New modality of aging control: restore principle as the paradigm
Authors: Park S. C. 
Published: September 2010

The scientific view of aging is still rather fragmented, because no sound unifying aging theory yet exists. Most hypotheses are rather limited, in the sense that they describe only the some aspect of the aging phenomenon, summarized in the aspect theory of aging. But it cannot be denied that the majority of hypotheses are based on a deterministic view of aging. This kind of concept presents a single strategy of aging control wholly dependent on the replacement principle, which purports the substitution of all possible tools, such as genes, cells, tissues and organs. But, recently a novel aging concept has been proposed, based on the possible control of aged cells. Therefore, the new concept of aging and a novel approach for the development of a strategic pathway to aging control are introduced, which may hopefully result in functional longevity.

The concept that aging is an irreversible, inevitable, universal process of an organism provides the basis of the deterministic view of aging. The underlying view of aging as a determined irresistible fate has conjured many hypothesis on the aging process such as aging clock hypothesis, genetic determinism, telomere hypothesis, wearing hypothesis, disposable soma hypothesis and error catastrophe hypothesis, etc. Although these hypotheses are under debates, the majority of scientists and the public are inclined to accept these ideas, preoccupied by the view that aging is a natural irresistible process leading to death. Based on the deterministic view on aging, it would be natural to adopt the replacement principle as the ultimate strategy for counteracting the aging process.

In other words, if the aging process were irreversible, inevitable, irresistible and universal, only the replacement principle provides a solution, that is, just substitute the aged material with new fresh material. Many replacement principles have been developed at various levels from genes to organs. However, when we examine the replacement principle, many gloomy aspects of its approaches can be identified. At the gene level, the fundamental question of existence of gerontogene has not been resolved, though many virtual gerontogenes have been suggested. In terms of the cell therapy approach, stem cell have recently attracted a great deal of attention, but still the problem of the stem cell niche and the mode of regulating stem cell development have not been unveiled. At the tissue or organ level, tissue patches, artificial organs and the transplantation approach have been elaborately pursued. However, it is well known that these methods are restricted because of our limited knowledge on the complex of coordinated development, bionanotechnology and immuno‐compatibility, etc. This reality encourages to depend on camouflage transient strategies such as plastic surgery or hormonal supplementation.

The complex nature of aging, denying the consensus explanation of aging, has led us to pursue historic views of aging. The core problem in understanding the aging process is the traditional prejudice concerning aging as a one‐way phenomenon based on the deterministic view. However, the aging process has now been revealed to be a reactive phenomenon based on adaptive response and designed to maintain the purpose of an organism, its LIFE. Aging‐related complicated changes in metabolism, signal transduction, stress response, cytoskeletal modulation, and in genetic control are adaptive and responsive, as opposed to the deterministic programmed systems, presumed to be operating in the aging process. Therefore, it is natural that large differences in the aging process are observed not only at the individual level but also at the interorgan level in the same individuals.

In our previous papers, we have reported that increased levels of caveolin are mainly responsible for the hyporesponsiveness of senescent cells through the modulation of receptor‐mediated endocytosis. And we have shown that the senescent phenotype of growth factor response loss can be resumed by simply reducing the caveolin status. Moreover, the adjustment of the caveolin status of old cells restored not only their functional efficiencies by adjusting the signal transduction apparatus but also their structural features, probably by modulating focal adhesion complex activities.

Therefore, it can be tentatively concluded that the fundamental notion of aging as a process of functional deterioration and morphological alteration are affected by caveolin status. Such data suggest that caveolin plays the role of gatekeeper in the aging process, for if increased, aging results, but if decreased, the senescent phenotype disappears. In addition to caveolins, there seem to be several other tentative gatekeeper molecules, such as amphiphysin and some G proteins.

If the existence of a molecular gatekeeper for aging were assumed, it would be natural to suppose that an aging field could be generated inside a cell, as regulated by the gatekeeper. This novel concept would explain the aging phenotype as an adaptive responsive phenomenon toward environmental stress. Since caveolin is one of the candidate gatekeepers, its simple increase or decrease might be responsible for many aspects of the aging phenotype. Therefore, we suggest that the aging phenotype can be explained in terms of a new aging hypothesis, namely the gate theory of aging. The characteristic features of this novel view of aging are its focus upon flexibility rather than irreversibility, manageability rather than inevitability, and individuality rather than generality.

