Overcoming Anabolic Resistance That Occurs With Aging

It’s well known that a gradual loss of skeletal muscle mass and strength occurs with aging. This phenomenon is termed “sarcopenia” and is known as a condition characterized by loss of skeletal muscle mass and function (1).  

Interestingly, the onset of muscle loss may begin as early as 25-30 years of age with the rate accelerating as one ages. This loss of strength and function has debilitating consequences for older adults such as an inability to perform the normal activities of daily living, an increase risk for falls, frailty, and dependency on others (2).  

Anabolic resistance is responsible, in part, for skeletal muscle atrophy with aging, muscle disuse, and during disease states. 

Anabolic resistance describes the reduced stimulation of muscle protein synthesis to a given dose of protein/amino acids and contributes to declines in skeletal muscle mass.

Physical inactivity induces: anabolic resistance (that is likely exacerbated with aging), insulin resistance, systemic inflammation, decreased satellite cell content, and decreased capillary density (3). 

The continuous dynamic interchange between muscle protein synthesis and muscle protein breakdown manages changes in muscle size. A change in muscle size requires a chronic imbalance favoring one process over the other (4).  

It’s been recently shown that the rate of muscle protein synthesis is more dynamic and responsive than muscle protein breakdown.

Therefore, recent research has primarily focused on searching for impairments in the muscle protein synthetic responses to the main anabolic stimuli, food intake, or physical activity in older populations. 

Recent work seems to suggest that the elderly show a blunted muscle protein synthetic response to amino acid administration (5,6) and physical activity (7,8) when compared with that in the young. 

It is speculated that impairments in protein digestion and amino acid absorption, insulin-mediated muscle tissue perfusion, amino acid uptake in muscle, or a reduced amount or activation status of key signaling proteins may contribute to this proposed anabolic resistance of muscle protein synthesis with aging (9). (see figure below)

Adapted from Nicholas et al. (9)



Two powerful stimulators of skeletal muscle protein synthesis are nutrition and exercise (7,10) which can be utilized acutely to sway the balance in favor of protein anabolism (i.e., net protein accretion). Exercise and nutritional strategies are quite promising and very practical approaches that can definitely slow or reverse progression of sarcopenia.

There is a lot of research that has investigated how aging affects on the ability of nutrition and exercise to stimulate muscle synthesis (4). 

It’s important to note that one of the primary factors thought to contribute to muscle loss with aging is an impaired ability for skeletal muscle of older adults to respond to anabolic stimuli, which is known as “anabolic resistance”.

Impeded nutrition response to aging

There is an intricate interplay that exists among amino acid availability, skeletal muscle protein synthesis, and aging. 

For example, ingesting relatively small quantities of essential amino acids (~7–10g) is capable of stimulating skeletal muscle protein synthesis in young individuals, whereas in older adults this response is not observed (5,11) indicating an impaired ability for relatively small quantities of amino acids to stimulate muscle protein synthesis in older adults.

However, consuming larger amounts of essential amino acids can stimulate skeletal muscle protein synthesis to a similar extent in both younger and older adults (12).  This indicates that a higher threshold is necessary for amino acids to stimulate muscle protein synthesis in older adults. 

In particular, the sensitivity of the branched chain amino acids; particularly leucine is inhibited with age.

Therefore, increasing the content of leucine in a given meal may serve as a strategy to promote muscle protein synthesis in older adults (13). 

The impaired response to small doses of protein/amino acids may contribute to the etiology of sarcopenia and may accelerate the rate of muscle/strength decrements in older adults who routinely consume small portions of protein.

Ingesting 25-30g of high-quality protein (14) or more than 2g of leucine (11) can overcome this impairment and stimulate muscle protein synthesis in older adults to similar degree as younger individuals.  

Age resistance response to insulin  

Meals consumed throughout the day typically consist of a mixture of macronutrients and present a very different stimulus to the muscle by exposing muscle to increasing circulating levels of anabolic hormones such as insulin and other metabolic substrates such as glucose and fatty acids.  

It’s clear from research that aging may be associated with a blunted protein anabolic response to a mixed meal, and that this impairment is primarily due to a resistance of skeletal muscle protein synthesis. The chronic inability for a mixed meal to stimulate skeletal muscle protein synthesis in older adults may contribute to the etiology of sarcopenia.

Postprandial (post-meal) insulin levels are capable of stimulating skeletal muscle protein synthesis in younger individuals, whereas in otherwise glucose tolerant older adults skeletal muscle protein synthesis is not increased in response to postprandial insulin (15).

Supraphysiological (above normal) levels of insulin do indeed stimulate muscle protein synthesis in older adults (16) which indicates that an age-related resistance of muscle protein synthesis occurs to normal levels of insulin.

The resistance of skeletal muscle protein synthesis to the anabolic actions of insulin likely represents a key contributor to the inability for a mixed meal to stimulate muscle protein synthesis in older adults.

