As indicated in the introductory paragraph, physicians have rarely investigated the Mendelian basis of unusually well-preserved structure and function. This should have a high priority for future research in aging. Meanwhile, we can take advantage of a large body of literature concerning mutations and allelic variations that lead to premature and severe expressions of senescent phenotypes. Many of these are severe loss or gain of function mutations that impact upon reproductive fitness and, therefore, would not fit the evolutionary definition of the types of alleles that impact upon senescence. For each such highly deleterious allele, however, there may be a number of “leaky alleles” or polymorphic variants whose phenotypic effects do indeed escape the force of natural selection. Moreover, alleles that confer unusual resistance to senescent phenotypes may exist in some individuals. Given this rationale, the author examined McKusick's Mendelian Inheritance in Man for loci that impacted upon a limited number of senescent phenotypes and concluded that almost 7 percent of entries had the potential to modulate the pathobiology of aging.56 Assuming a total of 100,000 genes, it became apparent that variants at many thousands of loci could potentially explain, in part, clinical observations indicating considerable variations in patterns of senescence among the geriatric population. A more recent unpublished preliminary study, based on a search of a computerized version of that catalogue, addressed certain deficiencies of the 1978 study, which considered only a limited numbers of phenotypes and which included several nonphenotypic criteria (relevance to certain postulated mechanisms of aging). This more recent study suggests that an even larger proportion of the human genome could play a role in the modulation of senescent phenotypes. Nevertheless, there remains the possibility that a subset of such loci could be of major importance, either because of an impact upon multiple senescent phenotypes or because of a potential to elucidate the pathogenesis of a single, but exceptionally common, senescent phenotype. The first category leads to what have been termed segmental progeroid syndromes.56 The second category leads to what have been termed unimodal progeroid syndromes.57 The prototypic example of a segmental progeroid syndrome is the Werner syndrome (WS).58 It is also known as “Progeria of the Adult” in order to distinguish it from the Hutchinson-Gilford syndrome (“Progeria of Childhood” or “Progeria,” a clinically and genetically distinct entity).59
WS is a rare autosomal recessive disorder discussed in detail in Chap. 33. For the reader of this chapter, however, it will be helpful to briefly review the phenotype in order to give some specific examples of important senescent phenotypes. WS patients appear normal until about the time of puberty, when they fail to undergo the usual adolescent growth spurt. They subsequently develop premature graying and thinning of scalp hair, atrophy of the skin, regional atrophy of subcutaneous fat, bilateral ocular cataracts, several varieties of arteriosclerosis (atherosclerosis, arteriolosclerosis, medial calcinosis), severe calcifications of heart valves, type-2 diabetes mellitus, osteoporosis, benign and malignant neoplasms, and gonadal atrophy. Caucasian WS subjects typically die of a myocardial infarction, at a median age of 47 years.58 Cancer appears to be a more common case of death among Japanese patients.60 It is important to point out that there are a number of clinical and cell biologic discordances with what is seen in “usual” aging, however.56 To cite just one example of a clinical discordance, the ratio of epithelial-mesenchymal neoplasms in WS is approximately 1:1, whereas the ratio in usual aging is about 10:1.61 Moreover, WS patients are extraordinarily susceptible to certain rare neoplasms. For example, acral lentiginous melanoma is about 1000 times more common than in controls in a Japanese series.61 There are cell biologic discordances as well. For example, while WS somatic cells exhibit a striking acceleration of replicative senescence, 62 transcription of the cFOS gene in senescent WS cells is quite responsive to mitogenic stimulation, unlike senescent cells from control subjects.63 WS subjects have null mutations at a member (WRN) of the RecQ family of DNA helicases.64-66 The WRN protein may therefore play a role in such basic DNA transactions as replication, recombination, repair, transcription, and chromosomal segregation. WS somatic cells are genetically unstable.67 These findings provide a reasonable explanation for the enhanced susceptibility to neoplasia. Perhaps more surprising, however, is this new evidence for a role of aberrant DNA metabolism and somatic mutation in the many other WS phenotypes. For example, posttranslational alterations in lens proteins have long been regarded as the cause of ocular cataracts.12 Research with WS, however, provides support for an alternative pathogenetic pathway, perhaps operative in a minor proportion of the population, involving aberrations in DNA transactions of lens epithelial cells. The research on WS has also revived interest in the somatic mutational hypothesis of the origin of atheromas.68
The discordances between the features of aging in WS and in “usual” aging suggest that the null mutations found in WS patients are best interpreted as leading to a private modulation of aging.67 In keeping with our introductory remarks, however, we should now ask whether there is any evidence that “leaky” mutations or polymorphisms at WRN can result in more modest modulations of senescent phenotypes, either deleterious or beneficial. Certain of these, particularly polymorphisms, might lead to more public modulations of aging. There are only hints that this may be the case. There is a single case-control association study that provides evidence that a polymorphic form of WRN may protect Japanese patients from myocardial infarction.69 There is also evidence that heterozygous carriers are hypersensitive to a genotoxic, carcinogenic agent, 4-nitroquinoline-1-oxide.70 This finding is consistent with a clinical study indicating a high prevalence of malignancies in first-degree relatives of WS patients.71
The three autosomal dominant mutations leading to early onset familial Alzheimer disease are good examples of unimodal progeroid syndromes.72-74 There is as yet no compelling evidence that these mutations have any significant systemic peripheral effects. These mutations are individually and collectively exceedingly rare and are best regarded as leading to private modulations of the senescent phenotype. However, the associated neuropathology usually cannot be differentiated from what is observed in the vastly more prevalent late-onset, “sporadic” forms of Alzheimer disease. Thus, like so many inborn errors of metabolism, these rare “experiments of nature” may reveal a pathogenetic pathway or relevance to a senescent phenotype that may impact upon as many as 47 percent of individuals who live past the age of 85 years.75 A variety of lines of evidence support this contention and indicate that the pathway involves the metabolism of the β-amyloid precursor protein.76 There is one well-accepted polymorphic locus, APOE, that modulates the common late-onset form.77 It can be regarded as leading to a public modulation of a senescent phenotype. Gene action at the APOE locus may be an example of antagonistic pleiotropy.78 If this is the case, the allele that is associated with increased susceptibility to Alzheimer disease (the epsilon 4 allele) may have provided enhanced reproductive fitness to ancestral carriers in some environments. It is a challenge for the future to discover the molecular basis and the environmental milieu for a putative beneficial effect early in life but a deleterious effect late in life. One highly speculative candidate area for research would be resistance to an infectious agent (e.g., Mycobacterium tuberculosis ) on the basis of an altered lipid metabolism.