Cellular and Molecular Aging

Cells eventually lose their ability to divide unless they become cancerous. This limit to cellular replicative capacity (Hayflick's limit or phenomenon) can be demonstrated in fibroblasts that are removed from the umbilical cord of neonates and cultured in vitro. The fibroblasts divide only until they are dense enough to contact each other--a phenomenon called contact inhibition. If diluted, the fibroblasts divide again until maximum density is reached. This process can be repeated; however, after about 50 divisions, the fibroblasts stop dividing regardless of their density. Hayflick's limit is thought to reflect in vivo processes; fibroblasts removed from elderly people tend to divide fewer times. Studies have shown that the loss of replicative capacity does not depend on the total time cells are cultured (chronologic age) but on the number of divisions (biologic age).

When cells divide so many times that they cannot divide again, they enlarge and exist for some time before they gradually die. Such cells differ in morphology and function from young cells that are still dividing and from young cells that have been experimentally manipulated to stop dividing.

One biologic mechanism for Hayflick's limit is understood. Telomeres (stretches of DNA at the end of chromosomes) are used as handles to move chromosomes during the telophase of meiosis. Telomeres are irreversibly shortened each time a cell divides. When they become too short, the cell can no longer divide.

In transformed (eg, cancerous) cells, the enzyme telomerase lengthens telomeres after telophase. The telomeres of transformed cells do not shorten after each division, and the cells thus become immortal, dividing far beyond Hayflick's limit. Normal postmitotic cells (except for fetal and germ cells) express telomerase in very small amounts but not enough to prevent their telomeres from shortening after each cell division.

The relevance of Hayflick's limit to senescence of the whole organism is unclear. Some cells (eg, intestinal epithelial cells) can divide throughout life, in part because they derive from progenitor stem cells, which do not exhibit Hayflick's limit. Usually, these cells do not divide continuously, but even if they did, they are not likely to cause functional failure during senescence. Rather, the likely cause is cells that divide very little (immune and endocrine cells) or not at all (neurons and muscle cells). Furthermore, senescence in metazoans (multicellular animals) composed entirely of postmitotic cells is just as predictable and robust as that in metazoans containing mitotic cells.

Mechanisms other than telomerase shortening may be involved in senescence. For example, messenger RNA (mRNA) transferred from senescent cells into young cells stops cell division in the young cells. The mRNA acts as a gerontogene (a gene that normally reduces life span), whose function may resemble that of a tumor suppressor gene (eg, p53). Mutations in gerontogenes may extend the number of divisions in cells, which can be expected to increase life span; however, certain mutations in gerontogenes (eg, mutations in p53) lead to uncontrolled cell division, cancer, and often death of the organism.

Necrosis and apoptosis: Cell death may occur by necrosis or apoptosis. Necrosis is due to physical or chemical insults (eg, metabolic inhibition, ischemia) that overwhelm normal cellular processes and make the cell nonviable. In necrosis, loss of ion gradients across the cell membrane leads to an influx of Ca and other ions, which triggers proteolysis and rupture of organelle membranes. Necrosis is a purely entropic phenomenon (characterized by a tendency to move toward randomness or disorder) due to loss of the cell's ability to transform external energy and perform normal functions.

In contrast, apoptosis is a genetically determined, regulated, orderly process by which a cell essentially commits suicide; usually, the stimulus for apoptosis is a physiologic signal or a very mild insult. A defining feature of apoptosis is fragmentation of the cell's DNA, produced by regulated activation of deoxyribonuclease. Several other biochemical processes that also lead to cell death are simultaneously induced. Apoptosis is essential for normal development and remodeling but has also been implicated in several age-related diseases, including Alzheimer's disease.

Identifying the primary process involved in cell death (necrosis or apoptosis) during aging helps determine whether aging is considered the result of entropic processes (if due primarily to necrosis) or of relatively simpler, more regulated processes (if due primarily to apoptosis).

This topic was last updated June 2006.