Dr. Pignolo is Assistant Professor and Director, Ralston-Penn Clinic for Osteoporosis & Related Bone Disorders, Department of Medicine, Division of Geriatric Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA.
Within the past 12 months, Dr. Pignolo reports no commercial conflicts of interest.
Albert Einstein College of Medicine, CCME staff and interMDnet staff have nothing to disclose.
Release Date: 01/11/2010
Termination Date: 01/11/2013
Estimated time to complete: 1 hour(s).
Albert Einstein College of Medicine designates this educational activity for a maximum of 1 AMA PRA Category 1 Credit(s)™. Physicians should only claim credit commensurate with the extent of their participation in the activity.
- Define characteristics of cellular aging
- List the key mechanisms responsible for cell senescence
- Discuss the relationship between cell aging in vitro and in vivo
- Describe the relationship between cell senescence and age-related diseases.
The term senescence is often used to describe aging at the cellular level, and after Hayflick’s original observations on the limited in vitro life span of normal human cells in culture,(1)(2) aging cells have often been referred to as undergoing replicative senescence. The life span of cells are usually measured in passages or, more accurately, in population doublings. The “age” of cells can be determined retrospectively as the percentage of life span completed from the point at which there is negligible cell division (e.g., cells that have undergone 25 doublings, and ultimately undergo 50 doublings, can be operationally described as 50% life span completed). Alternatively, the age of cells can be determined prospectively as the percentage of cells able to undergo DNA synthesis during a period of time equivalent to the longest cell cycle time, usually 24−30 hours.(3) Descriptive terms such as “early” or “late” passage or population doubling, or “young” and “old” are often employed to designate the relative age of cells in culture.
The Phenotype of Aging Cells
The definition of cell aging based on finite proliferative capacity is limited to those somatic cells that normally maintain their ability to divide in the organism and does not include germ line or certain stem cells which maintain an indefinite life span (Figure 1). Although replicative senescence has also been applied to animal cells in culture, particularly rodent−derived cells, in this situation there are the confounding variables such as "crisis" (or the mass loss of cells in culture) and spontaneous immortalization.
Figure 1. Replication Potential of Normal Human Cells.
Click above image to view full size.
Shown are cell types derived from the soma or germ line, their telomerase status, and replicative capacity.
Characteristics of an aging cell (or population of cells) in culture are mostly assumed as a function of replications, not time in culture. Cells can be kept in culture for an indefinite period of time in a quiescent (non−dividing), but metabolically active state, and only when they are induced to divide do the changes that we describe as replicative cell senescence occur. Besides an essentially irreversible growth−arrested state, other characteristics of senescence include apoptosis resistance (especially in fibroblasts),(4)(5)(6) altered gene expression (both of proliferation−related genes as well as of those unrelated to growth arrest),(7)(8)(9) as well as biomarkers that in the appropriate context may identify replicatively−aged, damaged or stressed cells.(10)(11)(12)(13)(14)(15)
Caveats and Limitations
Most of the studies on which knowledge of mechanisms of cell senescence is based have been performed on fibroblasts or fibroblast−like cells, and thus may not be generally applicable to other cells types. Studies in mammals are also limited, but there is growing evidence that cell senescence does occur in vivo with aging in general, as well as in specific examples of age−related pathology. However, cell senescence is not always replicative, since post−mitotic cells, such as neurons, do age. Finally, the aging of stem cells with long or indefinite life spans, as well as aging of cells outside the mesenchymal lineages (such as that of hematopoietic cells and their precursors), may also be different from that described for fibroblasts.