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REVIEW ARTICLE |
Division of Geriatrics, Department of Medicine, Saint Louis University School of Medicine, and Aging and Development Program, Department of Psychology, Washington University, St. Louis, Missouri.
Address correspondence to Herman T. Blumenthal, MD, PhD, 6203 Washington Ave., St. Louis, MO 63130.
"...[T]here is an increasing realization that some disorders may be caused by defective dynamics of protein folding. For a typical protein this means deciphering why some sequences of a poly-peptide chain may fold into an alpha-helical configuration, other regions form a beta-sheet silk-like conformation, and still other sequences form turns and loops."—Gina Kolata (1; p. 1038)
IN a previous essay (2), I noted that the major criteria commonly used to distinguish biological aging from the aging-related diseases are intrinsicality and universality, the first stipulating that the phenomenon be generated independent of extrinsic influences, and the second that it occur in all aged members of the species. It was also noted that the traditional medical model, based on the extrinsic causes of disease, is not sufficient for an understanding of the genesis of diseases with age at onset in the senescent period of the life span, when disorders such as cardiovascular and cerebrovascular disease, cancer, and Alzheimer's disease are at their peak prevalence rates. The reason for the exclusion of this age group from the traditional medical model is that risk factors and germ-line genetic risks progressively decline with advancing age, and that the oldest-old represent an elite population that has escaped these risks.
It is posited here that the foregoing phenomenon described by Kolata is an aberrant post-translational event consistent with biological aging, but that also gives rise to an intrinsically generated disease—amyloidosis.
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AN HISTORICAL PERSPECTIVE |
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Animal Models of Amyloidosis
The foregoing references (3–11) also provide historical information regarding animal models. Amyloid has been produced in animals by inducing a chronic infection, by the injection of casein, by exposure to gamma irradiation (13), regarded as a model of accelerated aging, by parabiosis in genetically homogeneous mice and hamsters (14,15), regarded as an example supporting an immunological theory of aging, and by other immunological procedures (16), implying a derivation of amyloid from immune complexes.
Early Clinical Observations on Amyloidosis
From a clinical perspective, the foregoing historical references (3–11) reveal that amyloid is linked with such chronic wasting diseases as tuberculosis and leprosy, with the lambda light chain immunoglobulin of multiple myeloma, and, especially significant here, it appears in cases without predisposing illness—of so-called "occult" origin. Moreover, it became evident from both clinical observations and animal models that there are other molecular forms of this disease (9,10).
Reports (3–11) also reveal early observations linking diabetes with amyloid deposits in the Islets of Langerhans and the amyloid in the brain associated with Alzheimer's disease. They also reveal that the prions of some dementing disorders display the histochemical characteristics of amyloid, as do the Lewy bodies of Parkinson's and diffuse Lewy body diseases.
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DEFINING THE AMYLOID PHENOTYPE |
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In a landmark review over a century later (in 1980), Glenner (17) detailed the microscopic, histochemical, and ultramicroscopic characteristics, designated here as the amyloid phenoype (Table 1 and Figures 1–4
). Table 1 provides information as to the various degrees of specificity of particular procedures, and the figures provide corresponding visual images. On the basis of the back-and-forth configuration of the beaded fibrils on X-ray crystallography, shown schematically in Figure 4, Glenner termed the amyloid as the beta fibrilloses. In addition to the proteins, amyloid contains glycosaminoglycans (18). Precursors, mediators, and enhancers have also been identified (19). And, while almost all amyloid deposits share these histochemical and structural criteria, there are, in addition, cases that are designated "amyloid-like" because they appear to fulfill all of the foregoing yardsticks with the exception that they are congo red negative (20).
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PROTEIN SYNTHESIS IN AGING |
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Enter Misfolding: Its Causes and Defenses
As Martin and colleagues (22) and Holliday (23) have elucidated, there are causes and defenses of biological aging. Since, as posited here, amyloid is the product of protein misfolding (1), a biological aging phenomenon attributable to errors in the post-translational phase of protein synthesis, its causes and defenses are also discussed.
The order of amino acids in a protein determines how it folds into a three-dimensional configuration, and how it assembles into complexes with other proteins. The appropriate folding of a protein is essential if it is to carry out its metabolic function. Protein folding is also critical for dismantling protein complexes, transporting proteins between cellular compartments, and preparing proteins for destruction. Molecular chaperones are proteins found in all cells, and they assist other proteins to fold and assemble. With regard to the aforementioned discovery of amyloid fibrils in E. coli, it is noteworthy that chaperones have also been identified in these microorganisms (24).
