Introduction: While many theories have been
proposed for the aging process, most have not
considered humans as a hierarchical system
made up of cybernetically interacting levels of
organization. To understand the aging process
and the diseases of aging, one must view the
human as the result of the total genomic DNA
in the single fertilized egg that proliferates,
differentiates and develops into an individual of
about 100 trillion cells, organized by different
cell types (pluri-potent stem cells, progenitor
stem cells, terminally-differentiated cells) into
multiple tissue, organ and organ systems which
interact with each other via endogenous factors
and with exogenous factors. Our hypothesis is
that both aging and diseases of aging are
dependent of the normal functioning of the
pluripotent stem cell pool. Methods: Human
pluripotent stem cells of human kidney, breast
and pancreas were isolated based on their lack
of expressed connexin genes and of gap
junctional intercellular communication (GJIC),
and on the use of antioxidants, modified
oxidative stress, and low calcium media.
Results: The presumptive human pluri-potent
stem cells did not express any connexins, had
telomerase activity, and could divide both
symmetrically and asymmetrically. When they
were induced to express connexins and perform
GJIC by modifying the medium, substrate, and
oxidative stress, they could differentiate into 3-
dimentional organoids.

When connexins were induced, cells could differentiate and lose their telomerase activity. When GJIC was inhibited in these cells, they did not terminally differentiate and could ultimately become neoplastically transformed. Conclusions: Our results suggest that human pluripotent stem cells are immortal and become mortal when induced to express connexins, to perform GJIC and to differentiate. Since not all organs of a human age at the same
rate, it is speculated that the stem cell pool
might be depleted differentially. Moreover,
when stem cells that are eliminated (e.g. in
pancreatic beta islets), the disease may be the
consequence (e.g. diabetes). The loss of insulin
as an extracellular regulator of cell function can,
in turn, cause a breakdown in homeostatic
control of cell proliferation, differentiation and
apoptosis in other tissues, leading to the multiple
sequelae of diseases in diabetes. When stem
cells are prevented from terminally differentiating and apoptosing, they could lead to the disease of carcinogenesis or artherogenesis. It appears that the levels of antioxidants, low oxygen tension and low calcium are critical factors needed to maintain the stem cell from differentiating, from dividing asymmetrically, losing telomerase activity and performing GJIC. Our results are not consistent with the Hayflick model of aging.