The gate theory of aging implies the possibility of adjusting the aging phenotype. Based on this theory, the restoration principle can be proposed as a novel approach to aging control. For example, the effect of nutrition and exercise, which result in changes in cellular cholesterol content and promoter methylation status, would profoundly influence the cellular caveolin status. Therefore, it can be presumed that the aging phenotype can be adjusted to induce restoration by modulating gatekeeper molecules, illustrated by caveolin. There may be many other tools, which can be used to augment the actions of aging‐related gatekeepers.

As society enters a new era of longevity, never before experienced problems concerning the elderly are generated at the social, economic, environmental, medical and cultural levels. However, most problems are based on the traditional concept of aging; that is the deterministic view on aging as an irreversible, inevitable, inefficient status. But, now it is clear that the aging process can be explained in a totally different way, as an adaptive response to age, which implies the possibility of restoration by adjusting the cellular apparatus. Actually, this new aspect of aging is readily illustrated by the superlongevity of people like centenarians. There are now many centenarians in good shape with a good status, and sound social skills.

The active attitude and the positive way of life shown by centenarians present the longlive community with a new concept; functional longevity. The adoption of this approach to life marks revolutionary conversion of the view of aging from simple longevity to functional longevity. The concept of functional longevity incorporates active participation, positive thinking, and responsible behavior. It may be concluded that the concept of functional longevity based on the gate theory of aging may be used to solve the emerging problems associated with aging and aged societies.

References

 1. Cho, K.A., Ryu, S.J., Oh, Y.S., Park, J.H., Lee, J.W., Kim, K.T., Jang, I.S. and Park, S.C. Morphological adjustment of senescent cells by modulating caveolin‐1 status. J. Biol. Chem. (2004) (epublication ahead of print).

2. Cho, K.A., Ryu, S.J., Park, J.S., Jang, I.S., Ahn, J.S., Kim, K.T. and Park, S.C. Senescent phenotype can be reversed by reduction of caveolin status. J. Biol. Chem.278, 27789–27795 (2003).

3. Jang, I.S., Yeo, E.J., Park, J.A., Ahn, J.S., Cho, K.A., Juhnn, Y.S. and Park, S.C. Altered cAMP signaling induced by lysophosphatidic acid in senescent human diploid fibroblasts. Biochem. Biophys. Res. Comm. 302, 778–784 (2003).

4. Yeo, E.J. and Park, S.C. Age‐dependent agonist‐specific dysregulation of membrane‐mediated signal transduction: emergence of gate theory of aging. Mech. Age Dev. 123, 1563–1578 (2002).

5. Yeo, E.J., Jang, I.S., Lim, H.K., Ha, K.S. and Park, S.C. Agonist‐specific differential changes of signal transduction pathway in senescent human diploid fibroblasts. Exp. Gerontol. 37, 871–883 (2002).

6. Park, S.C. Functional recovery of senescent cells through restoration of receptor‐mediated endocytosis, Mech. Age Dev. 123, 917–923 (2002).

7. Suh, Y.S., Lee, K.A., Kim, W.H., Han, B.G., Vijg J. and Park, S.C. Aging alters the apoptotic response to genotoxic stress. Nat. Med. 8, 3–4 (2002).

8. Park, W.Y., Park, J.S., Cho, K.A., Kim, D.I., Ko, Y.G., Seo, J.S. and Park, S.C. Up‐regulation of caveolin attenuates epidermal growth factor signaling in senescent cells. J. Biol. Chem. 275, 20847–20852 (2000).

9. Park, J.S., Park, W.Y., Cho, K.A., Kim, D.I., Jhun, B.H., Kim, S.R. and Park, S.C. Down‐regulation of amphipysin‐1 is responsible for reduced receptor‐mediated endocytosis in the senescent cells. FASEB J. 15, 1625–1627 (2001).

10. Suh, Y.S. and Park, S.C. Differential activation of mitogen activated protein kinase by methyl methane sulfonate in the kidney of young and old rats. Mutat. Res. 497, 11–18 (2001).