Amyloidosis: a Universal Disease of Aging?

Review Article

Amyloidosis: A Universal Disease of Aging?

Herman T. Blumenthal Downloaded from https://academic.oup.com/biomedgerontology/article/59/4/M361/637769 by guest on 23 September 2021

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.

‘‘...[T]here is an increasing realization that some disorders Animal Models of Amyloidosis may be caused by defective dynamics of protein folding. For The foregoing references (3–11) also provide historical a typical protein this means deciphering why some information regarding animal models. Amyloid has been sequences of a poly-peptide chain may fold into an alpha- produced in animals by inducing a chronic infection, by the helical configuration, other regions form a beta-sheet silk- injection of casein, by exposure to gamma irradiation (13), like conformation, and still other sequences form turns and loops.’’ regarded as a model of accelerated aging, by parabiosis in —Gina Kolata (1; p. 1038) genetically homogeneous mice and hamsters (14,15), regarded as an example supporting an immunological N a previous essay (2), I noted that the major criteria theory of aging, and by other immunological procedures Icommonly used to distinguish biological aging from the (16), implying a derivation of amyloid from immune aging-related diseases are intrinsicality and universality, the complexes. first stipulating that the phenomenon be generated independent of extrinsic influences, and the second that it Early Clinical Observations on Amyloidosis occur in all aged members of the species. It was also noted From a clinical perspective, the foregoing historical that the traditional medical model, based on the extrinsic references (3–11) reveal that amyloid is linked with such causes of disease, is not sufficient for an understanding of chronic wasting diseases as tuberculosis and leprosy, with the genesis of diseases with age at onset in the senescent the lambda light chain immunoglobulin of multiple period of the life span, when disorders such as cardiovas- myeloma, and, especially significant here, it appears in cular and cerebrovascular disease, cancer, and Alzheimer’s cases without predisposing illness—of so-called ‘‘occult’’ disease are at their peak prevalence rates. The reason for the origin. Moreover, it became evident from both clinical exclusion of this age group from the traditional medical observations and animal models that there are other model is that risk factors and germ-line genetic risks molecular forms of this disease (9,10). progressively decline with advancing age, and that the Reports (3–11) also reveal early observations linking oldest-old represent an elite population that has escaped diabetes with amyloid deposits in the Islets of Langerhans these risks. and the amyloid in the brain associated with Alzheimer’s It is posited here that the foregoing phenomenon disease. They also reveal that the prions of some dementing described by Kolata is an aberrant post-translational event disorders display the histochemical characteristics of consistent with biological aging, but that also gives rise to amyloid, as do the Lewy bodies of Parkinson’s and diffuse an intrinsically generated disease—amyloidosis. Lewy body diseases.

AN HISTORICAL PERSPECTIVE DEFINING THE AMYLOID PHENOTYPE A number of publications (3–11) provide an abundance of The foregoing reports (3–11) also date the first observa- historical information regarding amyloid, dating back to its tions on the gross and histochemical characteristics of earliest discoveries in late 19th century. Three, in particular amyloid to mid-19th century pathological observations. (3–5), provide information relevant to aging and aging- In a landmark review over a century later (in 1980), related diseases, suggesting that senile amyloidosis may be Glenner (17) detailed the microscopic, histochemical, and an almost universal phenomenon in many mammalian ultramicroscopic characteristics, designated here as the amy- animal species. They document an aging–amyloid associ- loid phenoype (Table 1 and Figures 1–4). Table 1 provides ation in mice, hamsters, cats, dogs, cattle, ducks, baboons, information as to the various degrees of specificity of horses, and humans. But amyloid fibrils are also present in particular procedures, and the figures provide corresponding the bacterium Escherichia coli (12), prompting an adver- visual images. On the basis of the back-and-forth config- tisement by Strategene that asks: ‘‘Do your E. coli cells have uration of the beaded fibrils on X-ray crystallography, mammalian envy?’’ Humor aside, this observation suggests shown schematically in Figure 4, Glenner termed the that the misfolding of proteins may be a universal biological amyloid as the beta fibrilloses. In addition to the proteins, phenomenon. amyloid contains glycosaminoglycans (18). Precursors,

