods You’ll Find Them In)

…Our bodies need 20 amino acids overall to develop and function, but the nine essential amino acids we get from our food are histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, and valine. Foods that contain adequate levels of these amino acids and can be easily digested and absorbed are considered “complete proteins.” They typically come from animal sources, so you can get a good dose of them from a juicy steak or pan-seared salmon…

Many plant proteins are considered incomplete, with a handful of exceptions such as tofu and edamame…

Leucine, isoleucine, and valine are the three branched-chain amino acids, and they’re your best friends when trying to build muscle. 

Leucine is the most powerful amino acid for muscle growth because it’s thought to stimulate the actual muscle protein synthesis process, but isoleucine and valine also play important supporting roles along the way…

1. Leucine

Leucine acts as a sort of “green light” to muscle growth. It triggers muscle protein synthesis “by signaling to pathways that other amino acids are available to start the muscle repair process post-exercise,” explains Samuel, adding that you need at least 2–3 grams of leucine to stimulate the process. 

Research also illustrates leucine’s role in promoting muscle growth and metabolic health. A small 2020 study published in the journal Nutrients, for example,found that leucine helped moderately reduce muscle damage in young men after a short bout of resistance exercise. This amino acid also helps heal wounds and balance blood sugar levels, according to the Cleveland Clinic.

2. Isoleucine

Isoleucine also contributes to muscle protein synthesis, playing a vital but not quite as influential role as leucine. It appears to increase muscle mass by promoting myogenesis, the process by which we actually form muscle tissue, according to a 2021 study in mice published in Food & Function.

BCAAs, especially isoleucine, also help increase the uptake of glucose into cells, according to Samuel. Because glucose is your body’s main fuel source, isoleucine may indirectly help boost your energy (although more research is needed). And the more energy you have, the harder you can hit your muscle-building workouts.

3. Valine

Valine acts as a complement to the other two BCAAs: It’s used to make glucose in the body and helps improve muscle protein synthesis when paired with leucine and adequate levels of other amino acids, Samuel says.

Plus, a 2023 study published in Bioscience, Biotechnology, & Biochemistry indicates that valine improves mitochondrial function, aka the body’s ability to generate energy from the food we eat…

Leucine: The Amino Acid That Matters Most for Muscle

“Originally it was thought that all three BCAAs play a direct role in muscle building,” says Paul Falcone, principal scientist at BODi. “But research indicates that much of the effect of branched-chain amino acids is really driven by leucine.”

That’s because leucine is key in the process of muscle protein synthesis, which enables muscle hypertrophy (growth).

Leucine has the ability to directly signal mTOR, one of the major nutrient sensor molecules and master regulators in the body that’s known for anabolic (growth) signaling. This helps make muscles absorb protein, which is key for their preservation and growth.

In this way, leucine is both a building block at a construction site and the contractor directing the process, Falcone says. Because it plays this dual role, it’s the most important amino acid for muscle building.

According to the USDA FoodData Central, some of the foods that contain the most leucine per serving include:

• Chicken
• Beef
• Pork
• Tuna
• Milk
• Cheese

“The amount of leucine that you have in protein is important,” Falcone says. “But leucine is not going to be effective on its own. It’s effective in the right amount, as a part of an essential amino acid blend or protein supplement. The leucine content of your protein is a major driver of its effect on muscle building.”

According to a 2017 position stand by the International Society of Sports Nutrition, your protein supplement should contain 700 to 3,000 mg of leucine per serving, in addition to a balanced array of essential amino acids.

What is Leucine? | Leucine Benefits, Dosage and Sources

Leucine dosage and when to take

Most research supports that between 20-40mg/kg body weight per day is adequate for supporting ideal levels of leucine in the body. One study showed that the timing of leucine supplementation did not make a difference (unlike BCAAs, which are recommended before or during a workout).^2,4 Keeping a consistent intake of leucine is key, especially for the effects it can have for preventing muscle breakdown on rest days.

Leucine Food Sources

Food	Leucine content (g per 100g)
Beef	2.9
Chicken breast	2.7
Tuna	2.4
Seeds	2.4
Pork	2.2
Nuts	1.5
Tofu	1.4
Eggs	1.1

I am including the following because it has alternate food sources and other info.