In addition to its many roles, insulin is a well described vasodilator through the activation of nitric oxide synthase (17). However, in older adults, insulin’s function as a vasodilator is impaired, which may further explain the resistance to muscle protein synthesis in older adults. 

Aging and resistance to exercise 

Resistance exercise

It is well accepted that resistance exercise stimulates skeletal muscle protein synthesis in young individuals, however, an acute bout of resistance exercise does not appear to elicit the same response in the skeletal muscle of older adults. 

This impairment is due to the inability of resistance exercise to substantially increase a key signaling mechanism that regulates the increase in muscle protein synthesis following resistance exercise (18).

This impaired protein synthesis response to an acute bout of resistance exercise seems to imply that resistance exercise is not beneficial as a strategy to slow, or even counter, sarcopenia, but this is definitely not the case! 

Resistance exercise is certainly capable of increasing muscle size and strength in older adults (19), and thus does represent a strategy that, at the very least, can be used to slow the trajectory of muscle loss with aging.

Aerobic exercise

Aerobic exercise has not historically received tremendous support as a countermeasure to sarcopenia, which is likely related to the general idea that aerobic exercise is thought to primarily produce metabolic adaptations in muscle rather than increasing muscle size and strength.

However, recent work has highlighted a potential role for aerobic exercise training as a strategy to slow sarcopenia.

The ability for aerobic exercise to increase muscle size and strength, especially in older adults, may be manifested through increasing resting muscle protein synthesis rates (20) or through increasing the sensitivity of skeletal muscle to insulin or a subsequent meal (21). 

It’s clear from the research that prior aerobic exercise can overcome the age-related resistance of muscle protein synthesis to insulin and restore the ability for insulin to stimulate muscle protein synthesis in older adults (21), highlighting that routine aerobic exercise may represent a strategy to overcome the resistance of muscle protein synthesis to insulin with aging.

In addition, the benefits of aerobic exercise in older adults may also work through indirect mechanisms.

Routine aerobic exercise has been shown to promote favorable effects on mitochondrial function and insulin sensitivity. These positive adaptations are not only beneficial to metabolic health, but dysfunction of these metabolic processes is also associated with aging and muscle wasting.  

Collectively, routine aerobic exercise may represent a very promising and practical strategy to overcome the age-related protein anabolic resistance to a mixed meal and preserve and/or improve muscle health and function in older adults. 

Nutritional strategies to overcome anabolic resistance to exercise in aging muscle   

Numerous studies have demonstrated that ingesting nutrients, particularly protein/amino acids, following a bout of resistance exercise enhances muscle protein synthesis and a net protein anabolic environment within the exercised muscle.

Consequently, extensive effort has been made to determine whether coupling exercise with nutritional strategies may serve as a means to overcome the protein synthesis impairments of aging skeletal muscle, particularly to resistance exercise.  

When older adults ingested 20g of essential amino acids shortly after a bout of resistance exercise, skeletal muscle protein synthesis was stimulated to a much greater degree than resistance exercise without nutrient ingestion (7,22). 

Interestingly, the overall stimulation of muscle protein synthesis in the immediate hours following this combination was similar between young and older adults. It appears that this improved muscle protein synthesis response could be the result of an enhanced ability for the combination of resistance exercise and essential amino acid ingestion to stimulate the signaling mechanism of muscle protein synthesis (22). 

These data support the notion that the age-related resistance of muscle protein synthesis to an acute bout of resistance exercise can be overcome with the ingestion of post-exercise nutrients.

However, recent data indicate that relative to younger individuals, older adults may require a larger quantity of protein/amino acids following resistance exercise to maximally stimulate muscle protein synthesis (23).

This latter finding suggests that the elevated threshold for protein/amino acids to stimulate muscle protein synthesis in older adults is also present even when preceded by exercise and that aging may require subtle alterations to exercise and nutritional strategies to maximize muscle growth and the ensuing improvements in muscle function.

Findings from a recent comprehensive review of the literature suggests that protein supplementation during resistance exercise training is associated with greater increased in muscle strength and lean body mass in both young and older adults (24). 

Key takeaways from the research 

One of the underlying factors thought to contribute to sarcopenia is an age-related alteration in the ability for stimuli such as protein/amino acids, insulin, and exercise to considerably increase muscle protein synthesis in older adults.

However, the capacity to stimulate skeletal muscle protein synthesis is conserved with age and when appropriate and targeted strategies are used; nutrition and exercise are able to enable muscle protein anabolism in older adults which can preserve/improve muscle size and function.

Consuming appropriate quantities of protein throughout a given day and performing regular exercise may preserve the protein synthesis response of skeletal muscle and slow the progression of muscle atrophy.

In particular, routine exercise serves to enhance insulin sensitivity and the protein anabolic actions of insulin on skeletal muscle.

Strategic coupling of exercise and nutrition also represents a practical strategy that has promise for restoring skeletal muscle size and function in those older adults who may already be at risk of sarcopenia.

References

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