Current Aging Science - Volume 4, Issue 3, 2011

Demographers expect the number of older persons to double to 86.7 million— or to 20.6% of the US population— by the year 2050. As has occurred over the past decade, the health care costs associated with older age are expected to steadily increase approximately 2% per year causing both a public health and personal burden. A key component to reducing health care costs and maintaining well-being in older persons is preserving physical function throughout the lifespan. The challenge to this objective is to combat the origin of the loss of physical function through treatment of chronic disease conditions. Another approach is to enhance physical function despite the occurrence of comorbid conditions through enhancement of the neuromuscular system. The neuromuscular system provides the necessary components for all locomotion, and is thus a logical choice for preventative therapies to target. This article will give a general overview of the models and risk factors that explain the development of physical disability.

Aging is associated with dramatic reductions in muscle strength and motor control, and many of these agerelated changes in muscle function result from adaptations in the central nervous system. Aging is associated with widespread qualitative and quantitative changes of the motor cortex. For example, advancing age has been suggested to result in cortical atrophy, reduced cortical excitability, reduced cortical plasticity, as well as neurochemical abnormalities.The associated functional effects of these changes likely influence numerous aspects of muscle performance such as muscle strength and motor control. For example, there is evidence to suggest that the muscle weakness associated with aging is partially due to impairments in the nervous system's ability to fully activate motor neurons- particularly in the larger proximal muscle groups. In this review article we discuss age-related changes in the motor cortex, as well as the abilityor lack thereof- of older adults to voluntarily activate skeletal muscle. We also provide perspectives on scientific and clinical questions that need to be addressed in the near future.

Alterations in motor unit behavior associated with aging deteriorate fine or gross motor performance. In human aging, the alterations depend on muscles and the habitual activity of each muscle. This paper will discuss the current knowledge on the adaptations in major aspects of motor unit behavior including recruitment order, mean and maximal discharge rate, synchronized discharges, oscillatory discharges, and discharge variability in elderly adults to identify unresolved problems. By considering studies on disuse in young adults and training in elderly adults, future research directions are proposed to help resolve the problems.

The neuromuscular system is one of the largest and most vital organ systems of the body. The function and mass of the neuromuscular system gradually deteriorate during the natural process of aging. The neuromuscular system is comprised of individual motor units, each of which features a single motor neuron and all the muscle fibers it innervates. Motor units also demonstrate age-related remodeling such as reduced number, muscle fiber atrophy, but an increased number of fibers per motor unit. Enabling communication between motor neurons and the muscle fibers they innervate is a specialized synapse known as the neuromuscular junction. Aging, too, elicits remodeling of this synapse joining motor nerve terminal endings with a small (< 0.1%) area of the muscle fiber's surface called the endplate. Aged neuromuscular junctions exhibit elevations in pre-synaptic nerve terminal branching, and in the post-synaptic distribution of receptor sites for neurotransmitter. This anatomical remodeling is coupled with age-related neurophysiological alterations including increased quantal content, with a more rapid rundown of endplate potential strength during continuous stimulation of the pre-synaptic neuron. Moreover, there is a growing body of evidence indicating that aging impacts the capacity of the NMJ to adapt to increased, as well as decreased physical activity. Because of the marked increase in the number of people considered to be aged in industrialized countries, it is essential to expand our understanding of the influence of aging on the neuromuscular system, its constituent motor units, and the neuromuscular junctions which allow neural cells and muscle fibers to effectively work together.

Skeletal muscle undergoes numerous morphological changes from early adulthood to old age including muscle size, configuration, and structure. This review discusses these changes, considers the limitations in interpreting studies, addresses the potential health implications, and describes some mechanisms and interventions to ameliorate aging-related changes in skeletal muscle. Discussion in each section focuses on measurement and analysis techniques of muscle morphology, limitations of human research, and the discussion uses animal work to support findings in humans. We examine the discrepancies in the study of fiber type distribution with age, and special emphasis is given to two topics: fiber-type distribution and intra- and intercellular fat. Finally, training adaptations and health implications are briefly discussed. The focus of the current review is the morphological changes that occur in skeletal muscle during the normal aging process, with emphasis on human studies.

Properly functioning skeletal muscle is critical for locomotion and performance of many activities of daily living. Muscle wasting and decreased function of skeletal muscle are important factors in many age-related morbidities. There are several pathways for generating ATP in skeletal muscle that allow adequate ATP supply to meet increased demand during muscle activity. A growing body of literature provides evidence that the aging process may be accompanied by changes in metabolic supply and demand during muscle contractions. Herein, we review a body of evidence that several pathways of ATP synthesis (anaerobic glycolysis, oxidative phosphorylation) may be impaired in aging skeletal muscle as well as several underlying molecular and cellular mechanisms. However, detrimental effects of aging on muscle energy metabolism are not universally accepted, particularly when physical inactivity is accounted for. We discuss this important concept as well as several potential countermeasures that may compress the period of morbidity in old age. In the second half of this review, we discuss how energetic demand of skeletal muscle is affected by aging, with specific focus on basal and contractile ATPase activity.