Top Foods High in Leucine — WebMD

Recommended Daily Amounts of Essential Amino Acids
Amino Acid	Recommended Daily Allowance
Histidine	14 milligrams
Isoleucine	19 milligrams
Leucine	42 milligrams
Lysine	38 milligrams
Methionine	19 milligrams
Phenylalanine	33 milligrams
Threonine	20 milligrams
Tryptophan	5 milligrams
Valine	24 milligrams

There are many dietary sources for leucine and other BCAAs. Consider these healthy sources of amino acids: 

Salmon

Get your amino acids from salmon, and you’ll also get omega-3 fatty acids. There are some health concerns about farmed salmon. Choose wild-caught or limit your servings per month.

Chickpeas

These nutritional superstars contain 7 grams of protein and 6 grams of fiber in just half a cup, and they are high in iron, too. Enjoy them as hummus or add them to soups, stews, curries, and salads.

Brown rice

Try brown rice instead of white. It has a nutty taste and a slightly chewy texture that many people enjoy.

Eggs

Even the American Heart Association says that an egg a day is okay. You’ll get 6 grams of protein in one egg. 

Soybeans

This versatile legume is available in a variety of forms, including tofu, tempeh, edamame, and roasted soybeans. Today, texturized soy protein is readily available in supermarkets. It can substitute meat in many dishes.

Nuts

Almonds, Brazil nuts, and cashews are good sources of essential amino acids. So are peanuts, although they are technically legumes instead of nuts.

Beef

Beef is one of the best sources of amino acids. To reduce your intake of fats and cholesterol, choose a lean cut or try grass-fed beef.

Protein Requirements and Recommendations for Older People: A Review

Abstract

Declines in skeletal muscle mass and strength are major contributors to increased mortality, morbidity and reduced quality of life in older people. Recommended Dietary Allowances/Intakes have failed to adequately consider the protein requirements of the elderly with respect to function. The aim of this paper was to review definitions of optimal protein status and the evidence base for optimal dietary protein. Current recommended protein intakes for older people do not account for the compensatory loss of muscle mass that occurs on lower protein intakes. Older people have lower rates of protein synthesis and whole-body proteolysis in response to an anabolic stimulus (food or resistance exercise). Recommendations for the level of adequate dietary intake of protein for older people should be informed by evidence derived from functional outcomes. Randomized controlled trials report a clear benefit of increased dietary protein on lean mass gain and leg strength, particularly when combined with resistance exercise. There is good consistent evidence (level III-2 to IV) that consumption of 1.0 to 1.3 g/kg/day dietary protein combined with twice-weekly progressive resistance exercise reduces age-related muscle mass loss. Older people appear to require 1.0 to 1.3 g/kg/day dietary protein to optimize physical function, particularly whilst undertaking resistance exercise recommendations.

And finally the LONG paper I mentioned at the beginning.

Anabolic Resistance in the Pathogenesis of Sarcopenia in the Elderly: Role of Nutrition and Exercise in Young and Old People

The term “sarcopenia” (from the Greek words “sarx”, i.e., flesh, and “penia”, i.e., loss) was first proposed by Rosenberg in 1989 to describe the age-related loss of muscle mass [1]. Later, this term referred to the decrease in muscle mass and/or strength with ageing.

Abstract

The development of sarcopenia in the elderly is associated with many potential factors and/or processes that impair the renovation and maintenance of skeletal muscle mass and strength as ageing progresses. Among them, a defect by skeletal muscle to respond to anabolic stimuli is to be considered. Common anabolic stimuli/signals in skeletal muscle are hormones (insulin, growth hormones, IGF-1, androgens, and β-agonists such epinephrine), substrates (amino acids such as protein precursors on top, but also glucose and fat, as source of energy), metabolites (such as β-agonists and HMB), various biochemical/intracellular mediators), physical exercise, neurogenic and immune-modulating factors, etc. Each of them may exhibit a reduced effect upon skeletal muscle in ageing. In this article, we overview the role of anabolic signals on muscle metabolism, as well as currently available evidence of resistance, at the skeletal muscle level, to anabolic factors, from both in vitro and in vivo studies. Some indications on how to augment the effects of anabolic signals on skeletal muscle are provided.