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Table 1. Procedures for Identifying Amyloid The order of amino acids in a protein determines how it Procedure Appearance Specificity folds into a three-dimensional configuration, and how it assembles into complexes with other proteins. The appro- 1. Conventional light microscopy priate folding of a protein is essential if it is to carry out its Hematoxylin-eosin Pink, amorphous Nonspecific metabolic function. Protein folding is also critical for Crystal of Metachromatic, Nonspecific methyl violet amorphous dismantling protein complexes, transporting proteins be- Van Gieson Yellow-orange, Differentiates amyloid tween cellular compartments, and preparing proteins for amorphous from collagen destruction. Molecular chaperones are proteins found in all Periodic acid Schiff Pale violet, amorphous Nonspecific cells, and they assist other proteins to fold and assemble. Congo red Pink orange, amorphous Not completely With regard to the aforementioned discovery of amyloid Downloaded from https://academic.oup.com/biomedgerontology/article/59/4/M361/637769 by guest on 23 September 2021 specific fibrils in E. coli, it is noteworthy that chaperones have also 2. Optical techniques been identified in these microorganisms (24). Ultraviolet Microscopy There are two primary causes of protein misfolding— Unstained Weakly autofluorescent Nonspecific inappropriate insertions of amino acids deriving from Thioflavin T Yellow fluorescence Some false positive mutations of its precursor DNA, and over-expression of Congo red Pink fluorescence Rare false positive a protein precursor. As Taubes (25) has noted, a single Polarized light Unstained Weakly birefringent Good specificity misspecified amino acid can result in a misfolded protein. Congo red Strongly birefringent Good specificity When misfolding occurs, the result is the deposition of 3. Electron microscopy Branched and unbranced Specific a material that is neither biologically active nor useful in the fibrils of varying length, assembly of structures. While each protein of a eukaryotic 40–120 angstroms in cell has as its primary structure a specific sequence of amino diameter, with fibrils acids, its functional capacity is determined by its full three- composed of paired dimensional configuration. helical filaments 24 nm As noted above, there are also molecules that are not wide with a periodicity a direct cause of amyloidosis, but have an enhancing or of 80 nm 4. X-ray crystallography Beta pleated configuration Specific accelerating effect. In the latter category are studies on senescence-accelerated mice. This strain exhibits an en- hanced oxidative stress attributable to an impaired Cu-Zn mediators, and enhancers have also been identified (19). superoxide dismutase, accompanied by a universal acceler- And, while almost all amyloid deposits share these ated senile amyloidosis (26,27). Advanced glycosylation histochemical and structural criteria, there are, in addition, end (AGE) products are also involved in the genesis of some cases that are designated ‘‘amyloid-like’’ because they forms of amyloidosis (28). Apolipoprotein E (APOE), appear to fulfill all of the foregoing yardsticks with the a high-density plasma lipoprotein, is not essential for exception that they are congo red negative (20). 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 PROTEIN SYNTHESIS IN AGING mechanisms, the defenses against oxygen-free radicals or Despite the enthusiasm generated by the Human Genome AGE products that may be causes of mutations, and the Project regarding an understanding of the control of protein ubiquitinization of faulty proteins followed by their synthesis, there are facets of this process that are not under degradation. Eukaryotic cells carefully monitor the accuracy genetic control. It has long been recognized by biogerontol- of protein assembly and folding in the endoplasmic ogists that there are aging phenomena attributable to errors reticulum (30). in the post-translational phase of protein synthesis. The A phenomenon common to all types of amyloid deposits often-reported observation that the tau protein of Alz- is a misfolding of the three-dimensional configuration of the heimer’s disease derives from such a post-translation error amyloidogenic proteins. Ingber (31) posits that proteins as in the phosphorylation of tau serves as an example. In well as other biological entities are constructed using a critique of the Human Genome Project, Fogle (21) adds a common form of architectural principle known as that small changes in the cellular machinery may alter its tensegrity—‘‘a system that stabilizes itself mechanically ability to make sense of the genetic program. As an because of the way in which tensional and compressive example, he demonstrates, with regard to mitochondrial forces are distributed and balanced within the structure.’’ As mutations, that the same mtDNA mutation can produce with other aging-related causes of errors in protein synthesis a variety of phenotypic disorders. for which there are defenses, there is also a defense against misfolding. To ensure the accuracy of protein folding and Enter Misfolding: Its Causes and Defenses assembly in the endoplasmic reticulum, when unfolded As Martin and colleagues (22) and Holliday (23) have proteins accumulate or proteins are misfolded, unassembled, elucidated, there are causes and defenses of biological or denatured as a result of various stresses, so-called stress aging. Since, as posited here, amyloid is the product of proteins activate a program to destroy mistakes (32). The protein misfolding (1), a biological aging phenomenon misfolded proteins are exported out of the endoplasmic attributable to errors in the post-translational phase of reticulum to the cytosol, and tagged there with ubiquitin for protein synthesis, its causes and defenses are also discussed. the destruction of the proteosome. An insulin-degrading AMYLOIDOSIS 363 Downloaded from https://academic.oup.com/biomedgerontology/article/59/4/M361/637769 by guest on 23 September 2021