There are two primary causes of protein misfolding—inappropriate insertions of amino acids deriving from mutations of its precursor DNA, and over-expression of a protein precursor. As Taubes (25) has noted, a single misspecified amino acid can result in a misfolded protein. When misfolding occurs, the result is the deposition of a material that is neither biologically active nor useful in the assembly of structures. While each protein of a eukaryotic cell has as its primary structure a specific sequence of amino acids, its functional capacity is determined by its full three-dimensional configuration.
As noted above, there are also molecules that are not a direct cause of amyloidosis, but have an enhancing or accelerating effect. In the latter category are studies on senescence-accelerated mice. This strain exhibits an enhanced oxidative stress attributable to an impaired Cu-Zn superoxide dismutase, accompanied by a universal accelerated senile amyloidosis (26,27). Advanced glycosylation end (AGE) products are also involved in the genesis of some forms of amyloidosis (28). Apolipoprotein E (APOE), a high-density plasma lipoprotein, is not essential for amyloid fibrillogenesis, but can facilitate the deposition of amyloid by binding with the amyloid fibril protein (29).
The essential defenses consist of DNA editing and repair mechanisms, the defenses against oxygen-free radicals or AGE products that may be causes of mutations, and the ubiquitinization of faulty proteins followed by their degradation. Eukaryotic cells carefully monitor the accuracy of protein assembly and folding in the endoplasmic reticulum (30).
A phenomenon common to all types of amyloid deposits is a misfolding of the three-dimensional configuration of the amyloidogenic proteins. Ingber (31) posits that proteins as well as other biological entities are constructed using a common form of architectural principle known as tensegrity—"a system that stabilizes itself mechanically because of the way in which tensional and compressive forces are distributed and balanced within the structure." As with other aging-related causes of errors in protein synthesis for which there are defenses, there is also a defense against misfolding. To ensure the accuracy of protein folding and assembly in the endoplasmic reticulum, when unfolded proteins accumulate or proteins are misfolded, unassembled, or denatured as a result of various stresses, so-called stress proteins activate a program to destroy mistakes (32). The misfolded proteins are exported out of the endoplasmic reticulum to the cytosol, and tagged there with ubiquitin for the destruction of the proteosome. An insulin-degrading enzyme has also been identified as a defense against the amyloid deposits of Alzheimer's disease (33).
To provide a perspective on the potential for acquiring amyloid, it should be noted that there are an estimated 100,000 different proteins, each with a different folded configuration. The longer the chain of amino acids, the greater the time required for appropriate folding. It is this post-transitional event, designated the second half of the genetic code, that provides proteins with their highly specific biological activity (1).
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REVISITING THE AMYLOID PHENOTYPE |
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The purpose in reiterating these characteristics of the phenotype of all amyloids is to provide a backdrop for the section that follows, demonstrating that it can derive from a large variety of genotypes.
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THE AMYLOID GENOTYPES |
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Despite the fact that amyloid is not a single chemical entity as reflected in its wide range of molecular weights (Table 2), its structural and cytochemical characteristics define its phenotype, a conclusion drawn by Glenner (17), who has subsumed all amyloids under the designation "the beta fibrilloses." Tables 3 and 4 list the systemic and localized forms of the amyloidotic diseases. Following are observations relevant to amyloid genotypes as reported in several reviews (5,8–10).
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In the AL amyloidoses, designated light chain deposition disease, the expressed light chains exhibit amino acid substitutions that arise from somatic mutations (37). The identification of an AL amyloid associated with a cardiomyopathy (38) is relevant to the determination of cause of death, as discussed later in this article. A common clinical manifestation of excessive amounts of immunoglobulin and amyloidosis is a polyneuropathy (39).
AA Amyloid
This amyloid is synthesized in the liver. It is an apolipoprotein deriving from a nonimmunoglobulin precursor, serum amyloid A (SAA), in association with interleukins 1 and 6. It is the amyloid type seen in animals injected with casein. A transgenic mouse model carrying the human interleukin-6 gene also exhibits AA amyloid (40). Moreover, rabbits immunized with thyroglobulin exhibit a systemic distribution of amyloid similar to human cases of AA amyloidosis in which the amyloid is generated by immune complexes (16,41).
It is also of historical note that, early in the 20th century, horses hyperimmunized to produce diphtheria antitoxin exhibited a systemic pattern of amyloidosis similar to human cases of AA type. Also in the past, AA amyloid was encountered most often in cases of tuberculosis, but it was also seen in association with bronchiectasis and chronic osteomyelitis. It remains present in countries where leprosy is endemic. But in developed countries, it is associated with the diseases shown in Table 3. The association of AA amyloid with chronic infectious diseases suggests that, although AA protein is a nonimmunoglobulin, immune complexes may have a role in its pathogenesis.