….

2.1. The Molecular Mechanisms behind Muscles Growth in Young Subjects: Exercise, Nutrients, and Hormones

Muscle growth, or muscle hypertrophy, is a complex process regulated by several molecular pathways. The primary pathways that promote muscle growth in response to exercise, nutrients, and growth signals include the IGF-1/PI3K (phosphoinositide 3-kinase)/Akt/mTOR pathway and hormones like testosterone and GH (Figure 1).

The IGF-1/PI3K/Akt/mTOR pathway is a vital signaling cascade in muscle growth that involves various interconnected mechanisms. Its activation increases protein synthesis, reduces protein degradation, and improves cell growth. The molecular mechanisms and interactions within this pathway are still being studied in human muscle physiology. When activated, mTOR promotes muscle hypertrophy by stimulating protein synthesis and cell growth [13]. The mTOR kinase is the main regulator of muscle protein synthesis and responds to the availability of nutrients, particularly amino acids and growth factors. Indeed, resistance exercise and nutrient intake, especially leucine-rich amino acids, activate the mTOR pathway essential for exercise-induced muscle protein synthesis and are, thus, necessary for increasing muscle protein synthesis following resistance exercise in young men…

The timing of exercise and protein intake also affect Akt activation and subsequent muscle protein synthesis. While exercise alone did not increase Akt and mTOR phosphorylation, protein ingestion afterward did so in a dose-dependent manner. As a matter of fact, Akt activation is a complex process influenced by exercise, nutrition, and specific amino acids, and further research is being conducted to fully understand its role in muscle growth and adaptation [18].

The upstream controller in this axis is the insulin-like growth factor-1 (IGF-1), which is crucial in promoting growth and anabolic processes in skeletal muscles [13]. IGF-1 is a key growth factor that regulates both anabolic and catabolic pathways in skeletal muscle…

Testosterone is one of the most potent naturally secreted androgenic-anabolic hormones, and its biological effects include promoting muscle growth. In muscle, testosterone stimulates protein synthesis (anabolic effect) and inhibits protein degradation (anti-catabolic effect) [25,26,27,28,29]. Testosterone plays a crucial role in muscle growth in response to exercise and nutrition. Various studies have shed light on this topic. Vingren et al. (2010) explored the physiological aspects of testosterone in resistance exercise and training, highlighting its upstream regulatory elements [28]. They found that testosterone enhances muscle protein synthesis, stimulates satellite cell activation and proliferation, and modulates anabolic signaling pathways such as mTOR and IGF-1. These findings suggest that testosterone plays a key role in mediating the anabolic response to resistance exercise…

2.2.1. Effects of Proteins and Amino Acids

…Leucine is particularly important as a key metabolic regulator of MPS through its activation of the mTOR pathway, and it acutely enhances skeletal MPS both in vitro [45,47,48,49,50] (also above) and in vivo [51]. In addition to the protein or the amino acids, other variables or factors, such as the coexistence of exercise, the pattern and/or the timing of nutrient administration, the age of subjects, the presence of comorbidities, etc., are important. Most reports have investigated the combined effect of protein and exercise…

Leucine, isoleucine, and valine, i.e., the branched-chain amino acids (BCAA), account for about one-third of all amino acid residues in muscle protein, and have been extensively studied regarding their direct regulatory role (due to leucine) on protein synthesis (see also above). Nevertheless, the demonstration of a clear-cut effect of BCAA alone, on skeletal muscle hypertrophy (i.e., a long-term effect) in humans is not sound. In a meta-analysis, leucine supplementation was reported to increase the muscle protein fractional synthesis rate, however, without changing either body lean mass or leg lean mass [61]. The effect of another amino acid, glutamine (non-essential), on skeletal muscle in humans, is yet uncertain and/or unwarranted…

The structure/form of nutrient intake (free AA vs. intact protein) with respect to the timing of administration (either before, or 1 to 3 h after, exercise) on the stimulation of skeletal muscle protein accretion is relevant too. While net amino acid uptake by skeletal muscle (measured by means of femoral arteriovenous sampling) was greater when free essential amino acids plus carbohydrates were ingested before, rather than after, resistance exercise [84], the ingestion of intact whey protein was similar irrespective of the administration time [85].