Figure 1. Hematoxylin eosin stain of kidney section showing a hyaline-like amyloid nodule in a glomerulus (3500). enzyme has also been identified as a defense against the section that follows, demonstrating that it can derive from amyloid deposits of Alzheimer’s disease (33). a large variety of genotypes. To provide a perspective on the potential for acquiring amyloid, it should be noted that there are an estimated THE AMYLOID GENOTYPES 100,000 different proteins, each with a different folded As the mysteries of molecular biology have unfolded, it configuration. The longer the chain of amino acids, the has become evident that there are many examples in which greater the time required for appropriate folding. It is this a 1:1 genotype–phenotype relationship does not apply. On post-transitional event, designated the second half of the the one hand, there is the observation that mutations of genetic code, that provides proteins with their highly a single gene can give rise to four different syndromes (35). specific biological activity (1). On the other hand, amyloid stands as an example that many genotypes can specify a single phenotype. REVISITING THE AMYLOID PHENOTYPE Despite the fact that amyloid is not a single chemical The term ‘‘amyloid phenotype’’ is used here to designate entity as reflected in its wide range of molecular weights lesions conforming to the characteristics shown in Table 1, (Table 2), its structural and cytochemical characteristics and defined by Cotran and colleagues (34) as a proteinaceous define its phenotype, a conclusion drawn by Glenner (17), substance deposited between cells in various tissues and who has subsumed all amyloids under the designation ‘‘the organs in a wide variety of clinical settings that ultimately beta fibrilloses.’’ Tables 3 and 4 list the systemic and produces pressure atrophy of the parenchymal elements of localized forms of the amyloidotic diseases. Following are organs. On a biochemical level, the amyloids share two observations relevant to amyloid genotypes as reported in commonalities—sulfated glycosaminoglycans and charac- several reviews (5,8–10). teristic fibrillar proteins. The sulfated glycosaminoglycans, the amyloid-P component, is a pentagonally structured AL Immunoglobulin Light Chain Amyloids molecule found intimately associated with all types of This category of the amyloids is a product of plasma cells, amyloid fibrils. It represents only 5% of the amyloid fibril, most often of the gamma type. In only 5%–10% of cases is the remaining 95% consisting of the fibrillar proteins. the AL type associated with multiple myeloma. The most The purpose in reiterating these characteristics of the often encountered cases are of ‘‘occult’’ origin (i.e., without phenotype of all amyloids is to provide a backdrop for the an associated disease). In the systemic form, amyloid 364 BLUMENTHAL Downloaded from https://academic.oup.com/biomedgerontology/article/59/4/M361/637769 by guest on 23 September 2021

