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
     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
     "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
     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