2.2.3. Effect of Other Substrates

Protein synthesis is an energy-requiring process [86]; therefore, energy-providing substrates such as glucose and fat may affect protein turnover too. The activities of the cellular pathways controlling protein turnover are bio-energetically expensive and therefore depend on intracellular energy availability (i.e., macronutrient intake) [87].

Glucose

Glucose increased muscle protein synthesis in vitro [88]. Testing glucose-induced or derived substrates separately, tissue ATP decreased during incubation with lactate, and lactate + pyruvate supported protein synthesis better than pyruvate or glucose. The data on the effects in humans of either glucose or fat on protein metabolism, specifically on skeletal muscle, are scarce, complex, and not univocal [42]. Enteral glucose administration did not affect either duodenal mucosal protein FSR or the activities of mucosal proteases [89]. An oral glucose load, and the simultaneous glucose-induced stimulation of insulin secretion, did not alter the rate of whole-body protein synthesis or breakdown [90]. Similarly, glucose ingestion added to a protein dose that maximally stimulated MPS, despite greater insulin increments, did not show either additive or synergistic effects on either the stimulation of MPS or the inhibition of muscle protein breakdown [91]. The co-ingestion of carbohydrates with protein did not further augment the post-exercise stimulation of muscle protein synthesis…

Lipids and Ketones

The effects of either lipid or ketone infusion/administration in humans are complex. Lipid infusion in humans did not affect proteolysis [96]. In contrast, medium-chain fatty acid infusion apparently increased leucine oxidation and, therefore, net protein catabolism [97]. Thus, the effects on whole-body protein degradation may depend on the fatty acid length [98]. The increase in FFA decreased basal muscle protein synthesis, but not the anabolic effect of leucine [99]. When associated with dietary protein ingestion, neither acute nor short-term dietary fat overload impaired skeletal MPS in overweight/obese men in the post-prandial phase, thus excluding a role by dietary accumulation of intramuscular lipids on the anabolic response to meal ingestion [100]. The infusion of 3OHButyrate decreased both whole body and forearm protein turnover (measured by phenylalanine/tyrosine tracers), as well as phenylalanine catabolism, in post-absorptive conditions, whereas it did not modify the insulin-induced effects following an euglycemic clamp [96]. In another study, 3OHButyrate infusion did not change whole-body leucine turnover, decreased leucine oxidation, and increased the non-oxidative portion of leucine disposal, while muscle PS increased, demonstrating an anabolic effect of 3OHButyrate at this level [101].

[There is a whole lot more info. And then they get into us old folks. — GC]

3.2. Anabolic Resistance in Ageing: Human Studies

Elderly subjects exhibit many abnormalities in protein metabolism in respect to younger subjects, here concisely summarized:

1. An increased splanchnic “trapping” of the ingested substrates, henceforth reducing amino acid delivery to peripheral tissues, such as skeletal muscle. Google AI — Aging and Clinical States: In older adults or those with certain metabolic conditions, splanchnic uptake can become hyperactive (a process called splanchnic sequestration). This means too many amino acids get trapped in the gut/liver, leaving less available for the muscles. This contributes to age-related muscle loss (sarcopenia)
2. A decreased amino acid utilization by muscle, and/or the requirement for a greater AA load/delivery to stimulate appropriately PS in muscle, compatible with an anabolic-resistant state. In other words, the skeletal muscle in ageing might be less sensitive to lower (normal) levels of amino acids than that in young adults, and may thus require more protein to acutely stimulate muscle protein synthesis above rest, to achieve the required accretion of muscle proteins.
3. A decrease in energy production otherwise required to sustain the energy-expensive PS.
4. Altered protein digestion.
5. A decrease in transluminal AA transport.
6. An intestinal microbiota different from that of younger people.

