• Abstract and Figures
• Public Full-text

Appendix B The Cell Biology of Aging Introduction spans that seem to be “programmed” into them accord- ing to species. Mechanisms underlying this programmed The distinction between the effects of aging as a aging could involve an intrinsic genetic component of chronological process and diseases whose prevalence the tissues (24), and/or an extrinsic “neuroendocrine increase with advancing age remains blurred. Condi- pacemaker” (16,17). tions once thought to be inevitable companions of old The genetic version of the biological clock is bol- age are now known to in fact be pathological in origin stered by the observation that the survival time of and thus possibly treatable and preventable. One ex- tissues grafted (or transferred) from an older animal ample is senile dementia, no longer the mysterious fate into a younger one of the same species seems to de- of the very old, but often a clinical manifestation of pend on the age of the donor and is not influenced arteriosclerotic or biochemical brain disease. by the “younger” environment into which it has been Further research may elucidate the mechanisms introduced (24). Similarly, when nuclei from younger underlying aging and their possible connection to age- cells are transplanted into the cytoplasm of older cells, related diseases, leading to the development of medi- the recipients then live longer and regain the ability cal techniques that delay the onset and progression to replicate. These observations all suggest that a of symptoms. While it may not lead to actual exten- “clock” controlling aging does exist and may be located sion of the human life span, such knowledge could re- in the nucleus, possibly in the genetic material (24). duce the prevalence and impact of chronic conditions Genetic diseases that accelerate aging and abbreviate that affect many elderly persons and drain our health life spans further support intrinsic genetic control of care resources, allowing marked improvement in the aging, Werner’s syndrome, for example, is a rare general well-being and productivity of the growing autosomal recessive disease (i.e., the gene for the dis- elderly segment of the population. ease is not carried on a sex chromosome and two The cell is the physiological building block in all copies of it must be present for the disease to appear) higher organisms, including humans. Any investiga- involving retarded growth, premature graying and tion of mechanisms underlying the aging process must loss of hair, cataracts, teeth loss, osteoporosis, aduh- therefore look at how different cell types are altered onset diabetes, generalized atherosclerosis, and a me- over time to produce the structural and biochemical dian life span of 47’ years. Cultured fibroblasts from changes normally associated with aging. Numerous people with Werner’s syndrome exhibit a markedly biological signs of aging have already been identified abbreviated life span (23,53). Hutchinson-Gilford Pro- in cells both within the human organism and grown geria syndrome, another rare “age-accelerating” genetic on artificial media. This section reviews the theories disease, has similar symptoms that appear by age 1 and evidence concerning mechanisms underlying and a median life span of 12 years. More than 80 per- biological aging. cent of the deaths are due to heart disease (23). Lo- calization of the exact gene lesions and their role in Theories about cellular mechanisms accelerating the aging process in these diseases could reveal genetic mechanisms involved in normal aging. of aging The control of aging by a “neuroendocrine pace- maker” extrinsic to the tissues involved is supported Theories about the cellular mechanisms underlying by evidence of progressive changes in neural and en- the aging process can be divided into two broad cate- docrine regulatory systems throughout adult life (17); gories: 1) those involving a “biological clock” that or- such changes would produce a “cascade” of alterations chestrates degenerative processes and determines life in neural, endocrine, and tissue interactions, leading span; and 2) those involving accumulated damage, mu- to the dysfunction of cells in the ovary, liver, and other tations, and waste products in certain cells. target tissues (16). This neuroendocrine pacemaker could produce both cellular and physiological changes BIOLOGICAL CLOCK THEORIES associated with aging. The mechanism driving these The biological clock theory proposes that an orga- regulatory changes may involve the cumulative impact nism is inherently programmed to begin aging at a cer- of specific hormones on the brain over time, After a tain rate according to its chronological age. Evidence certain amount of exposure, negative feedback at the for this theory includes the observation that different hypothalamic level would cause changes in the homeo- species of higher vertebrates have very specific life static set points, causing ahered neuroendocrine out- 413 414 ● Tecttno/ogy and Aging in America put and the observed functional and structural changes mature death and early onset of dementia and various associated with