6 minute read

Cellular Aging: Basic Phenomena

Senescence And Differentiation

Although most of the studies of cellular senescence have focused on similarities to aging, some have considered homologies with developmental processes. A commonly held view is that cellular aging may follow a differentiation lineage model. In fact, it has been suggested that the finite life span of cells may represent a differentiation of cell types, and that the process of diploid cell growth may have an in vivo counterpart in hyperplastic processes (uncontrolled proliferation). Chronological time appears to be significantly less important than division events in the progression of the phenomenon. Although the state of differentiation may change in cells that senesce in vitro, there is, in fact, no evidence that the changes in gene expression observed in fetal cells as they senesce, in vitro, are tantamount to differentiation, in vivo. While analogous changes can be found, they are greatly outnumbered by the dissimilar features that characterize these two distinct phenomena. Hence, a comparison of senescence-associated changes and differences that exist between fetal and postnatal cells reveals little similarity.

At least some analogous similarities exist between senescence in fetal fibroblasts and developmental changes that occur in vivo. For example, it has been observed that addition of platelet-derived growth factor-BB (PDGF-BB) stimulates an increased mRNA abundance of the transcript encoding PDGF-A chain in fetal and newborns and a relatively small response in adult cells. Senescence in vitro of newborn fibroblasts appears to result in the acquisition of the adult phenotype by decreasing their response to PDGF-BB. On the other hand, there are a number of differences reported between cell lines established from fetal and adult tissues that are related to growth factor requirements for proliferation and migration that remain disparate, even as these cultures become senescent. For example, fetal dermal fibroblasts will proliferate in either plasma or serum, while adult dermal fibroblasts require serum. It is also noteworthy that the expression of some genes, such as SOD-2, increases during proliferative senescence but only in some types of fibroblasts; in other types of fibroblasts no change is observed (see Allen, et al., 1999). It might be expected that cells placed in culture will be deprived of those signals that direct the normal sequence of developmental pathways, and that differentiation, if it occurs, is to an aberrant state. Alternatively, fetal cell lines may arise from different precursor cells than adult fibroblasts, and thus merely differentiate to a different fibroblast type. What is apparent from studies of senescence is that similarities as well as discrepancies are observed when it is compared to either aging or development. As a result of this, the model is obviously less useful for predicting aging or development changes in vivo than it is for studying known changes in an isolated cell system.



ALLEN, R. G.; TRESINI, M.; KEOGH, B. P.; DOGGETT, D. L.; and CRISTOFALO, V. J. "Differences in Electron Transport Potential Antioxidant Defenses and Oxidant Generation in Young and Senescent Fetal Lung Fibroblasts (WI-38)." Journal of Cellular Physiology 180 (1999): 114–122.

BRUCE, S. A.; and DEAMOND, S. F. "Longitudinal Study of In Vivo Wound Repair and In Vitro Cellular Senescence of Dermal Fibroblasts." Experimental Gerontology 26 (1991): 17–27.

CARREL, A., and EBLING, A. H. "Age and Multiplication of Fibroblasts." Journal of Experimental Medicine 34 (1921): 599–523.

CRISTOFALO, V. J.; VOLKER, C.; FRANCIS, M. K.; and TRESINI, M. "Age-Dependent Modifications of Gene Expression in Human Fibroblasts." Critical Reviews in Eukaryotic Gene Expression 8 (1998): 43–80.

CRISTOFALO, V. J., and PIGNOLO, R. J. "Cell Culture As a Model." In Handbook of Physiology: Aging. Edited by E. J. Masoro. New York: Oxford University Press, 1984. Pages 53–82.

CRISTOFALO, V. J.; PIGNOLO, R. P.; CIANCIARULO, F. L.; DIPAOLO, B. R.; and ROTENBERG, M. O. "Changes in Gene Expression During Senesence in Culture." Experimental Gerontology 27 (1992): 429–432.

CRISTOFALO, V. J.; DOGGETT, D. L.; BROOKS-FREDERICH, K. M. and PHILLIPS, P. D. "Growth Factors as Probes of Cell Aging." Experimental Gerontology 24 (1989): 367–374.

CRISTOFALO, V. J.; ALLEN, R. G.; PIGNOLO, R. P.; MARTIN, B. M.; and BECK, J. C. "Relationship between Donor Age and the Replicative Life Spans of Human Cells in Culture: A Reevaluation." Proceedings of the National Academy of Sciences of the United States of America 95 (1998): 10614–10619.

CRISTOFALO, V. J.; VOLKER, C.; and ALLEN, R. G. "Use of the Fibroblast Model in the Study of Cellular Senescence." In Aging Methods and Protocols. Edited by Y. Barnett and C. R. Barnett. Totowa, N.J.: Humana Press, 1984.