Figure 2. Electron micrograph of a glomerulus from the same kidney as in Figure 1. End ¼ endothelium; BM ¼ basement membrane; E ¼ capillary passageway; AM ¼ nodular aggregates of amyloid ﬁbrils (311,000). deposits can be found in the heart, lungs, liver, spleen, exhibited a systemic pattern of amyloidosis similar to kidney, gastrointestinal tract, pancreas, and adrenals (36). In human cases of AA type. Also in the past, AA amyloid was the localized form, plasma cells are often seen adjacent to encountered most often in cases of tuberculosis, but it was the amyloid deposits. also seen in association with bronchiectasis and chronic In the AL amyloidoses, designated light chain deposition osteomyelitis. It remains present in countries where leprosy disease, the expressed light chains exhibit amino acid is endemic. But in developed countries, it is associated with substitutions that arise from somatic mutations (37). The the diseases shown in Table 3. The association of AA identiﬁcation of an AL amyloid associated with a cardiomy- amyloid with chronic infectious diseases suggests that, opathy (38) is relevant to the determination of cause of although AA protein is a nonimmunoglobulin, immune death, as discussed later in this article. A common clinical complexes may have a role in its pathogenesis. manifestation of excessive amounts of immunoglobulin and amyloidosis is a polyneuropathy (39). AF (Familial-Hereditary) Amyloidoses AA Amyloid This category of amyloidosis is associated with a variety of proteins—gamma trace, a beta protein different from This amyloid is synthesized in the liver. It is an those linked with Alzheimer’s disease and other beta apolipoprotein deriving from a nonimmunoglobulin pre- associated disorders, several variants of transthyreretin, cursor, serum amyloid A (SAA), in association with inter- and even AA type. Their clinical manifestations also vary: leukins 1 and 6. It is the amyloid type seen in animals some are neuropathic, others nephropathic, and still others injected with casein. A transgenic mouse model carrying the cardiopathic. 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 The AE (Endocrine) Amyloids AA amyloidosis in which the amyloid is generated by These amyloids are all in the localized category, and they immune complexes (16,41). are mostly derived from hypersecreted hormonal polypep- It is also of historical note that, early in the 20th century, tides. They are present in the Islets of Langerhans of the horses hyperimmunized to produce diphtheria antitoxin pancreas, in medullary carcinoma of the thyroid, in the AMYLOIDOSIS 365 Downloaded from https://academic.oup.com/biomedgerontology/article/59/4/M361/637769 by guest on 23 September 2021

Figure 3. Electron micrograph of the twisted ﬁbrils of an amyloid nodule (3100,000). parathyroid glands, in the anterior hypophysis, and as atrial protein variants. The localized transthyretin variants are natriuretic amyloid deposits in the heart. found in the seminal vesicles, the joints, and the heart. The AE amyloids are strikingly aging related. Amyloid beta proteins of the brain are associated with the plaques of deposits of the anterior hypophysis occur in 90%–95% of Alzheimer’s disease, the vessels of cerebral amyloid people aged older than 80 years. Amyloid of the Islets angiopathy, and the neuronal inclusions of Parkinson’s occurs in over 50% of elderly people and in over 90% of and diffuse Lewy body diseases. noninsulin-dependent diabetics; atrial natriuretic amyloid deposits of the heart is seen in 65% of those older than 70 Some Amyloidotic Complexities years (42–45). There are cases in which more than a single type of It is of note that the amino acid sequence of the amylin amyloid is detected, as well as instances in which the same polypeptide has a 43%–46% homology with that of the disease in different patients may be associated with different calcitonin-related polypeptide (44), and that a mutation of amyloid types (48–53). There are other complexities. Senile the amylin peptide, designated S2OG, has been identiﬁed in aortic amyloid extending into the common carotid artery is Japanese diabetics (46). present in the media in 97% of patients older than 50 years, and in the intima in 35% of these patients (54). The intimal The Amyloid of Long-Term Dialysis and medial amyloids differ in their protein composition. This category is a B-2 microglobulin-derived amyloid It has been posited that combinations of two types of associated with long-term chronic hemodialysis. It occurs in amyloid in some cases may represent two independent approximately 70% of patients undergoing this procedure. disorders in the same patient (55), and that the presence of The fact that patients aged older than 65 years represent the other types in association with AA may indicate that AA is most rapidly growing segment with end-stage renal disease of importance for the formation of all types of amyloid (56). (47) suggests that this phenomenon may also have an aging association. A Summation Tables 3 and 4 list the vast array of disorders associated The Asc (Senesce-Related) Amyloids with the amyloid genotypes, as to whether they occur on These amyloids occur in both localized and disseminated a localized or disseminated basis. There are complexities forms. They most often derive from transthyretin or beta that appear to defy the rules governing genotype–phenotype 366 BLUMENTHAL

