Review
Effect of aging on cellular mechanotransduction

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Abstract

Aging is becoming a critical heath care issue and a burgeoning economic burden on society. Mechanotransduction is the ability of the cell to sense, process, and respond to mechanical stimuli and is an important regulator of physiologic function that has been found to play a role in regulating gene expression, protein synthesis, cell differentiation, tissue growth, and most recently, the pathophysiology of disease. Here we will review some of the recent findings of this field and attempt, where possible, to present changes in mechanotransduction that are associated with the aging process in several selected physiological systems, including musculoskeletal, cardiovascular, neuronal, respiratory systems and skin.

Introduction

The aged population now comprises the fastest growing segment of people living in the United States. Living longer is associated with higher morbidity. Indeed, health care spending per capita for the elderly population is over three and five times higher than that of a working-age person and child, respectively (Hartman et al., 2008).

It is thought that mechanical forces are a primary regulator of several biological functions. Indeed, mechanical signals have been shown to mediate the development of a variety of tissues (e.g. skeletal muscle, bone, cartilage, blood vessels and heart), and can affect diverse cellular processes including cell growth, differentiation, cellular migration, gene expression, protein synthesis, and apoptosis (Alenghat and Ingber, 2002, Ingber, 2003a). Given the potential importance that mechanical signaling function have in maintaining cellular homeostasis it is not surprising that changes in mechanotransduction may also play a role in the pathophysiology of disease (Ingber, 2003a). Recent data strongly supports this notion as it is becoming recognized that many aspects of sarcopenia, cardiovascular and respiratory disease may be related to alteration in cellular mechanotransduction (Blough and Linderman, 2000, Rice et al., 2007b, Pardo et al., 2008, Hwee and Bodine, 2009). The study of age-associated alterations in cellular mechanotransduction has only recently begun to be appreciated for its potential role in mediating cellular function and dysfunction. Here we will investigate the possibility that the ability of the cell to sense, process, and respond to mechanical stimuli is altered with aging and that these changes may be involved in the etiology of aging-associated disease. In order to focus our discussion, we have chosen to examine how aging may affect mechanotransduction processes in: (1) musculoskeletal system (including skeletal muscle, bone and joint), (2) cardiovascular system, (3) neuronal system, (4) respiratory system, and (5) skin.

Section snippets

Mechanotransduction processes

The process of converting an external mechanical force into an internal cellular response is termed mechanotransduction (Wang et al., 1993, Davies, 1995, Alenghat and Ingber, 2002, Jaalouk and Lammerding, 2009). This process consists of three distinct phases (1) signal transduction, (2) signal propagation, and (3) cellular response (Fig. 1). Mechanical forces exerted on cell/tissue can result in alterations of cell membrane tension. The integration of external forces into a biochemical

Aging is associated with declines in skeletal muscle mass and function

The age-related loss of skeletal muscle mass and muscle strength, known as sarcopenia, is a health problem that is expected to only increase in coming years as a greater portion of the population lives longer (Castillo et al., 2003, Dirks et al., 2006, Melov et al., 2007). The maintenance of muscle mass and function with increasing age is directly related to quality of life, disease prevention, and has profound socioeconomic significance. Sarcopenia is characterized by a loss of skeletal muscle

Effects of aging on bone structure

Bone health and structure, like muscle, is regulated by mechanical loading. During growth, body weight and muscular forces increase the loading on the growing bone which in turn acts to augment bone strength and mass. In the third decade of life muscle strength generally begins to decrease which is associated with gradual decline in bone loading and bone mass (Sumner and Andriacchi, 1996). In addition to changes in bone loading, non-mechanical factors are also thought to contribute to

Effects of aging on joint structure

Joints can be classified into three basic groups based upon how the bones within the joint are connected: fibrous, cartilaginous, and synovial (Benjamin et al., 1995, Khan et al., 2007). It is well accepted that mechanical loading can influence joint structure and function. These alterations can occur during development and aging. For example, the fibrous suture joints in the skull are eventually replaced by bone in early childhood (Mao, 2002). Similarly, increased loading over a lifetime can

Aging affects cardiovascular structure and function

Aging-associated heart diseases are major cause of death, accounting for about 29% of total deaths in the elderly (Heron et al., 2008). The cardiovascular system is exquisitely sensitive to mechanical stimuli. Indeed, mechanotransduction processes are important in the development of the heart and for the control of blood pressure as well as cardiac output. Like skeletal muscle and bone, increased cardiac loading can also result in cellular growth and hypertrophy. Diseases of mechanotransduction

Aging brain and Alzheimer's disease

The aging brain is characterized by a shrinkage of brain mass, the degeneration of synaptic transmission, a loss of neurons, and a decrease in the abundance of chemical messengers (Dickstein et al., 2007). These age-associated alterations, if localized to the hippocampus and cerebral cortex, can result in memory impairment and the decline of cognitive function. Alzheimer's disease (AD) is the most common progressive neurodegenerative disease, and is one of top five causes of death in the

Age-associated changes in respiratory structure and function

Respiratory diseases cause approximately 6% of total deaths in people 65 years of age and older (Heron et al., 2008). Almost all components of the respiratory system, including lung parenchyma, pulmonary and bronchial vascular systems, and diaphragm, are affected by aging. As we age, the lung is thought to become less elastic, and muscles of the chest wall and diaphragm lose mass and strength (Mays et al., 1989). Therefore, the respiratory system experiences an increase in dead space and a

Age-associated changes in skin structure and function

Although skin is a durable system, its structural character and physiological function undergo dramatic changes with age (Waller and Maibach, 2005, Farage et al., 2007, Puizina-Ivic, 2008, Robert et al., 2009). The decrease in epidermal thickness is accelerated with age, especially in exposed areas such as the face, neck, forearms, and hands, due to a slower renewal rate of epidermal cells (Boss and Seegmiller, 1981). Aged epidermis contains fewer melanocytes and immunocompetent Langerhans

Conclusions and future directions

The ability of the cell to sense, process, and respond to mechanical stimuli appears to be altered with aging and these changes have been shown to be associated with increased susceptibility to mechanical damage, increased apoptosis, alterations in intracellular signaling, and a dysregulation of gene expression. These age-associated impairments appear to be ubiquitous, but are not well understood given the complexity of cellular mechanotransduction and the difficulty of studying

Acknowledgement

This work was supported in part by NIH Grant AG-027103-1 to E.B.

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