Any of the above-listed potential factors could explain why elderly people would require, and/or are recommended to assume, at least ≈ 50% more protein than either young or mature subjects [66]. In the following sections, we report the literature data on protein turnover in ageing, both in basal and “post-absorptive” conditions, and following nutrition, exercise, and response to hormones.

…

However, at variance with these earlier reports, more recent studies consistently failed to confirm the earlier findings of decreased basal muscle protein synthesis in elderly subjects, showing little or no differences between young and old adults…

It should, however, be recognized that basal muscle protein turnover could particularly be altered in frail, elderly subjects, being potentially associated also with a chronic, subtle, systemic inflammatory state and/or other co-morbidities [198,199]. Indeed, inflammatory mediators, such as cytokines, particularly TNFα, may impair skeletal muscle protein FSR, by interfering with the phosphorylation of the mammalian target of the rapamycin (mTOR) pathway [150], critically involved in the regulation of mRNA translation, muscle protein synthesis, and growth [200]. Therefore, it is currently accepted that basal skeletal muscle protein turnover is near-normal in healthy elderly subjects. In contrast, a different, complex picture can emerge when studying the response in ageing of skeletal muscle protein turnover to anabolic stimuli, such as substrates (i.e., mixed meals, protein, amino acid mixtures, other metabolites), exercise, anabolic hormones, or their combinations.

Elderly subjects exhibit some peculiarities in the handling of oral feeding. Using the essential amino acid leucine as a tracer, a greater first-pass splanchnic uptake of ingested amino acid(s) was reported in the elderly rather than in young people, suggesting that a lower proportion of ingested amino acid reached the peripheral circulation [195]. Such a greater splanchnic extraction could limit the amino-acid-mediated stimulation of muscle protein synthesis in peripheral tissues such as skeletal muscle. Consequently, sustaining splanchnic vs. muscle protein synthesis could indicate a “metabolic priority” during recovery from metabolic stress in healthy elderly persons. Such a mechanism might become more relevant in older individuals suffering from chronic diseases and/or subjected to poly-medications [201]. However, in contrast with the above report, it was also reported that oral amino acids stimulated muscle protein anabolism in the elderly, despite the higher first-pass splanchnic extraction [202].

A protein pulse rather than a spread (or continued) oral feeding stimulated the best protein accretion in the elderly [203]…

Generally speaking, dietary protein supplementation can augment the gains in skeletal muscle mass and strength mediated by resistance exercise… Verdijk et al. compared the increment(s) in skeletal muscle mass and strength following 3 months of resistance exercise training, with or without protein ingestion, either prior to or immediately after each exercise session in elderly males who habitually consumed about 1.0 g protein/kg per day [210]. They concluded that timed protein supplementation prior to and after each exercise bout did not further increase skeletal muscle hypertrophy…

No impairment of muscle protein synthesis to protein intake was detected in elderly subjects after ingestion of large amounts of carbohydrates and proteins [211], or of either moderate (≈115 g) [212] or large (≈300 g) amounts of beef [213]. By comparing sarcopenic (≈80 y) and healthy (≈70 y) older men, the ingestion of ≈20 g of a leucine-enriched whey protein load, increased muscle protein synthesis rates to the same extent in both groups [214].

In older adults, following the ingestion of mixed meals containing combinations of animal (beef) and vegetal proteins, the whole-body anabolic response linearly increased with increasing protein intake, primarily due to the suppression of protein breakdown. Notably, muscle protein synthesis (i.e., one factor contributing to the net protein accretion, or balance, together with the suppression of protein degradation) was further stimulated by a protein dose (70 g) above that previously considered as “optimal” in the elderly (≈35 g/kg BW) [215], yet attaining the same maximal response as that of young subjects. However, at the 40 g dose, the stimulation of muscle protein synthesis in the elderly was lower than that observed in the young volunteers, therefore compatible with anabolic resistance in the former group at a “lower” (i.e., 40 g) mixed protein dose (see also below). The above-reported protein dose(s) stimulating MPS in older subjects were, however, greater than the 20 g high-quality, whey protein dose that produced the maximal effect on MPS in young people, either exercising or not [72]. The muscle protein synthetic response to the combined ingestion of protein and carbohydrate (i.e., an additional energy source) was not impaired in healthy older men [216]. Similarly, the co-ingestion of carbohydrates with protein and free leucine stimulated muscle protein synthesis to the same extent in young and elderly lean men [217]…

A ten-day administration of a supplement containing fast-digestive proteins (soluble milk proteins compared to casein alone) could overcome muscle anabolic resistance in the elderly [205]. Furthermore, oral EAA ingestion exhibited a retarded albeit still sustained response of MPS in the elderly as compared to young subjects [58].

