ReviewEffect of aging on cellular mechanotransduction
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.
References (232)
- et al.
Renal transplantation in diabetic patients
Transplant Proc.
(2006) - et al.
Calcium dysregulation in Alzheimer's disease
Neurochem. Int.
(2008) - et al.
Effects of age on plasma matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs)
J. Card. Fail
(2007) - et al.
Age-associated changes in cardiac matrix and integrins
Mech. Ageing Dev.
(2001) - et al.
Age-related changes in the proteoglycans of human skin. Specific cleavage of decorin to yield a major catabolic fragment in adult skin
J. Biol. Chem.
(2003) - et al.
Sarcopenia in elderly men and women: the Rancho Bernardo study
Am. J. Prev. Med.
(2003) - et al.
The role of insulin and neurotrophic factor signaling in brain aging and Alzheimer's Disease
Exp. Gerontol.
(2007) - et al.
Cumulative effects of aging and mechanical ventilation on in vitro diaphragm function
Chest
(2003) - et al.
Dysregulation of tau phosphorylation is a hypothesized point of convergence in the pathogenesis of alzheimer's disease, frontotemporal dementia and schizophrenia with therapeutic implications
Prog. Neuropsychopharmacol. Biol. Psychiatry
(2006) - et al.
Mitochondrial DNA mutations, energy metabolism and apoptosis in aging muscle
Ageing Res. Rev.
(2006)
Preoperative assessment of the elderly patient
Dermatol. Clin.
Mechanotransduction, asthma, and airway smooth muscle
Drug Discov. Today Dis. Models
MLC-kinase/phosphatase control of Ca2+ signal transduction in airway smooth muscles
J. Theor. Biol.
Collagen fragmentation promotes oxidative stress and elevates matrix metalloproteinase-1 in fibroblasts in aged human skin
Am. J. Pathol.
Fibroblast biology in three-dimensional collagen matrices
Trends Cell Biol.
Isolated ventricular myocytes from failing and non-failing human heart; the relation of age and clinical status of patients to isoproterenol response
J. Mol. Cell Cardiol.
Superoxide dismutase gene expression in skeletal muscle: fiber-specific effect of age
Mech. Ageing Dev.
mTOR is the rapamycin-sensitive kinase that confers mechanically-induced phosphorylation of the hydrophobic motif site Thr(389) in p70(S6k)
FEBS Lett.
Intracellular Ca2+ stores and extracellular Ca2+ are required in the real-time Ca2+ response of bone cells experiencing fluid flow
J. Biomech.
Control of capillary growth and differentiation by extracellular matrix. Use of a tensegrity (tensional integrity) mechanism for signal processing
Chest
Tensegrity-based mechanosensing from macro to micro
Prog. Biophys. Mol. Biol.
Age-related changes in lamin A/C expression in cardiomyocytes
Am. J. Physiol. Heart Circ. Physiol.
Mechanotransduction: all signals point to cytoskeleton, matrix, and integrins
Sci. STKE
Smooth-muscle myosin light-chain kinase content is increased in human sensitized airways
Am. J. Respir. Crit. Care Med.
Airway smooth muscle dynamics: a common pathway of airway obstruction in asthma
Eur. Respir. J.
Exercise stimulates the mitogen-activated protein kinase pathway in human skeletal muscle
J. Clin. Invest.
Interactive effects of PTH and mechanical stress on nitric oxide and PGE2 production by primary mouse osteoblastic cells
Am. J. Physiol. Endocrinol. Metab.
Impact of sarcoglycan complex on mechanical signal transduction in murine skeletal muscle
Am. J. Physiol. Cell Physiol.
Fibrocartilage associated with human tendons and their pulleys
J. Anat.
The aging cardiomyocyte: a mini-review
Gerontology
Stretching increases calcium influx and efflux in cultured pulmonary arterial smooth muscle cells
Am. J. Physiol.
Lack of skeletal muscle hypertrophy in very aged male Fischer 344 x Brown Norway rats
J. Appl. Physiol.
Aging alters mechanical and contractile properties of the Fisher 344/Nnia X Norway/Binia rat aorta
Biogerontology
Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo
Nat. Cell Biol.
A role for Ca(2+)-conducting ion channels in mechanically-induced signal transduction of airway epithelial cells
J. Cell Sci.
Matrix gene expression and decompensated heart failure: the aged SHR model
Cardiovasc. Res.
Age-related physiological changes and their clinical significance
West J. Med.
The mitochondrial-lysosomal axis theory of aging: accumulation of damaged mitochondria as a result of imperfect autophagocytosis
Eur. J. Biochem.
Front and back by Rho and Rac
Nat. Cell Biol.
Aging changes in voltage-gated calcium currents in hippocampal CA1 neurons
J. Neurosci.
Arachidonic acid metabolites as endothelium-derived hyperpolarizing factors
Hypertension
Effects of age and gender on rat upper airway muscle contractile properties
J. Gerontol. A Biol. Sci. Med. Sci.
Aging impairs IGF-I receptor activation and induces skeletal resistance to IGF-I
J. Bone Miner. Res.
Hypertrophy and proliferation of skeletal muscle fibers from aged quail
J. Appl. Physiol.
Mechanical signals and IGF-I gene splicing in vitro in relation to development of skeletal muscle
J. Cell Physiol.
Ca(2+) regulates fluid shear-induced cytoskeletal reorganization and gene expression in osteoblasts
Am. J. Physiol. Cell Physiol.
Different ontogeny of rate of force generation and shortening velocity in guinea pig trachealis
J. Appl. Physiol.
Role of nitric oxide and prostaglandins in mechanically induced bone formation
J. Bone Miner. Res.
Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow
J. Bone Miner. Res.
Flow-mediated endothelial mechanotransduction
Physiol. Rev.
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