ReviewCellular senescence and organismal aging
Introduction
Cellular senescence was first described by Hayflick and Moorfield in 1961 who observed that cultures of normal human fibroblasts had a limited replicative potential and eventually became irreversibly arrested (Hayflick and Moorhead, 1961, Campisi and d’Adda di Fagagna, 2007, Sedivy et al., 2007). The majority of senescent cells assume a characteristic flattened and enlarged morphology, and over the years a large number of molecular phenotypes have been described, such as changes in gene expression, protein processing and chromatin organization (Gonos et al., 1998, Shelton et al., 1999, Schwarze et al., 2002, Semov et al., 2002, Narita et al., 2003, Zhang et al., 2003, Zhang et al., 2005, Zhang et al., 2007, Yoon et al., 2004, Pascal et al., 2005, Xie et al., 2005, Cong et al., 2006, Funayama et al., 2006, Trougakos et al., 2006, Zdanov et al., 2006). The growth arrest occurs mostly in G1 phase (Pignolo et al., 1998). Although individual cells arrest rapidly, probably within the duration of a single cell cycle, cultures are typically quite asynchronous with increasing proportions of cells withdrawing into senescence over a period of several weeks (Herbig et al., 2003, Herbig et al., 2004). Senescent cells maintain metabolic activity and can remain viable essentially indefinitely (Matsumura et al., 1979, Pignolo et al., 1994). An important component of this stability in culture may be the capacity of senescent cells to resist apoptosis (Marcotte et al., 2004, Hampel et al., 2005).
Conceptually, there are two broad categories of replicative cellular senescence. The first is initiated by dysfunctional telomeres or other forms of genotoxic stress eliciting a DNA damage response mediated primarily by the p53 tumor suppressor pathway (d’Adda di Fagagna et al., 2003, Herbig et al., 2004). The second, much less understood response does not involve telomeres or DNA damage, and is characterized by the upregulation of the CDKN2A gene (cyclin-dependent kinase inhibitor p16INK4a). These basic distinctions are however complicated by the fact that p16 can be upregulated by a wide variety of stresses, including some forms of genotoxic damage.
The relationship between elapsed cell divisions and the onset of senescence was clearly apparent from early in vitro studies, and led to proposals that senescence may contribute to in vivo organismal aging phenotypes (Hayflick, 1985). This view was reinforced by findings that cells explanted from old donors were capable of fewer in vitro population doublings than those from young individuals (Martin et al., 1970, Le Guilly et al., 1973, Rheinwald and Green, 1975, Schneider and Mitsui, 1976, Bierman, 1978, Bruce et al., 1986). The gradual attrition of telomeres subsequently provided the molecular mechanism for the cell division clock (Harley et al., 1990, Bodnar et al., 1998). It has been proposed that the term “cellular senescence” be reserved for those phenomena based on an inherent counting mechanism, with other terms, such as “stasis” to be applied to the large variety of stress-induced arrests (Drayton and Peters, 2002, Wright and Shay, 2002). Recent usage has however favored irreversible cell cycle arrest as the defining feature, and “cellular senescence” is now commonly used to encompass states induced by stress and signaling imbalances (Collado et al., 2007).
It is important to note that the intrinsic cell division clock can be significantly affected by extrinsic influences, such as reactive oxygen species, which accelerate the rate of telomere shortening (von Zglinicki, 2002). Although senescent cells display a number of phenotypes that discriminate them from quiescent cells, it has also been suggested that senescence could be considered a form of terminal differentiation (Bayreuther et al., 1988, Seshadri and Campisi, 1990). This view has recently been given new life by observations that downregulation of Wnt signaling may be a factor in triggering the onset of senescence (Ye et al., 2007). Thus, in addition to being influenced by the environment, senescence may also respond to developmental or endocrine cues.
