Human longevity and aging: possible role of reactive oxygen species.


Cutler RG.




Ann N Y Acad Sci


A brief overview has been given of the biological nature of human aging processes, where it has been emphasized that, in addition to the diseases of aging, there is also great economic loss as a result of human aging processes that began many years before medical costs related to aging begin to escalate. Because of the ubiquitous nature of aging, reducing the function of essentially all physiological processes, it appears that the only long-term solution to human aging problems is to decrease uniformly the aging rate of the entire body. Although the uniform decrease of aging rate has usually been considered impossible, where emphasis has consequently been placed on diseases of aging by the medically-orientated investigator, there is now at least one theoretical argument, accompanied by some experimental data, that suggests that progress can be made in achieving this goal. This progress has been based on the longevity determinant gene hypothesis predicting the existence of a relatively few key regulatory factors governing aging rate of the entire organism. If this hypothesis is not true, then indeed the prospect for significant intervention into human aging would appear impossible in the near future. Experiments have been briefly reviewed testing the longevity determinant gene hypothesis, the possibility that aging may be a result of dysdifferentiation and if aging rate is determined by mechanisms acting to stabilize the differentiated state of cells. In testing the dysdifferentiation hypothesis of aging, there is not yet much data one way or the other. It is evident, however, that changes in gene expression do occur with age, sometimes involving endogenous retroviruses or oncogenes. Other morphological evidence shows an increase with age in unusual cell type such as metaplasia cells. However, there is considerably more evidence indicating that aging may be a result of genetic instability (as it is in cancer) and that longer-lived species appear to have a more stable genetic apparatus and superior protective mechanisms against reactive oxygen species. There is a striking similarity in this model of aging and models of cancer, and much might be gained in bringing together these two fields of research. Taking all of these data together, as summarized in Table 14, it appears we may be on the right track and that mechanisms acting to protect DNA against oxidative damage may be one class of longevity determinant mechanisms. There is of course much work remaining to be done, some of which is listed in Table 15 in terms of our knowledge and our gaps of knowledge in this field.