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ABSTRACT

  • The current unprecedented rate of growth of the population over age 85 years underscores the importance of investigating genetic factors modulating age-related disabilities and diseases. An equally important and neglected task, however, is to discover genetic factors leading to unusual degrees of maintenance of structure and function in late life (successful or elite aging).

  • There are six stages in the life cycle of humans: developing, maturing, reproducing, sageing (characterized by extensive use of physiological and behavioral compensations), senescing (characterized by increasing degrees of homeostatic failures), and dying. Gene action at all of these stages is relevant to the biology of aging.

  • Senescence can occur in the absence of overt specific disease entities but cannot easily be dissociated from disease states. Senescent changes in tissues may be direct precursors of common late-onset diseases via mechanisms that remain to be fully elucidated. One example is somatic mutation, a precursor of the many neoplasms that emerge in late life. Late-onset diseases may therefore be viewed as senescent phenotypes.

  • Senescent phenotypes are nonadaptive traits that occur because of the decline in the force of natural selection with respect to the age of gene effects. Senescence is not “programmed” in the sense that determinative, sequential gene action programs development.

  • Two broad classes of gene action are postulated to differentially modulate senescent phenotypes and life span. The first involves constitutional mutations with neutral effects on reproductive fitness but with deleterious effects late in the life course, thus escaping the force of natural selection. These modulations can be regarded as private in that their frequencies in various populations are largely functions of genetic drift. The second involves genes with antagonistic pleiotropic actions. These involve allelic variants selected to enhance reproductive fitness but with deleterious effects late in the life course. Because such alleles are likely to spread widely within many populations, they can be considered to lead to public modulations of senescence. Polymorphisms, rather than rare mutations, are more likely to be responsible for differential public modulations within populations.

  • It is probably the case that variants at thousands of genetic loci have the potential to modulate the pathobiology of senescence. These can be divided into two classes: variants that lead to segmental progeroid syndromes, which impact upon multiple senescent phenotypes, and variants that lead to unimodal progeroid syndromes, which impact upon a single tissue or phenotype. The prototypic example of a segmental progeroid syndrome is the Werner syndrome (“Progeria of The Adult”). It is caused by null mutations at a member of the RecQ class of DNA helicases and leads to accelerated replicative senescence and a mutator phenotype. Although it is best viewed as a private modulation of aging, polymorphic forms of the gene might prove to be of more general significance. Examples of unimodal progeroid syndromes include familial forms of dementias of the Alzheimer type. These are also rare private modulations, but these may inform us as to general pathogenetic mechanisms. The apolipoprotein E locus, ...

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