Given that senescence results in the arrest of proliferation, its potential for opposing cancer development was pointed out some time ago (Sager, 1991). This notion was strongly reinforced by the discovery that activation of oncogenes in normal cells could trigger senescence (Serrano et al., 1997). Recent data have indeed implicated cellular senescence as an important in vivo tumor suppressor mechanism in a variety of human and mouse tissues (Braig et al., 2005, Chen et al., 2005, Collado et al., 2005, Michaloglou et al., 2005, Courtois-Cox et al., 2006, Cosme-Blanco et al., 2007, Feldser and Greider, 2007, Ventura et al., 2007, Xue et al., 2007). In addition to being on sound experimental footing, the tumor suppressive function of senescence also provides a rational explanation for its evolution. The possible role of senescence in age-associated dysfunction is often justified by invoking the concept of antagonistic pleiotropy (Williams, 1957, Rose, 1991, Kirkwood and Austad, 2000, Campisi, 2005), namely, that beneficial traits (such as cancer suppression) under selection in reproductively active individuals may have unselected and unintended effects in more advanced age.
In contrast to tumor suppression, the connections between cellular senescence and the aging of organisms are significantly more tenuous. In this review we focus on these links and their implications. Elucidating these relationships is expected to advance our comprehension of the mechanisms involved in age-related diseases as well as normal aging processes.
Section snippets
Telomeres
Telomeres shorten with each round of genome duplication, an unavoidable consequence of the RNA priming mechanism of DNA replication (Olovnikov, 1973). The minimum rate of telomere shortening in human cells (30–50 bp per cell division) is slightly in excess of that predicted by the “end-replication problem”, and probably stems from further exonucleolytic processing of chromosome ends (Sfeir et al., 2005). Telomere attrition can be accelerated by a number of factors, such as oxidative damage (von
Accumulation of senescent cells in vivo
To the extent that senescent cells are considered to confer deleterious effects, including the promotion of organismal aging, it is crucial to distinguish them from the majority of healthy but quiescent cells found in normal tissues. The original definition of irreversible arrest is clearly not feasible in this context, a situation that has led to a concerted search for biomarkers to assess the increasingly numerous molecular phenotypes of senescent cells. Unfortunately, to date no biomarker
Senescent cells at sites of age-related pathology
The presence of senescence-associated markers at sites of age-related pathologies have provided further links between cellular senescence and aging. Telomere length as a function of donor age was found to decrease more rapidly in arterial than in venous endothelial cells, and telomere loss was greater in intimal than in medial cells (Chang and Harley, 1995). Other studies found that age-dependent telomere attrition is faster in the distal than in the proximal segment of the abdominal aorta,
CDKN2A (p16) and aging
The cyclin-dependent kinase inhibitor p16 has emerged as an important player in aging and age-related disease. Biochemically, p16 inactivates CDK4 and CDK6, which maintains pRB in its active, hypophosphorylated form and consequently blocks cell cycle progression in G1 (Sherr and Roberts, 1999). Genetically, p16 is an important and potent tumor suppressor and is frequently inactivated in several human cancers, such as melanoma. Because p16 expression can be upregulated by a wide variety of
Physiological relevance of senescent cells in vivo
Senescent cells are generated in response to a number of stimuli. Telomere attrition and oncogene activation are the best understood triggers, but a variety of stresses, disease or pathological conditions, and environmental and nutritional factors are also likely to play important roles. Although it is now possible to detect and even quantify senescent cells in vivo with some confidence, the physiological consequences of the existence of such cells are only beginning to be unravelled. Broadly
Perspectives
The role of cellular senescence in a variety of age-associated pathologies is becoming increasingly accepted. As discussed above, compelling experimental evidence has now linked increased rates of cellular senescence with accelerated aging. The extent to which, if any, cellular senescence contributes to the natural life span of any one species however remains to be established. As a case in point, although quantitative estimates of in vivo cellular senescence are just beginning to emerge, the
Acknowledgement
J.C.J. and J.M.S. were supported, in part, by grant R01 AG016694 from the NIH and a Senior Scholar Award in Aging from the Ellison Medical Fundation, both to J.M.S.
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