Messenger - Vol. 1, No. 1, Page 7 Fall 1991 Tick Tock; tracking the cellular clock Vincent Cristofalo, Delaware '62, wants to know why our life clock winds down. Looking beyond the clock face to the structure and function of the springs and cogs themselves, he studies aging in human cells, the smallest independent unit of the human body. Cristofalo, who received a Ph.D. in physiology and biology from the University, has devoted more than 25 years to studying senescence, or the aging of human cells. His research has been recognized as instrumental in bringing more rigorous standards to the scientific study of aging, and Cristofalo is continuing his pathfinding role as the first director of the Medical College of Pennsylvania's new Center for Gerontological Research. In November, he will complete a one-year term as president of the Gerontological Society of America, an organization of 7,500 members with a multi-disciplinary focus that includes clinical medicine, biological sciences, behavioral and social sciences and social research planning. There are sometimes popular misconceptions about the purpose of aging research, the most common being that scientists are seeking immortality for humans. "One of the goals of aging research is to understand the mechanism of aging, not necessarily to extend the lifespan of individuals but to extend their healthy years," Cristofalo says. "As the percentage of the population living into their 80's and 90's increases, social and economic problems will inevitably result. We researchers hope to understand the process of aging so that these elderly can be more active and productive." Cristofalo says he believes understanding aging involves more than looking at the face of the clock--more than documenting changes in the whole organism, such as thinning skin or wasting muscle, or tackling individual diseases of the elderly, such as Alzheimer's disease or atherosclerosis. "Every tissue and cell type probably has a different trajectory of aging and possibly a different mechanism. But, if you take one cell type and understand the basis by which that cell keeps time, this information becomes one part of a mosaic that may give us a picture for the whole argument," he says. This quest has driven Cristofalo's career and has resulted in more than 265 publications; membership on the editorial boards of 13 publications; academic positions at Temple University and the Wistar Institute, an independent research group; appointments in five different units at the University of Pennsylvania; and the nine-year directorship of the University of Pennsylvania's Center for the Study of Aging. Today, he holds one of the few endowed chairs for aging research, the Audrey Meyer Mars Professor of Gerontological Research, at the Medical College of Pennsylvania, and with it, has the potential to create a nationally known center in the field of aging. Cristofalo says he became interested in cell biology while a graduate student at the University of Delaware, which he attended from 1958-1961. His mentors in the then Department of Biological Sciences were Raphael R. Ronkin; Arnold M. Clark, professor emeritus of biological sciences; and John C. Wriston, professor emeritus of chemistry. Leaving Delaware in 1961 for post-doctoral training under a fellowship at the Fels Research Institute at Temple's School of Medicine, he studied "the finer aspects of metabolism in normal and cancerous livers." Then, as a research fellow at the Wistar Institute in 1963, he returned to the study of cells in culture and entered with enthusiasm the new research area of cell aging. "I realized that, at the cell level, aging was the alternative to becoming tumor-like," he says, "and as I began to put these ideas together, that concept has more or less directed my research for the last 20 years." Cristofalo's laboratory group at the University of Pennsylvania center has been able to show that some human cells have a clock-like mechanism that determines the cell's lifespan. In this case, fibroblast cells "know" their age by "counting" certain molecular events, and other species may have similar mechanisms. "What we and others have found out is that a particular cell type knows nothing of chronological time," Cristofalo says. "It appears to count DNA replications, so the trajectory of aging is determined by intrinsic, sequential molecular events. Some cells, such as nerve cells, don't divide at all, but it's probably safe to say each cell type might have its own type of 'clock' mechanism." DNA, a molecule in the nucleus of the cell, encodes heredity and holds the blueprint for producing proteins. Cristofalo's team also showed that certain hormones, including hydrocortisone, can extend the life span of cells, and recent clinical trials conducted by the Medical College of Wisconsin appear to confirm his earlier result. In the July, 1990, New England Journal of Medicine, Wisconsin researchers reported that human growth hormone injections in men over 60 increased muscle and lean tissue, decreased fatty tissue and increased skin thickness. "Everyone in the world called me about this (Wisconsin) growth hormone paper," he says, "A German news magazine called at 6:30 a.m. to get my opinion. This study shows what we proved at the cellular level: that some hormones can modulate aging. What hasn't been shown is that hormones changed the overall aging trajectory for humans as a whole. "The way I picture aging is really the result of two kinds of changes," Cristofalo says. "First, there are changes in the expression of genes. Some genes turn on and others turn off as we age. Superimposed over that are environmental effects such as smoking, cosmic rays and the like. Both of these can be modified by protective action. Researchers at Boston have shown that the appearance of cataracts can be modified with high doses of Vitamin C. Post-menopausal bone thinning can be decreased with estrogen, and it's possible to lower high levels of cholesterol to prevent damage to blood vessels. But, the challenge remains to understand how aging works and why it works at different rates in different species." Among the goals of aging research is to understand the increased vulnerability of the elderly to disease. "Something happens that increases our vulnerability to a range of diseases, from arthritis, to cancer, to type 2 diabetes to infectious diseases. Why is that?" he asks. At the same time, he points out, the very aging of the cells seems to block tumor production. "We know now that if you put the cells of rats or mice into tissue culture, they invariably will spontaneously transform into tumor-like cells, while human cells do not. The increased stability of human cells in culture is at the basis of their increased life span. Apparently, in order to live a long time, we have to have genes that prevent us from having our normal cells become tumor cells. "Senescence may be the mechanism that prevents our normal cells from growing inappropriately and from becoming tumor cells. Senescence changes may represent an expression of what are initially mechanisms that prevent tumor production," he says. That some elderly people still get tumors if they live long enough, he adds, is an indication "that this is not a perfect mechanism. It 'leaks.' " "One important aspect of aging is the failing capacity for regeneration and repair," Cristofalo says. "If you compare the aging of humans to the aging of automobiles, one important difference is that people can fix themselves. But we don't repair ourselves as well as we get older. Cell proliferation is an important part of the repair process." After devoting a lifetime to aging research, Cristofalo, 58, was asked about his personal philosophy of aging. The researcher, who plays basketball and jogs and gave up cigarettes 22 years ago, replied: "I've thought about it. I think a philosophy of aging has to be identified long before one faces the problems of aging. In other words, begin to think about and to modify one's behavior as early as possible: teen-age years or even before. The second thing is that old adage, 'moderation in all things.' That concept keeps resurfacing with more and more scientific data to support it. A third thing, which again was known by many people but now has acquired scientific evidence for its support, is the concept that exercise and staying active, not only physically but also mentally active, is important to healthy aging." --Cornelia Weil