Table 2. Molecular Weights of Amyloid Types

Genotype Precursor Molecular Weight (Daltons) AL Immunoglobulin lambda light chain 8000–25,000 AA Serum AA (SAA) 8800–12,500 AF Transthyretin variants 14,000 AE Prohormone or hormone Asc Transthyretin variants 5000–12000 Notes: Varies with speciﬁc prohormone or hormone. Downloaded from https://academic.oup.com/biomedgerontology/article/59/4/M361/637769 by guest on 23 September 2021

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 immunoglob- Figure 4. Schematic representation of an amyloid fibril demonstrating the ulin light chain transthyretin variants, atrial natriuretic twisted beta-pleated configuration of the polypeptide filaments. The black blocks polypeptide, or of Asc derivation are particularly relevant represent the alignment of the Congo red dye molecules. [Originally from to cause of death in aged people. The consequences of such Cooper (58) as modified by Cohen and Crawford (7).] deposits can be clinically undetected arrhythmias, atrial standstill, heart failure, or a restrictive cardiomyopathy with relationships. The same amyloid genotype is associated with fatal heart failure (61–63). Thus, heart failure, commonly a remarkably varied array of derivative biochemical attributed to coronary heart disease, may be due to an substances. For example Sara-iva (57) has reported that amyloid-induced cardiomyopathy in aged individual. more than 40 different mutations of transthyretin are associated with amyloid deposition. Finally, there are cases THE BIMODAL PLOT in which more than a single type of amyloid is detected, as As previously noted (20), the bimodal paradigm posits well as cases in which the same disease in different patients that the same phenotypic disease may appear throughout the is associated with different amyloid types. life span, but via different pathogenetic pathways. During The large number of clinically manifest diseases associ- the juvenile period, it is of hereditary or congenital origin. ated with amyloid deposits (over 60 in Tables 3 and 4) During the period of maximum reproductive capacity stands as a striking example supporting the concept of (roughly between ages 15 and 35), in accord with different pathogenetic pathways leading to the same end- evolutionary theory, resistance to disease is at a maximum point lesion. and disease prevalence at its lowest, thereby ensuring the survival of the species. As reproductive capacity pro- AMYLOID AND THE AGING-DISEASE CONUNDRUM gressively declines (the postmaturity period), diseases While some of the foregoing discussion has touched on derive from late-acting inherited mutant genes or from risk various ways in which amyloidosis and aging are associated, factors such as obesity, hyperlipidemias, tobacco consump- this section focuses on a more direct link between biological tion, and a sedentary lifestyle. It is further posited that the aging and amyloidosis because it bears on the issue of the diseases of senescence may derive directly from biological separation of biological aging from the aging-associated aging, based at least in part on the aforementioned diseases and the notion of death at the end of the life span in progressive decline, with advancing age, of the influence the absence of disease. of genetic and environmental risks. Focal deposits of amyloid are not likely to be detected Table 5 shows the application of the bimodal paradigm to clinically and, therefore, are not likely to be reported on the amyloidotic disorders. The juvenile and senescence death certificates (58). With the declining autopsy rate and periods of the life span show a moderate number of the fact that cytochemical procedures for the presence of amyloidotic disorders. What is most striking is the large amyloid are not routinely carried out in conventional number of diseases in the familial-hereditary category autopsies, focal deposits often go unreported. attributable, in large part, to transthyretin mutations. The Nevertheless, amyloid deposits of the heart and brain amyloid plaques of the brain provide an example of different deriving from a mutant transthyretin appear to be far more pathogenic pathways to the same phenotypic lesion in common than generally appreciated (59,60). In his com- compliance with the bimodal paradigm. In Down’s mentary, Benson (60) notes that such variants have been syndrome, the plaques derive from an overproduction of identified in the central nervous system in diseases such as the amyloid precursor protein (APP). The plaques of early- Alzheimer’s, Gerstmann-Straussler-Scheinker, and Hunting- onset Alzheimer’s disease are associated with presenilin ton diseases. In a tabulation of 50 transthyretin variants, 26 mutations l and 2. The plaques of late-onset Alzheimer’s showed amyloid deposits in the heart, 12 in the eye, and 6 in disease are linked with mutations of APP along with the the leptomeninges. Two reports taken together (61,62), APOE4 gene as a predisposing factor in some cases. In sum, AMYLOIDOSIS 367