DIMRI, G. P.; LEE, X.; BASILE, G.; ACOSTA, M.; SCOTT, G.; ROSKELLEY, C.; MEDRANO, E. E.; LINSKENS, M.; RUBELJ, I.; PEREIRA-SMITH, O.; PEACOCKE, M.; and CAMPISI, J. "A Biomarker that Identifies Senescent Human Cells in Culture and in Aging Skin In Vivo." Proceedings of the National Academy of Sciences of the United States of America 92 (1995): 9363–9367.

FENG, J.; FUNK, W. D.; WANG, S.-S.; WEINRICH, S. L.; AVILION, A. A.; CHIU, C.-C.; ADAMS, R. R.; CHANG, E.; ALLSOPP, R. C.; YU, J.; LE, S.; WEST, M. D.; HARLEY, C. B.; ANDREWS, W. H.; GREIDER, C. W.; and VILLEPONTEAU, B. "The RNA Component of Human Telomerase." Science 269 (1995): 1236–1241.

GORMAN, S. D., and CRISTOFALO, V. J. "Reinitiation of Cellular DNA Synthesis in BrdUSelected Nondividing Senescent WI-38 Cells by Simian Virus 40 Infection." Journal of Cellular Physiology 125 (1985): 122–126.

HAYFLICK, L., and MOORHEAD, P. S. "The Serial Cultivation of Human Diploid Cell Strains." Experimental Cell Research 25 (1961): 585–621.

LIN, A. W.; BARRADAS, M.; STONE, J. C.; VAN AELST, L.; SERRANO, M.; and LOWE, S. W. "Premature Senescence Involving p53 and p16 Is Activated in Response to Constitutive MEK/MAPK Mitogenic Signaling." Genes and Development 12 (1998): 3008–3019.

LUMPKIN, C. K., JR.; MCCLUNG, J. K.; PEREIRA-SMITH, O. M.; and SMITH, J. R. "Existence of High Abundance Antiproliferative mRNA's in Senescent Human Diploid Fibroblasts." Science 232 (1986): 393–395.

MEDCALF, A. S. C.; KLEIN-SZANTO, A. J. P.; and CRISTOFALO, V. J. "Expression of p21 Is Not Required for Senescence of Human Fibroblasts." Cancer Research 56 (1996): 4582–4585.

OHTANI, N.; ZEBEDEE, Z.; HUOT, T. J. G.; STINSON, J. A.; SUGIMOTO, M.; OHASHI, Y.; SHARROCKS, A. D.; PETERS, G.; and HARA, E. "Opposing Effects of Ets and Id Proteins on p16INK4a Expression During Cellular Senescence." Nature 409 (2001): 1067–1070.

OSHIMA, J.; CAMPISI, J.; TANNOCK, C. A.; and MARTIN, G. M. "Regulation of c-fos Expression in Senescing Werner Syndrome Fibroblasts Differs from That Observed in Senescing Fibroblasts from Normal Donors." Journal of Cellular Physiology 162 (1995): 277–283.

PIGNOLO, R. J.; ROTENBERG, M. O.; and CRISTOFALO, V. J. "Alterations in Contact and Density-Dependent Arrest State in Senescent WI-38 Cells." In Vitro Cellular and Developmental Biology 30A (1994): 471–476.

ROBBINS, E.; LEVINE, E. M.; and EAGLE, H. "Morphologic Changes Accompanying Senescence of Cultured Human Diploid Cells." Journal of Experimental Medicine 131 (1970): 1211–1222.

RUBIN, H. "Cell Aging In Vivo and In Vitro." Mechanisms of Ageing and Development 98 (1997): 1-35.

SEVERINO, J.; ALLEN, R. G.; BALIN, S.; BALIN, A.; and CRISTOFALO, V. J. "Is β-Galactosidase Staining a Marker of Senescence In Vitro and In Vivo?" Experimental Cell Research 257 (2000): 162–171.

SHELTON, D. N.; CHANG, E.; WHITTIER, P. S.; CHOI, D.; and FUNK, W. D. "Microarray Analysis of Replicative Senescence." Current Biology 9 (1999): 939–945.

SMITH, J. R., and WHITNEY, R. G. "Intraclonal Variation in the Proliferative Potential of Human Diploid Fibroblasts: Stochastic Mechanisms for Cellular Aging." Science 207 (1980): 82–84.

Additional topics

Medicine EncyclopediaAging Healthy - Part 1Cellular Aging: Basic Phenomena - Changes In Cell Morphology And Contact, Senescence And Cell-cycle Progression, Growth Signals And Senescence