Degenerative diseases, such as Parkinson’s, Alzheimer’s and muscle atrophy, in which the bodies capacity to regenerate new tissue can no longer keep up with tissue death often accompany human aging, are debilitating for individuals and represent a major problem for society. One intriguing possibility is that stem cells residing in aged organs retain their intrinsic ability to regenerate but are not properly triggered in when surrounded by old tissue. Specifically, productive responses of aged stem cells and repair of old tissues can be rescued in an animal model, when young and old mice share blood circulation. These findings, and their more recent extrapolation, strongly suggest that the development of effective hESC-based therapies in old people critically requires much improved understanding of why stem cells do not repair older organs even when they have the capacity to do so. In this respect, our current scientific evidence strongly suggests that any stem cell: local or transplanted, adult or embryonic will not efficiently work in older individuals, unless these cells are provided with a “youthful” surroundings, which protect them form the negative signals emanating from an aged body. More specifically, our most recent work suggests that it is not simply the lack of “positive” factors in an old body that causes a decreased regeneration with age or simply the presence of these factors in young organism that causes “youthful” tissue repair. In contrast, we provide evidence that aged circulation-blood and aged organs contain factors that inhibit the ability of any stem cell to engage in tissue repair; and this negative influence of aged body applies to all cell subsets currently hoped to be used for therapeutic purposes, e.g. embryonic stem cells and their derivatives, adult stem cells and entirely differentiated tissue containing a resource of dedicated stem cells. These findings mean that in order to capture the tremendous therapeutic potential of human embryonic stem cells in the elderly, it is necessary to understand the nature of the inhibitory “culprits” typical of aged body and to design molecular devices that would protect these cells and thus, would enable productive tissue repair in the old. These aims will be approached in the proposed study with the goal to restore the activity of the key determinants of stem cell regenerative potential back to those typical of a young organism and thus, to enable therapeutic applications based on hESC in older people afflicted by degenerative disorders.
Statement of Benefit to California:
Degenerative diseases in which the bodies capacity to regenerate new tissue can no longer keep up with tissue death is a major problem for society in general and for State of California in particular. The lack of tissue repair that eventually leads to the loss of organ function is undeniable and devastating trait of aging that causes many degenerative disorders, exemplified by Parkinson’s, Alzheimer’s and muscle atrophy. Therefore, Californians with life-long skills, expertise and invaluable knowledge can no longer contribute to society and do not enjoy life fully. In recent years biologists and clinicians realized that practical therapies would only emerge when the balance between the regenerative and the degenerative processes were properly understood in biomedical terms.
The development of effective therapies for age-related degenerative diseases critically requires much improved understanding of why stem cells in older tissue are not engaging in tissue repair even when the have the capacity to do so. Current work suggests that it is not simply the lack of “positive” external factors that causes a decreased regeneration with age, but that there is an elevation in dominant “negative” factors in the old, and thus the regenerative responses of stem cells and their derivatives (including hESC-based approaches) will be incapacitated in old organism, unless these cells are provided with a “youthful” environment.
This proposal describes steps to rejuvenate stem cell responses in the old, to insure that the health prognosis is significantly improved for older Californians, especially those afflicted with degenerative disorders, and that the results of these studies are translated as rapidly as possible to the clinical setting where their practical benefit can be fully utilized. Thus this work seeks not only to improve the quality of life for our older citizens, but also to reduce the health-cost associated with treating currently incurable degenerative diseases.