Replicative stress, stem cells and aging

Abstract

DNA synthesis is a remarkably vulnerable phase in the cell cycle. In addition to introduction of errors during semi-conservative replication, the inherently labile structure of the replication fork, as well as numerous pitfalls encountered in the course of fork progression, make the normally stable double stranded molecule susceptible to collapse and recombination. As described in this issue, maintenance of genome integrity in the face of such events is essential to prevent the premature onset of agerelated diseases. At the organismal level, the roles for such maintenance are numerous; however, the preservation of stem and progenitor cell pools may be particularly important as indicated by several genetically engineered mouse models. Stresses on stem and progenitor cell pools, in the form of telomere shortening (Terc −/− ) or other genome maintenance failures (ATR mKO , Ku86 −/− , LIG4 Y288C , XPD R722W/R722W , etc.), have been shown to degrade tissue renewal capacity and accelerate the appearance of age-related phenotypes. In the case of telomere shortening, exhaustion of replicative potential appears to be at least partially dependent on the cell cycle regulatory component of the DNA damage response. Therefore, both the genome maintenance mechanisms that counter DNA damage and the cell cycle checkpoint responses to damage strongly influence the onset of age-related diseases and do so, at least in part, by affecting long-term stem and progenitor cell potential.

Hallmarks of the ageing lung

“…Endogenous stem cell exhaustion, due to repetitive and persistent injuries, has been implicated as a driving factor for several age-related diseases [102][103][104][105]. In particular, in high-turnover organs a constant asymmetric division and differentiation of stem cells is proposed to maintain tissue homeostasis and self-renewal.…”

Using Mice to Examine p53 Functions in Cancer, Aging, and Longevity

“…It has been proposed that aging phenotypes may result in part from functional depletion of the stem and progenitor cell compartments because of age-associated reductions in self-renewal, proliferation, and differentiation (Van Zant and Liang 2003;Chen 2004;Dumble et al 2004;Pelicci 2004;Sharpless and DePinho 2004;Campisi 2005;Rando 2006;Rodier et al 2007;Sharpless and DePinho 2007;Rossi et al 2008;Ruzankina et al 2008). Recent studies showing increases of the senescence effector p16 INK4A protein levels and activity correlating with reduced function in aged stem and progenitor cells support this idea (Janzen et al 2006;Krishnamurthy et al 2006;Molofsky et al 2006).…”

“…It is well established that mammalian cells incur various types of damage with age, and the damage itself or the cellular damage responses could both contribute to aging phenotypes (Garinis et al 2008;Maslov and Vijg 2009). Many have hypothesized that tissue atrophy and functional decline are a result not only of increased cellular damage and genomic instability in mature somatic cells, but of failures in regenerative function in stem and progenitor cell compartments (Van Zant and Liang 2003;Chen 2004;Dumble et al 2004;Pelicci 2004;Sharpless and DePinho 2004;Campisi 2005;Rando 2006;Rodier et al 2007;Sharpless and DePinho 2007;Rossi et al 2008;Ruzankina et al 2008). Thus, one possibility is that declines in stem/progenitor cell selfrenewal and differentiation are critical components of aging and that age-associated changes in p53 antiproliferative function could have effects on stem/progenitor function.…”

Cellular senescence, ageing and disease

“…Stem cells express telomerase and are unlikely to become senescent in response to telomere shortening (Ruzankina and Brown 2007). However, it may still be possible for stem cells to enter senescence in response to DNA damage (Ruzankina et al 2008), consequently taking up valuable space in stem cell niches (Lynch 2006), reducing the stem cell pool, leading to an age-related loss in regenerative capacity. Also, if senescent cells persist in tissues, their altered secretome may have detrimental consequences on the local tissue and this may include stem cell niches.…”