Table 3. Systemic Amyloidoses Table 4. Localized Amyloidoses

Genetic Genetic Designate Derivative Protein Clinical Disorder Designate Derivative Protein Clinical Manifestations AL Immunoglobulin Myeloma, monoclonal AL Immunoglobulin Nodular deposits in skin, larynx, light chain gammopathy, Waldenstroms light chain tongue, skull, eye, lung, macroglobulinemia, restrictive urogenital tract cardiomyopathy, occult dyscrasias AF Cystatin C GLU Icelandic-type amyloid angiopathy AA Apolipoprotein (SAA) Rheumatoid arthritis, ankylosing variant (gamma trace) with cerebral hemorrhage spondylitis, regional enteritis, Beta protein variant Dutch-type amyloid angiopathy ulcerative colitis, Hodgkin’s with cerebral hemorrhage Downloaded from https://academic.oup.com/biomedgerontology/article/59/4/M361/637769 by guest on 23 September 2021 disease, renal cell carcinoma, cystic Not known Cutaneous bullous as papular fibrosis, other connective tissue amyloid deposits diseases, heroin drug abuse AE Precalcitonin Medullary carcinoma of the thyroid Predominantly Neuropathic Calcitonin-related Amyloid deposits in islets AF type I Met 30 transthyretin Portuguese, Japanese, Swedish peptide of Langerhans variant kindreds Amylin Amyloidosis of islets of Gly49/IIe33 transthyretin Jewish kindreds Langerhans in aging and NIDDM variants Prolactin Amyloid deposits in anterior AF type II Ser84 transthyretin Swiss and German kindreds, hypophysis variant Indiana–Maryland type Atrial natriuretic Heart and rarely at site of insulin AF type III ? Arg AA variant Scottish and Irish kindreds, polypeptide injection Iowa type (neuropathic APP Beta protein Down’s syndrome, dementia of and nephropathic) variants Alzheimer’s type, Parkinsonian AF type IV Not known Finnish kindred dementia, Lewy body dementia, Predominantly Nephropathic sporadic amyloid angiopathy, AF Apolipoprotein (SAA) Familial Mediterranean fever prion disease, inclusion body Not known Ostertag type myositis Not known Muckle-Wells type, deafness, Asc Transthyretin Heart, joints, seminal vesicles limb pain, urticaria variants No designate B-2 microglobulin Periocular and renal amyloid Predominantly Cardiomyopathic ? Keratin derived Localized macular and papular AF ? Met 10 transthyretin Danish type skin lesions variant Not known Corneal and conjunctival amyloid Ala60 transthyretin Appalachian type deposits variant Note: From Pepys (10), with modifications. Not known Cardiomyopathy with persistent NIDDM ¼ noninsulin-dependent diabetes mellitus. atrial standstill Asc Transthyretin variant Senile systemic amyloidosis a continuum between biological aging and disease, and those expressing an ambiguity regarding this relationship. the life span distribution of the amyloidotic disorders Although not directly related to the aging-disease conforms to the previously posited bimodal distribution (4). conundrum, it is nevertheless noteworthy that, in mice These distinctive features of the amyloidotic disorders exhibiting extended longevity by caloric restriction or may also serve as a model for testing the concept that some genetic manipulation, there is a failure to de-link the two of the phenotypes of other age-dependent degenerative phenomena. The experimental mice with extended life spans diseases may derive directly from biological aging. Future die of the same spectrum of diseases as control or wild-type articles are planned in which this model will be tested for its mice (66). Disease onset is postponed, not eliminated. applicability to age-associated disorders such as cardiovas- The foregoing declarative statement is the most recent cular and cerebrovascular disease, diabetes, cancer, and one favoring a dichotomy. On its face, it precludes the Alzheimer’s disease. assignment of a causal role to biological aging in the generation of the aging-associated diseases. To support their CONCLUSION position, the authors invoke the criteria of intrinsicality and universality. While amyloid is secondarily deposited in ‘‘Aging, in our view, makes us ever more susceptible to such association with certain tumors and several other disorders, ills as heart disease, Alzheimer’s disease, stroke and cancer for the most part, it occurs as an ‘‘occult’’ intrinsically but these age-related conditions are superimposed on aging, generated phenomenon. As to universality, amyloid fibrils not equivalent to it’’ (64). have not only been demonstrated in many mammalian The appendix to a previous essay (65) contained opinions species, but they have even been identified in bacteria. as to the relationship between biological aging and the age- Moreover, in human studies on participants of advanced associated diseases, stretching from Greek and Roman times age, the prevalence of amyloid deposits in the heart comes to the Middle Ages and on to the past two centuries. These close to universality. opinions were assembled into three categories: those The authors further note that if the major age-associated favoring a separation of the two phenomena, those favoring diseases were eliminated, only approximately 15 years 368 BLUMENTHAL

