Perspectives in Biology and Medicine

AGEING AND DISEASE: PROTEINS AS THE MOLECULAR LINK SURESH I. S. RATTAN* Is ageing a disease? The most common answer is: No. Yet a multibillion-dollar cosmetic market thrives and flourishes by selling promises to "cure" ageing. This dichotomy between what we know intuitively about ageing and what we wishfully believe about it remains. Although it is well known that most diseases show marked increases with age, the connection between the ageing process and the incidence of age-related diseases is highly underestimated. Recent developments in gerontology are unearthing the molecular link between ageing and disease , thereby pointing toward new approaches and strategies for biomedical research and therapy. The highly complex nature of the ageing process is only beginning to be understood in biochemical and molecular terms. Over the last 30 years, numerous experimental and descriptive studies have, by and large, established what happens in cells, tissues, organs, and organisms during ageing. Volumes of data are available that list structural, physiological , biochemical, and, more recently, molecular changes in a wide variety of experimental systems undergoing ageing. Together, these data build up a gross picture of the underlying biology of the ageing process. An increased frequency of diseases involving almost all parts of the body is one aspect of this picture [1, 2]. Some of the diseases most commonly associated with old age include atherosclerosis, arthritis, amyloidosis, cataract, chronic renal failure, diabetes , osteoporosis, senile dementia, and cancers of most types. At the same time, various other impairments of bodily functions, such as delayed wound healing, slower metabolic clearance of drugs, reduced absorption of nutrients, and increased susceptibility to infections and hypothermia are observed more frequently in old age. It is often wrongly *Laboratory ofCellular Ageing, Department ofChemistry, Aarhus University, DK-8000 Aarhus-C, Denmark.© 1991 by The University of Chicago. All rights reserved. 003 1 -5982/9 1 /3404-0747$0 1 .00 526 Suresh I. S. Rattan ¦ Ageing and Disease assumed that each age-related disease has its own particular cause distinct and separate from the cause of other disease. In this article, therefore , I wish to explore the molecular link between diseases of old age and the process of ageing per se. What Is Ageing? The life of almost all multicellular organisms begins with a single cell that undergoes a remarkably complicated process of growth, cell division , differentiation, and development, resulting in a highly organized structure. Compared with the complexity of the processes involved during development, maturation, and reproduction, it should be a relatively small feat to maintain the fully developed body forever. This is because organisms are equipped with several repair, maintenance, and defense mechanisms, such as DNA repair systems, free radical scavenging systems , cellular replacement systems, immune system, and detoxifying systems, and these protect the body for a large proportion of its total life span. Yet it is the intrinsic and progressive failure of maintenance at almost all levels of organization, typically in the postreproductive period, that characterizes the ageing process [1, 3]. Since maximum achievable life spans and rates of ageing differ greatly from one species to another and appear to reflect evolutionarily stabilised strategies, these must clearly be subject to a strong element of genetic control. Various experimental animals have been used for studies of the basic mechanisms of ageing. Of these, the use of the cell culture system as a model of ageing has contributed most. The Hayflick phenomenon of limited proliferative capacity of normal diploid cells [4] has been confirmed with the use of many cell types, including fibroblasts, glial cells, endothelial cells, articular cartilage cells, bone marrow cells, melanocytes , keratinocytes, and retinal pigment epithelial cells. Numerous studies have shown correlation between the life span of cells in culture and many age-related cellular, physiological, and biochemical changes observed in vivo. These include observed relationships between cellular proliferative capacity and maximum life spans of donor species, the ages of the donors within a species, and donors suffering from premature ageing syndromes [5, 6]. It is beyond the scope of this article to give even a brief survey of the present state of knowledge in the field of cellular, biochemical, and molecular ageing, for which the reader should consult any of several recent reviews...