AF (Familial-Hereditary) Amyloidoses
This category of amyloidosis is associated with a variety of proteins—gamma trace, a beta protein different from those linked with Alzheimer's disease and other beta associated disorders, several variants of transthyreretin, and even AA type. Their clinical manifestations also vary: some are neuropathic, others nephropathic, and still others cardiopathic.
The AE (Endocrine) Amyloids
These amyloids are all in the localized category, and they are mostly derived from hypersecreted hormonal polypeptides. They are present in the Islets of Langerhans of the pancreas, in medullary carcinoma of the thyroid, in the parathyroid glands, in the anterior hypophysis, and as atrial natriuretic amyloid deposits in the heart.
AE amyloids are strikingly aging related. Amyloid deposits of the anterior hypophysis occur in 90%–95% of people aged older than 80 years. Amyloid of the Islets occurs in over 50% of elderly people and in over 90% of noninsulin-dependent diabetics; atrial natriuretic amyloid deposits of the heart is seen in 65% of those older than 70 years (42–45).
It is of note that the amino acid sequence of the amylin polypeptide has a 43%–46% homology with that of the calcitonin-related polypeptide (44), and that a mutation of the amylin peptide, designated S2OG, has been identified in Japanese diabetics (46).
The Amyloid of Long-Term Dialysis
This category is a B-2 microglobulin-derived amyloid associated with long-term chronic hemodialysis. It occurs in approximately 70% of patients undergoing this procedure. The fact that patients aged older than 65 years represent the most rapidly growing segment with end-stage renal disease (47) suggests that this phenomenon may also have an aging association.
The Asc (Senesce-Related) Amyloids
These amyloids occur in both localized and disseminated forms. They most often derive from transthyretin or beta protein variants. The localized transthyretin variants are found in the seminal vesicles, the joints, and the heart. The beta proteins of the brain are associated with the plaques of Alzheimer's disease, the vessels of cerebral amyloid angiopathy, and the neuronal inclusions of Parkinson's and diffuse Lewy body diseases.
Some Amyloidotic Complexities
There are cases in which more than a single type of amyloid is detected, as well as instances in which the same disease in different patients may be associated with different amyloid types (48–53). There are other complexities. Senile aortic amyloid extending into the common carotid artery is present in the media in 97% of patients older than 50 years, and in the intima in 35% of these patients (54). The intimal and medial amyloids differ in their protein composition.
It has been posited that combinations of two types of amyloid in some cases may represent two independent disorders in the same patient (55), and that the presence of other types in association with AA may indicate that AA is of importance for the formation of all types of amyloid (56).
A Summation
Tables 3 and 4 list the vast array of disorders associated with the amyloid genotypes, as to whether they occur on a localized or disseminated basis. There are complexities that appear to defy the rules governing genotype–phenotype relationships. The same amyloid genotype is associated with a remarkably varied array of derivative biochemical substances. For example Sara-iva (57) has reported that more than 40 different mutations of transthyretin are associated with amyloid deposition. Finally, there are cases in which more than a single type of amyloid is detected, as well as cases in which the same disease in different patients is associated with different amyloid types.
The large number of clinically manifest diseases associated with amyloid deposits (over 60 in Tables 3 and 4) stands as a striking example supporting the concept of different pathogenetic pathways leading to the same end-point lesion.
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AMYLOID AND THE AGING-DISEASE CONUNDRUM |
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Focal deposits of amyloid are not likely to be detected clinically and, therefore, are not likely to be reported on death certificates (58). With the declining autopsy rate and the fact that cytochemical procedures for the presence of amyloid are not routinely carried out in conventional autopsies, focal deposits often go unreported.
Nevertheless, amyloid deposits of the heart and brain deriving from a mutant transthyretin appear to be far more common than generally appreciated (59,60). In his commentary, Benson (60) notes that such variants have been identified in the central nervous system in diseases such as Alzheimer's, Gerstmann-Straussler-Scheinker, and Huntington diseases. In a tabulation of 50 transthyretin variants, 26 showed amyloid deposits in the heart, 12 in the eye, and 6 in the leptomeninges. Two reports taken together (61,62), representing several hundred aged patients, showed Asc amyloid A atrial deposits in 80%–100% of cases. One study (62) of 100 aged hearts revealed that 91 had amyloid deposits in the heart. These findings confirm the earlier speculation that amyloid may be present in all aged individuals in varying amounts.
