Human stem cells as targets for the aging and diseases of aging processes.
While many theories have been proposed for the aging process, and many debates on the matter of aging and the diseases of aging being either the result of the same or independent processes, 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 pluri-potent stem cell pool. Specifically, the concept involves the cybernetic feedback between the 'quantity' of the stem cell pool in each tissue niche with the 'quality' of the stem cells in the pool. The process of gap junctional inter-cellular communication (GJIC), which has been implicated in the evolution from the single cell organism to the multi-cellular organisms, requiring growth control, differentiation, apoptosis, adaptive response capability of differentiated cells and senescence, is speculated to be a shared mechanism in stem cell biology and in many chronic disease processes (teratogenesis; carcinogenesis, atherogenesis, diabetigenesis, etc.). Specifically, stem cells are assumed to be 'immortal' until induced to express their connexin genes and have functional GJIC, at which time they can differentiate and become 'mortal'. As long as the stem cells are communicating with their differentiated daughters via some extra-cellular soluble negative growth factor, the homeostatic control of their growth and differentiation is maintained for the organism. However, if the stem cell pool is depleted by any process, replacement of tissue due to wear and tear is diminished. The dependence of this tissue/organ to maintain homeostatic control of other organ systems then diminishes, leading to 'systems failure'. In addition, if the stem cells in the pool have been exposed to agents that prevent the normal terminal differentiation of that cell, but whereby these 'initiated' stem cells can be expanded in any tissue, clones of partially differentiated and non-functional appear in the tissue. This diminishes the efficacy of that tissue to function properly and, thereby, also contributes to 'system failure' by contributing to the breakdown of homeostatic organ system control. One clear example, that of carcinogenesis, illustrates this point.
Trosko
James E
JE
Department of Pediatrics and Human Development, Michigan State University, East Lansing 48824, USA. james.trosko@ht.msu.edu
D000375:Aging; D017209:Apoptosis; D002450:Cell Communication; D002455:Cell Division; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D008954:Models, Biological; D008962:Models, Theoretical; D013234:Stem Cells / Q000166:cytology* / Q000378:metabolism