Many age changes in living organisms can be explained by cumulative effects of cell loss over time. For example, the very common phenomenon of hair graying with age is caused by depletion of hair follicle melanocytes (Commo et al., 2004). Melanocyte density in human epidermis declines gradually with age at a rate approximately 0.8% per year (Gilchrest et al., 1979). Hair graying is a relatively benign phenomenon, but cell loss can also lead to more serious consequences.
Recent studies found that such conditions as atherosclerosis, atherosclerotic inflammation, and consequent thromboembolic complications could be linked to age-related exhaustion of progenitor cells responsible for arterial repair (Goldschmidt-Clermont, 2003; Libby, 2003; Rauscher et al., 2003). Taking these progenitor cells from young mice and adding them to experimental animals prevents atherosclerosis progression and atherosclerotic inflammation (Goldschmidt-Clermont, 2003; Rauscher et al., 2003).
Age-dependent decline in cardiac function is also linked to the failure of cardiac stem cells to replace dying myocytes with new functioning cells (Capogrossi, 2004). It was found that aging-impaired cardiac angio-genic function could be restored by adding endothelial precursor cells derived from the young bone marrow (Edelberg et al., 2002).
Chronic renal failure is known to be associated with decreased number of endothelial progenitor cells (Choi et al., 2004). People with diminished numbers of nephrons in their kidneys are more likely to suffer from hypertension (Keller et al., 2003), and the number of glomeruli decreases with human age (Nyengaard and Bendtsen, 1992).
Humans generally lose 30-40% of their skeletal muscle fibers by age 80 (Leeuwenburgh, 2003), which contributes to such adverse health outcomes as sarcopenia and frailty. Loss of striated muscle cells in such places as rhabdosphincter from 87.6% in a 5-week-old child to only 34.2% in a 91-year-old has obvious implications for urological failure—incontinence (Strasser, 2000).
A progressive loss of dopaminergic neurons in substantia nigra results in Parkinson's disease, loss of GABAergic neurons in striatum produces Huntington's disease, loss of motor neurons is responsible for amyo-trophic lateral sclerosis, and loss of neurons in cortex causes Alzheimer's disease over time (Baizabal et al., 2003). A study of cerebella from normal males aged 19-84 years revealed that the global white matter was reduced by 26% with age, and a selective 40% loss of both Purkinje and granule cells was observed in the anterior lobe. Furthermore a 30% loss of volume, mostly due to a cortical volume loss, was found in the anterior lobe, which is predominantly involved in motor control (Andersen et al., 2003).
The phenomenon of human aging of menopause also is caused by loss of ovarian cells. For example, the female human fetus at age 4-5 months possesses 6-7 million eggs (oocytes). By birth, this number drops to 1-2 million and declines even further. At the start of puberty in normal girls, there are only 0.3-0.5 million eggs—just only 4-8% of initial numbers (Gosden, 1985; Finch and Kirkwood, 2000; Wallace and Kelsey, 2004). It is now well established that the exhaustion of the ovarian follicle numbers over time is responsible for menopause (reproductive aging and failure), and women having higher ovarian reserve have longer reproductive lifespans (Wallace and Kelsey, 2004). When young ovaries were transplanted to old post-reproductive mice, their reproductive function was restored for a while (Cargill et al., 2003). This example illustrates a general idea that aging largely occurs because of cell loss, which starts early in life.
Loss of cells with age is not limited to the human species and is observed in other animals as well. For example, a nematode C. elegans demonstrates a gradual, progressive deterioration of muscle, resembling human sarcopenia (Herndon et al., 2002). The authors of this study also found that the behavioral ability of nematodes was a better predictor of life expectancy than chronological age.
Interestingly, caloric restriction can prevent cell loss (Cohen et al., 2004; McKiernan et al., 2004), which may explain why caloric restriction delays the onset of numerous age-associated diseases and can significantly increase lifespan in mammals (Masoro, 2003).
In terms of reliability theory the loss of cells with age is a loss of system redundancy, and therefore this chapter will focus further on the effects of redundancy loss on systems aging and failure.
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