8. AGE RELATED DISEASES; HELICASES AND AGING
Advances in molecular biology are making it easier to identify genes responsible for monogenic hereditary disorders. However, identifying genes for age-related common disorders including cancer, dementia, arteriosclerosis, hypertension, diabetes mellitus, and osteoporosis is still difficult, partly because most of these disorders are polygenic. A strategy to overcome such a difficulty is to identify genes responsible for age-related monogenic hereditary disorders, followed by clarifying the processes in which the gene products are involved. These causative genes and processes can then be studied in the corresponding non-hereditary age-related disorders, a strategy which has already succeeded with several such disorders, especially cancers. Aging is a complex and multifactorial process. This makes aging studies difficult.
In analogy to the strategy for studying common age-related disorders, studying monogenic hereditary disorders that manifest some agerelated phenotypes in cells, tissues, and the total organism would be helpful for clarifying the mechanisms of aging. One example is cloning of the gene (WRN) responsible for Werner syndrome (WS), a well-known segmental progeroid syndrome with many age-related phenotypes (1). This gene encodes a protein that has the seven helicase motifs conserved in most helicases, and the WRN protein has been shown to have helicase activity. This implies that a decline of probably pleiotropic and fundamental function in this and other helicases underlies the pleiotropic and universal nature of ordinary aging. Consistent with this implication, in addition to WS, at least six human disorders that manifest age-related phenotypes are caused by aberrations of five proteins that have the seven-helicase motifs.
These six disorders are xeroderma pigmentosum (XP), Cockayne syndrome (CS), trichothiodystrophy (TTD), Bloom syndrome (BS), X-linked a-thalassemia: mental retardation syndrome (ATR-X), and Juberg-Marsidi syndrome (JMS). Although not all proteins that have the seven-helicase motifs have helicase activity, disorders that are caused by an aberration of such proteins have been tentatively called helicase disorders (2) in this review. Is, then, an aberration of helicases involved in ordinary human aging? And if so, how does the aberration affect aging? A possible strategy to answer these questions is clarification of the pathways generating age-related phenotypes in helicase disorders, followed by study of these pathways in ordinary aging. Following this strategy, this paper reviews recent reports about helicase disorders and considers the following four subjects. First, how do age-related phenotypes occur in each helicase disorder? Second, what are the common causative pathways in helicase disorders?
Third, are these pathways involved in ordinary aging? Fourth, if so, how are these pathways involved in ordinary aging?
Helicases are a diverse group of enzymes defined by their ability to promote the unwinding of duplex nucleic acid molecules by breaking the hydrogen bonds holding the strands of the duplex together (3 and references therein). They function in the fundamental processes of life, including DNA replication, DNA repair, recombination, transcription, RNA processing, and translation. To participate in the specific pathways in these processes, each helicase has unique amino acid sequences that bind with different molecules. In contrast, most helicases have conserved amino acid sequences known as the seven-helicase motifs (I, Ia, II, III, IV, V, and VI), which reflect helicase activity in many cases. More than 30 human proteins are predicted to be putative helicases, mostly based on their having the seven-helicase motifs.