Research Cancer

Molecular Basis of Cancer, Aging and Aged-Related Diseases

The questions of how and why we age have rattled our imagination since the beginning of time and remain to be one of the most complex problems in modern biology. Advanced research in molecular biology and genetics in the last fifty years have produced a number of models to explain the mechanism of aging. These include oxidative damage (ROS) associated with cellular metabolism, genome instabilities (telomere shortening, mitochondrial mutation, chromosomal pathologies, etc.), and systemic aging. However, a unified theory of aging has yet to emerge and the molecular basis underlying this process has yet to be deciphered. One reason behind such disparity is due to the fact that much of the work in this area has been focused on model organisms such as C. elegan, yeast and drosophila, simply for their short life span and ease of genetic manipulation. Although the basic mechanism of aging might be similar to some extent, the manifestation of functional decline and pathology related to aging are likely to be entirely different in human than it is in C. elegan or yeast. An attempt to generalize these findings to higher organisms could be misleading. The problem associated with the current models of aging lies in their inability to accommodate experimental observations from complex organisms such as mice and human (a review by Guarante et al discussed the evidence for and against some of these models).

Comprehensive study on human aging has yet to be reported. Much of our knowledge in this field came from studies of cell culture, particularly, fibroblasts. However, the conclusions that emerged from some of these studies are presently in question. For example, cellular senescence (the terminal state of the cellular life span) has been widely accepted as the cause of aging. A recent re-examination of fibroblasts does not show a correlation with the donor age, which suggests that aging is operated by a mechanism different from the inability of cells to undergo self-renewal. More recently, telomere shortening has been implicated as the cause of cellular aging, and has attracted much attention. However, this optimism should be treated with caution. Although telomere shortening may play an important role in cellular aging, its involvement in the aging process is not observable for all mammals. Studies of telomerase knockout mice showed that these transgenic animals did not display signs of rapid aging in the first few generations. Even more puzzling, mice have telomeres that are three times longer than ours, yet they don’t live three times as long (the average life span for mice is ~2.5 yrs compared to ~90 yrs for human). Furthermore, human senescent cells still carry residual telomeres in length similar to that of many eukaryotes. The conflicting findings illustrated here clearly demand a more comprehensive study, where gene is not studied one or tens at a time, but rather at the genomics level, where all 50,000 genes or so are interrogated simultaneously and where genes can be knock-in or knock-out selectively, spatially and temporally. If we are going to succeed in deciphering the genetics codes of human aging, studies of fibroblast cell culture alone are not sufficient, a cooperative effort must be directed toward examining the cellular collections and tissues/organs derived from individuals comprised of different aged-groups, ethnic and gender backgrounds.

Research Interests

Our research program is designed to capture the global aspects of human aging and elucidate the molecular mechanisms of aged-related diseases such as cancer. The areas of interests include:

(i) The genetic basis of cellular and tissue/organ aging
(ii) The mechanisms of physiologic and aged-related diseases
(iii) Assessing gene functions
(iv) Validating the “Mitotic Model of Aging”

This part of our research program is directed toward validating the recently proposed “Mitotic Model of Aging” (Danith H. Ly, Richard A. Lerner, and Peter G. Schultz). Genome-wide transcript profiling of fibroblasts derived from natural and catastrophic (Hutchinson Gilford progeria, Werner syndrome, Bloom syndrome, and Ataxia Telangestaxia) aging suggests that the underlying mechanism of the natural aging process involves a breakdown in the cell mitotic machinery. Such dysfunction eventually leads to chromosomal pathologies that result in misregulation of key structural, signaling, transcription silencing, and metabolic genes associated with the aging phenotypes, such as osteoporosis, Alzheimer’s disease, arthritis, and so forth. Our recent analysis suggests that the cell cycle checkpoints and transcription silencers play an important role in this process. A number of these genes have already been found to be downregulated with advancing age. Understanding their specific involves in the cell cycle will also help us better understand the molecular switches that determine whether the cells age or become cancerous (immortal).

Polyploidy in transformed cells has been recognized for a long time, but neither its molecular mechanism nor its biological significance has been characterized. The observation that cells derived from old-age individuals and individuals with progeria, and to some extent old age, exhibit relatively high proportion of 4C DNA content, reminiscence of the observation in transformed cells, posts an interesting question. Is cancer a disease of aging? Whether this particular phenotype emerges from the same origin is presently unknown, although, our recent finding suggested that it is.

References
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Collaborators:
Professor Peter G. Schultz (The Scripps Research Institute)
Professor Richard Lerner (The Scripps Research Institute)
Dr. Qihong Huang (The Scripps Research Institute)
Dr. Kent Osborn (The Scripps Research Institute)
Dr. Tim Wiltshire (Genomics Institute of the Novartis Research Foundation)