Table 5. Distribution of Amyloidotic Disorders on the Bimodal certain age-related diseases. Amyloidosis is not the only Life Span Plot disease deriving from misfolded protein. It is subsumed Segment 1 Segment 3 Segment 4 under a category of diseases associated with this biological (Juvenile Onset) (Postmaturity) (Senescence Onset) phenomenon designated ‘‘conformational diseases’’ (67). As Down’s syndrome Sporadic plasma cell Senile local and Dobson (68) has noted: ‘‘... with sufficient patience and (beta protein dyscrasias (immunoglobulin systemic cunning, conditions could be found in which seemingly any variant) light chains) amyloidoses protein could form amyloid fibrils. This observation (Asc transthyretin suggested that the ability to form such fibrils is ‘generic’ variants) to proteins, although the propensity to form such structures Cystic fibrosis Sporadic inflammatory, Amyloidosis of Islets under given circumstances can vary greatly from one protein Downloaded from https://academic.oup.com/biomedgerontology/article/59/4/M361/637769 by guest on 23 September 2021 (AA variant) autoimmune, and neoplastic of Langerhans (AE to another.’’ diseases. (AA variants) amylin protein) Restrictive Familial-hereditary types I Sporadic amyloid The position taken here is that aging and the age- cardiomyopathy and II (transthyretin angiopathy (beta associated diseases connect in many different ways, in- (AF variant) variants) protein variant) cluding some in which biological aging assumes a causal Odontogenic tumors Familial hereditary Alzheimer’s role. It has been the objective of this article to demonstrate (AA variant) type III (AA variant) Parkinson’s and the ways in which amyloidosis and biological aging are diffuse Lewy body linked. Others that may follow may identify other ways in diseases (beta protein variants) which biological aging and particular age-associated Muckle-Wells Familial-hereditary Danish Dialysis-associated diseases are causally linked. As to amyloidosis, the evidence syndrome and Appalachian types amyloidosis (B-2 supports the conclusion that amyloidosis is both a biological (AA variants) (transthyretin variants) microglobulin) aging phenomenon as well as a disease. Hodgkin’s disease Familial-hereditary Restrictive (AL vaiant) Icelandic amyloid cardiomyopathy angiopathy (gamma (atrial natriuretic ACKNOWLEDGMENT trace protein) polypeptide) Address correspondence to Herman T. 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