Amyloid deposits in the heart, whether of immunoglobulin light chain transthyretin variants, atrial natriuretic polypeptide, or of Asc derivation are particularly relevant to cause of death in aged people. The consequences of such deposits can be clinically undetected arrhythmias, atrial standstill, heart failure, or a restrictive cardiomyopathy with fatal heart failure (61–63). Thus, heart failure, commonly attributed to coronary heart disease, may be due to an amyloid-induced cardiomyopathy in aged individual.
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THE BIMODAL PLOT |
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Table 5 shows the application of the bimodal paradigm to the amyloidotic disorders. The juvenile and senescence periods of the life span show a moderate number of amyloidotic disorders. What is most striking is the large number of diseases in the familial-hereditary category attributable, in large part, to transthyretin mutations. The amyloid plaques of the brain provide an example of different pathogenic pathways to the same phenotypic lesion in compliance with the bimodal paradigm. In Down's syndrome, the plaques derive from an overproduction of the amyloid precursor protein (APP). The plaques of early-onset Alzheimer's disease are associated with presenilin mutations l and 2. The plaques of late-onset Alzheimer's disease are linked with mutations of APP along with the APOE4 gene as a predisposing factor in some cases. In sum, the life span distribution of the amyloidotic disorders conforms to the previously posited bimodal distribution (4).
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CONCLUSION |
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"Aging, in our view, makes us ever more susceptible to such ills as heart disease, Alzheimer's disease, stroke and cancer but these age-related conditions are superimposed on aging, not equivalent to it" (64).
The appendix to a previous essay (65) contained opinions as to the relationship between biological aging and the age-associated diseases, stretching from Greek and Roman times to the Middle Ages and on to the past two centuries. These opinions were assembled into three categories: those favoring a separation of the two phenomena, those favoring a continuum between biological aging and disease, and those expressing an ambiguity regarding this relationship.
Although not directly related to the aging-disease conundrum, it is nevertheless noteworthy that, in mice exhibiting extended longevity by caloric restriction or genetic manipulation, there is a failure to de-link the two phenomena. The experimental mice with extended life spans die of the same spectrum of diseases as control or wild-type mice (66). Disease onset is postponed, not eliminated.
The foregoing declarative statement is the most recent one favoring a dichotomy. On its face, it precludes the assignment of a causal role to biological aging in the generation of the aging-associated diseases. To support their position, the authors invoke the criteria of intrinsicality and universality. While amyloid is secondarily deposited in association with certain tumors and several other disorders, for the most part, it occurs as an "occult" intrinsically generated phenomenon. As to universality, amyloid fibrils have not only been demonstrated in many mammalian species, but they have even been identified in bacteria. Moreover, in human studies on participants of advanced age, the prevalence of amyloid deposits in the heart comes close to universality.
The authors further note that if the major age-associated diseases were eliminated, only approximately 15 years would be added to the human life span. In the unlikely prospect that the age-associated diseases were eliminated, it is presumed that death at the end of the life span would be the result of some biological aging phenomenon. While specifically noting other common diseases of the senescent period of the life span, it makes no mention of the ubiquity of amyloidosis. This perhaps reflects the paucity of studies dealing with amyloidosis in the current gerontological literature.
As detailed at the outset of this article, between the years 1957 and 1988 there was a period of active research on the association of amyloidosis and aging in a fairly large number of mammalian species, including humans. With that history in mind, and with the discovery in 1996 of misfolding of proteins as an errant post-translational event that results in the generation of amyloid proteins, a consideration of the relationship between amyloidosis and aging appears again to be in order, particularly since faulty post-translation events in the synthesis of proteins has long been recognized as an event associated with biological aging and certain age-related diseases. Amyloidosis is not the only disease deriving from misfolded protein. It is subsumed under a category of diseases associated with this biological phenomenon designated "conformational diseases" (67). As Dobson (68) has noted: "... with sufficient patience and cunning, conditions could be found in which seemingly any protein could form amyloid fibrils. This observation suggested that the ability to form such fibrils is ‘generic’ to proteins, although the propensity to form such structures under given circumstances can vary greatly from one protein to another."
The position taken here is that aging and the age-associated diseases connect in many different ways, including some in which biological aging assumes a causal role. It has been the objective of this article to demonstrate the ways in which amyloidosis and biological aging are linked. Others that may follow may identify other ways in which biological aging and particular age-associated diseases are causally linked. As to amyloidosis, the evidence supports the conclusion that amyloidosis is both a biological aging phenomenon as well as a disease.
Received July 9, 2003
Accepted July 18, 2003
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REFERENCES |
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An Historical Perspective
Defining the Amyloid Phenotype
