Cell renewal and cell loss in the tissues of aging mammals

This review led the authors to the conclusion that large age dependent losses of essential cells, especially of the nonrenewable type, are not established with certainty, especially as regards the central nervous system. The life span of an animal may indeed be controlled by groups of essential cells in specific tissues and organs. These cells may be programmed to a definite life span just as other cells are programmed to cell death during normal development, differentiation and renewal. The key cell populations which may be involved in aging include neurons in specific regions of the central nervous system, the pacemaker cells of the heart and cells of the immune system. Decreases in vital functions of the body may lead to increased mortality. Both slowly and rapidly renewing cell populations demonstrate decreased ability to proliferate and renew with age. Decreases in the proliferative activity of intestinal epithelia are 3 fold: a decreased rate of cell production, an increased turnover time, and a gradual lengthening of the progenitor (stem) cell cycle due to an increase in the G1 phase. The decreases in proliferative activity of tissues with age are more than likely concomitant to, rather than a direct result of, senescence. It has been suggested that mammalian cells, such as fibroblasts, may be limited to a definite number of population doublings both in vitro and in vivo. Such limitations of cell populations to proliferate could lead to discrete life spans of various species. However, additional data are needed on all types of renewing cell populations in man and other animals before a hypothesis of limited population doublings can be considered as holding for the in vivo condition. Calculations on the possible number of cell population doublings in other tissues of the mouse, rat and man lead to similar conclusions. Liver cells have the potential of a complete turnover of once, twice and 53 times during the life of the mouse, rat and man, respectively. If rapidly renewing cell populations are considered, such as the colonic epithelium, these figures become 365 (mouse and rat) and 5,100 (man) population doublings. Finally, Krohn (1966) carried out serial skin transplant studies in the mouse. He kept his transplants alive for up to 7 yr, which is about 3 times the normal life span of the mouse. These results indicate that mouse epidermal cells are capable of undergoing at least 150 doublings before the transplants die. To explain the continuing cell proliferation of e.g. intestinal epithelium, it has been suggested that rapidly renewing cell populations set aside stem cells, which do not reproduce for long periods, thus serving as a reservoir which can be called upon to renew cell populations; this has been referred to as the 'clonal succession' hypothesis, which, however, appeared to be untrue. It is concluded that the mammalian life span is not limited by a finite growth capability of one or more of its renewal cell populations (although more observations are needed).