Functional and structural decline of the neuromuscular system is a recognized cause of decreased strength, impaired performance of daily living activities, and loss of independence in the elderly. However, in mammals, including humans, age-related loss of strength is greater than loss of muscle mass, so the underlying mechanisms remain only partially understood. This review focuses on the mechanisms underlying impaired skeletal muscle function with aging, including external calcium-dependent skeletal muscle contraction; increased voltage-sensitive calcium channel Cav1.1 β1asubunit and junctional face protein JP-45 and decreased Cav1.1 (α1) expression, and the potential role of these and other recently discovered molecules of the muscle T-tubule/sarcoplasmic reticulum junction in excitation-contraction uncoupling. We also examined neural influences and trophic factors, particularly insulin-like growth factor-I (IGF-1). Better insight into the triad proteins' involvement in muscle ECC and nerve/muscle interactions and regulation will lead to more rational interventions to delay or prevent muscle weakness with aging. The focus of this review is on the proteins mediating excitation-contraction coupling (ECC) and their expression and regulation in humans and rodent models of skeletal muscle functional decline with aging. Age-dependent changes in proteins other than those related to ECC, muscle composition, clinical assessment and interventions, have been extensively reviewed recently [1-3].

The loss of lean muscle mass occurring with advancing age is termed sarcopenia. This condition often leads to a concomitant loss of strength, increased frailty and risk of falls and an overall loss of functional independence in the elderly. Muscle protein metabolism is a dynamic process characterized by the balance between the synthesis and breakdown of muscle proteins. A disturbance of this equilibrium can lead to the loss of muscle mass, and a perturbation of muscle protein turnover with aging has been proposed to play a role in the development of sarcopenia. However, basal muscle protein synthesis and breakdown rates do not differ between young and old adults, which has led to the hypothesis that older adults are resistant to anabolic stimuli. In support of this hypothesis, older adults have either no response or a blunted response to nutrients, insulin and resistance exercise, and this anabolic resistance is likely a key factor in the loss of skeletal muscle mass with aging. Recent studies have investigated potential interventions to overcome this anabolic resistance. In particular, combining resistance exercise with essential amino acid supplementation restores the muscle protein anabolic response in older men. The novel rehabilitation technique of performing light resistance exercise during blood flow restriction was also successful in overcoming the anabolic resistance to exercise. Future research is needed to determine whether these novel interventions will be successful in preventing sarcopenia and improving muscle strength and function in older adults.

Age-related muscle atrophy is due to loss of muscle fibers as well as atrophy of the remaining fibers. Evidence shows that loss of myofibers may be, in part, due to apoptosis. Two major apoptotic pathways have been extensively studied which are the mitochondrion-mediated and receptor-mediated pathways. However, other pathways exist, such as the p53 pathway. To date, it is not completely clear what pathways are responsible for loss of fibers in age-related muscle atrophy. Evidence suggests that multiple pathways may play a role. In this review article the effects of aging on the mitochondrion-, receptor-, and p53-mediated apoptotic pathways in skeletal muscle are discussed.

Vertebrate skeletal muscle fibers have two traits that make them unique: the fibers are multinucleated and their nuclei are post-mitotic. The activity and mass of the muscles in the body make them susceptible to constant injury. When this occurs, myonuclei can be increased or replaced by the adult stem cells of muscle, satellite cells (SCs). These SCs are vital for normal growth, repair and regeneration. This review collates recent studies to determine the size of the nuclear domains and its change with activity. The relationship between the percent change in myonuclear number, cross-sectional area, and myonuclear domain indicates that the nucleus generally maintains a highly regulated domain size in spite of large variations in fiber size. The SC divides to add nuclei for growth and repair, and the SC identification and number are discussed. It is concluded that SC number does not reflect a change in regenerative ability by the muscle. However, the SC number increases with changes in muscular activity, and any reduced number of satellite cells in the elderly does not appear to reflect a decline in reparative or regenerative ability. The effects of aging on SC function are reviewed, and the significance of the SC's connective tissue environment is emphasized as being a major factor in the decrement of the SC's ability to repair and regenerate the aging muscle. Therefore growth factors and cytokines in the connective tissue around the SC are major influences in the decline of SC function with age.

Age related muscle loss, known as sarcopenia, is a major factor in disability, loss of mobility and quality of life in the elderly. There are many proposed mechanisms of age-related muscle loss that include the endocrine system. A variety of hormones regulate growth, development and metabolism throughout the lifespan. Hormone activity may change with age as a result of reduced hormone secretion or decreased tissue responsiveness. This review will focus on the complex interplay between the endocrine system, aging and skeletal muscle and will present possible benefits of therapeutic interventions for sarcopenia.