In older men, skeletal muscle was also less responsive to the anabolic effects of leucine in the postprandial phase than in the young controls [219]. Also, a higher proportion of leucine within an essential amino acid mixture was required for the optimal stimulation of muscle protein synthesis in the elderly, rather than in young subjects…

3.2.6. Deleterious Effects of Bed Rest in the Elderly

A condition opposite to exercise is bed rest, an undesired situation very common in hospitalized older subjects, as well as in those old persons in whom, for a variety of factors, physical activity is restrained and/or abolished, either voluntarily or not [156,225,226,227]. In older adults, bed rest significantly restrained the EAA-induced increase in MPS, through a reduction in mTORC1 signaling and amino acid transport [228]. EAA supplementation above RDA may help to preserve muscle function in the elderly during inactivity

3.2.7. Effect of the Inflammatory State

Acute and chronic inflammation retain undesired effects on skeletal muscle mass and protein metabolism. Thus, age-associated inflammation (either subtle or overt) may negatively affect the anabolic sensitivity of skeletal muscle in the elderly. Toth et al. reported a strong relationship exists between MPS and circulating concentrations of several markers of immune activation [199]. At the mechanistic level, cytokines, in particularly, TNF-α, may impair MPS by blunting the phosphorylation of proteins in the mammalian target of the rapamycin (mTOR) intracellular signaling pathway…

3.3.1. The Effect of Complex Nutritional Supplements

Although natural foods rich in high-quality protein (dairy products, meat, and egg) can adequately stimulate protein anabolism as efficiently as that of protein-rich supplements and/or of specifically designed amino acid mixtures, the advantage of using specific nutritional supplements remains questionable…

3.3.2. Specific Effects of Leucine Addition

The addition of leucine to other nutritional products may be a valid supplement to be used in the elderly, although with somehow limited effects [240]. Older subjects consuming a leucine supplement showed a greater increase in MPS rates from baseline than the controls, but not in lean body mass or muscle function [61]. In a recent study in older men (74 y), co-ingestion of 2.5 g leucine with 20 g casein resulted in a 22% higher muscle protein synthetic rate compared with ingestion of casein alone [241].

The leucine effect seems to be dose-dependent. Leucine added as a supplement (3–5 g) to either whey protein or EAA solutions in either younger or older men, showed comparable increments in skeletal muscle myofibrillar protein synthesis (MyoPS), at variance with no sustained stimulation observed in control subjects receiving only 1.8 g leucine [242,243]. However, the leucine effect in skeletal muscle of aged people might be impaired, as mTORC1 activation is defective, and sensitivity and responsiveness of muscle protein synthesis to amino acids decreased [50]. Conversely, the basal activation of mTOR seems to be higher. A combined effect of age-related impairment of muscle signaling and insufficient availability/delivery of nutrients and growth factors to the muscle might contribute to sarcopenia. Thus, whether ageing per se affects mTORC1 signaling is yet uncertain, because of the common association between poor protein assumption, reduced/absent physical activity, and concurrent diseases. In studies in which habitual protein intake exceeded 1.0–1.1 g/kg/day, and included a moderate/high proportion of dairy protein, prolonged leucine supplementation (2.5 g daily for six months) did not increase muscle mass or strength in healthy type 2 diabetic older adult

3.3.3. Exercise Strategies

The primary target(s) of sarcopenia prevention/amelioration is the reduction in the risk of falls and fractures and the maintenance of independence in everyday tasks. The interventions applied to attain these targets look very similar to those aimed at the amelioration of general health status with ageing, such as improvements in muscle mass and strength, bone density, cardiovascular fitness, maximal oxygen consumption, endurance, and energy metabolism, in addition to the reduction in insulin resistance and the associated risk of diabetes mellitus, coronary heart disease, hypertension, and obesity [245]. In other words, the benefits of regular exercise translate into an improvement in the quality of life of elderly populations. Practicing regular exercise is a prerequisite to attain and maintain these benefits over time. In order to attain these key objectives, much attention has to be devoted to the implementation of specific exercise programs, aiming at increasing the awareness of their safety, required constancy, and compliance.