aging. age-related degenerative neurological disorders. This neuroendocrine pacemaker could also produce Aberrant proteins could also accumulate both inside age-related disease by affecting genetic activity, and outside cells due to age-related defects in the leading to disturbances in immune function, prolifera- genetic material or in other protein-manufacturing tion of arterial walls, malignant growths, and other machinery in the cell. The chemicals and structures conditions that are associated with aging and limited responsible for “decoding” and implementing genetic life span in mammals (17). information could alter with age, resulting in struc- It is not known, however, whether observed age- turally faulty proteins that would be unable to func- related changes in hormonal regulation and balance tion normally (31). are a cause or an effect of the aging process (30). Fur- Accumulated insults to the cell over time—whether thermore, the biological clock may have both an in- metabolic, environmental, or viral--could thus lead to trinsic genetic and an extrinsic neuroendocrine com- cellular degeneration, loss of function, cessation of ponent. Much research remains to be done before any division, and cell death with a diminution of function conclusions may be drawn concerning programmed in various body organs. Such acquired lesions could aging. also lead to the formation of malignant cells and can- cer. The damage could be exacerbated by the aging ACCUMULATION OF DAMAGE: FREE RADICALS immune system’s decreasing ability to detect and de- AND OTHER HARMFUL AGENTS stroy aberrant cells and materials in the body. The other major cellular theory of aging involves the Much research remains to be done, however, on the accumulation of physical and biochemical damage to accumulation of either genetic or nongenetic cellular both genetic and nongenetic components of body cells lesions as a function of age, and on the role of such over time. Such cumulative damage would most af- lesions in the aging process. Such knowledge could fect cells that do not normally divide, like liver, heart lead to preventive or therapeutic techniques that pre- muscle, and nerve cells. vent or correct this age-related damage along with any Free radicals are byproducts of cellular metabolism associated debilitating symptoms. that are capable of generating chemical reactions de- structive to parts of the cell. As the cell continues to metabolize over time, such damage may increase. Biological signs of aging Some evidence suggests that free-radical damage may be responsible for decomposition of certain cell parts Certain systemic changes are generally acknowl- and the subsequent accumulation of lipofuscin (“age edged to characterize “normal” aging. Those body pigments”) in various body tissues. Accumulation of functions that decline with age include: renal blood lipofuscin, and of partially digested materials that have flow (44), cardiac output (especially during exercise; also been found in aging cells, may impair cell func- 20), glucose tolerance (1), vital lung capacity (27), and tion and contribute to cell aging (3,4). Thus, the meta- cellular immunity (2). bolic process itself may damage the cell over time and The great variation in the incidence and degree of contribute to aging. such age-related changes and diseases between peo- Accumulated damage with age could also be mani- ple of the same age suggests that individual behavior fested by genetic lesions produced by mutations or me- and physiology influence the aging process. Better un- chanical disruptions of the chromosomes (37,41,48). derstanding of causal factors underlying age-related Such damage could be exacerbated by a possible age- conditions could thus lead to better preventive and related deficiency in genetic repair mechanisms (13,36) therapeutic treatments. and could result in the manufacture of faulty proteins This section briefly reviews what is known and not (e.g., enzymes, hormones, neurotransmitters) that can- known about the cellular basis of these and other not work properly (18). biological changes occurring with age, and what con- Several of the genetic ‘(age-accelerating” diseases, in- nections there might be between these changes and cluding xeroderma pigmentosum and Cockayne’s syn- age-related disease. The etiology and clinical impact drome, seem to involve defects in the cells’ genetic re- of many of these “signs” are not known. pair mechanisms (23)53). People afflicted with either disease show increased frequencies of chromosomal CELL LOSS aberrations and their body cells are unusually sensitive Cell death in certain tissues could contribute to the to the mutation-inducing properties of ultraviolet light. degeneration and death of the organism. In fact, while The symptoms of both of these diseases include pre- it is not the sole cause, the loss of cells in certain re- App. B—The Cc/l Biology of Aging ● 415 gions of the body is thought to contribute significantly off and renewed constantly (as in the skin or intestine) to the aging process. Such loss is particularly impor- may decrease with age and lead to a net loss of cells.

Load more

  8

Copy Link