Year: 2020
Type: article
Abstract: hy do we get old?How much of aging is genetic?And in what genes?There is clearly a genetic basis of aging, as demonstrated from yeast to worms to humans. 1 As one example, different mouse strains have different potential lifespans.Much effort has been invested in understanding the genetic underpinnings of lifespan differences between the long-lived C57Bl/6 strain and the short-lived DBA/2 strain, with 50% mortality in captivity by 914 and 687 days, respectively.2Quantitative trait loci mapping in C57Bl/6 X DBA/2 (BXD) recombinant inbred strains identified a locus on chromosome 11 that is linked to lifespan, narrowing the trait conferring region to 18.6 Mb. 3 These previous studies have also shown that the fraction of mouse hematopoietic stem and progenitor cells (HSPC) that lose function in response to hydroxyurea (HU) treatment is inversely correlated with lifespan across BXD strains, including for the chromosome 11 locus.In this issue of Haematologica, Brown et al. explored the genetic differences within this locus that contribute to both HU sensitivity and longevity.4 The authors show that a relatively small region on chromosome 11 is tightly linked to HU sensitivity of HSPC, as BXD recombinant strains that possessed this region displayed the high or low sensitivity of the DBA/2 or C57Bl/6 HSPC, respectively, even when almost all other genes were from the other strain.Previous work had demonstrated that this region suffices to confer the short or long lifespan of the donor strain.3 Notably, the authors demonstrated that HU sensitivity and longevity differences mediated by this locus did NOT coincide, surprisingly, with differences in cell cycling, telomere length, HSPC number, DNA damage responses, senescence or viability.Thus, simple explanations for HSPC sensitivity to HU, which could also account for earlier stem cell exhaustion and aging, such as increased cycling, impaired DNA damage responses or precocious senescence, do not appear to account for strain differences.Their subsequent analyses revealed that this locus confers differential expression of the pituitary tumor-transforming gene-1 (Pttg1)/Securin gene, with substantially higher expression conferred by the DBA/2 locus.Interestingly, the yeast homolog of Pttg1 is Pds1p, shown to regulate the intra-S-phase checkpoint and responses to HU in yeast, 5 which is consistent with PTTG1 regulation of HU sensitivity.Also, intriguingly, PTTG1 is an inhibitor of separase, the cysteine protease that opens cohesin rings during the metaphase to anaphase transition, suggesting a role for PTTG1 in the cell cycle.Still, while PTTG1 overexpression has been shown to lower progression through S phase and increase senescence and DNA damage in human fibroblasts, 6 Brown et al. demonstrate that these phenotypes are not observed to differ for HSPC from the congenic strains.4 Notably, genetic varia-
Source: Haematologica
Author: James DeGregori
Institution: University of Colorado Anschutz
Language: English
Subfield: Aging
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,157
OpenAlex ID: W3004030636