Following regular training, older subjects can increase muscle strength as much as that of younger control subjects, even by threefold, over a few months. This result is initially accomplished by neural adaptation(s) and greater muscle fiber recruitment, while more prolonged resistance training leads to an increase in muscle mass/size too, (partially) restoring the loss of the cross-sectional area of type II muscle fibers occurring with ageing [246]. Resistance training contributes to improvement in the functional capacity of the levels of physical activity and allows participation in daily living activities to be maintained, thus being motivationally efficient too. Specific protocols for the implementation of exercise to combat sarcopenia in ageing, in the old [247], as well as the oldest-old (80–85 y) [248] and the physically frail [249], have been proposed.

Both resistance/strength/weight exercise and endurance/aerobic training of skeletal muscles may be useful in the prevention and treatment of sarcopenia. Strenght training can positively affect the neuromuscular system, and increase hormone concentrations and the MPS rate [250]; however, from a recent meta-analysis, the benefit of combining dietary supplements and exercise is not so straightforward among different populations [251].

Exercise training has been consistently shown to be highly effective in slowing down and possibly preventing the insurgence of sarcopenia in older people, counteracting the loss of muscle mass, and strength, and an increase in intramuscular fat infiltrations. While stressing the importance of a personalized approach, general physical activity guidelines suggest that a combination of aerobic exercise, progressive resistance training, and balance training might be the ideal intervention for a sarcopenic population. Of note in a mixed training involving aerobic, strength, and balance exercises was effective in improving or preserving motoneuronal health and neuromuscular junction (NMJ) stability, together with muscle mass, strength, and functionality in an old, sarcopenic population [252]. These sarcopenic subjects were trained three times per week for 2 years with a mix of aerobic, strength, and balance exercises matched with nutritional advice [252]. The same group of researchers followed older dancers for 6 months, reporting a major stability in neuromuscular junctions and a superior functional performance despite no differences in muscle size…

New exercise technologies, and supplementation by antioxidants, vitamin D, eicosapentaenoic acid, or ursolic acid, as well as activation of peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α), may be considered too…

A number of reports have also investigated the optimal daily distribution of food protein, as well as the timing of the administration with respect to exercise performance (see also above).

In regard to food protein distribution over the three main daily meals, it was reported that non-frail elderly subjects consume dietary proteins more evenly than pre-frail and frail subjects, thus suggesting that the daily protein load should be consumed as ≈30 g protein (in a representative 75 kg subject) at each of the three daily mealtimes [264]. Conversely, in a subsequent randomized-controlled trial, the pattern of meal-protein intake (i.e., even vs. not even) over the day did not affect lean body mass, muscle strength, or other functional outcomes, as well as whole-body protein kinetics and MPS over 8 weeks in older adults [265].

With respect to the timing of food protein food administration with exercise (i.e., before, at the beginning, i.e., at t = 0′, or after exercise performance), in the only published study in the elderly, the early intake of a protein supplement immediately before (at t = 0′) each bout of resistance-type exercise in a 12-week intervention study in the elderly sustained skeletal muscle hypertrophy, as opposed to having no effect with the supplement intake taken 2 h after exercise [266]. Notably, protein ingestion in the evening/night before sleep increased Muscle Protein Synthesis throughout the night in healthy older men [267].

A list and the quantities of common foods providing ≈ 30 g of protein are reported in Table 4. (data compiled from ref. [268]) The quantities of animal foods are lower than those of vegetal foods (except for soybeans and quinoa), because of their balanced content of essential amino acids. The reported quantities are only indicative, because most of these foods have not been specifically tested in controlled studies of stimulation of skeletal MPS with exercise in the elderly.

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