Page 12 - 2020_02-Haematologica-web

Editorials
Of mice, genes and aging.
James DeGregori
Department of Biochemistry and Molecular Genetics, University of Colorado Anschutz Medical Campus, Aurora, CO, USA E-mail: JAMES DEGREGORI - james.degregori@cuanschutz.edu
doi:10.3324/haematol.2019.238683
Why do we get old? How much of aging is genet- ic? And in what genes? There is clearly a genet- ic 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% mor- tality in captivity by 914 and 687 days, respectively.2 Quantitative 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 stud- ies 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 differ- ences within this locus that contribute to both HU sensi- tivity 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, sur- prisingly, 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 con- fers differential expression of the pituitary tumor-trans- forming 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 transi- tion, 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. demon- strate that these phenotypes are not observed to differ for HSPC from the congenic strains.4 Notably, genetic varia-
tion in Pttg1 (together with other mitotic checkpoint genes) is associated with chromosomal aberrations in
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healthy humans. Given that inherited defects in genome
stability often result in premature aging,8 PTTG1 level- dependent impacts on chromosomal segregation during mitosis could influence longevity.
They further demonstrate that the DBA/2 locus dis- plays an apparent duplication that results in a longer pro- moter for the Pttg1 gene, and this longer promoter confers greater transcriptional activity in reporter assays. Much of evolutionary change is associated with alterations of gene expression (without necessarily changing the activity of the encoded protein), involving mutations in cis-regulato- ry elements.9 The evolution of lifespan may similarly involve changes in gene expression, rather than the activ- ity of the gene products. Finally, they showed that ectopic PTTG1 expression in C57Bl/6 HSPC to levels approximating those in DBA/2 cells was sufficient to increase their susceptibility to HU, and downregulation of PTTG1 in HSPC with the DBA/2 locus resulted in a trend towards reduced sensitivity to HU. While more research is needed, variation in the Pttg1 gene is a strong candidate as a regulator of aging.
Previous studies have shown that CpG DNA methyla- tion profiles across tissues for selected genes can be used as an aging clock, able to predict chronological age as well as “biological age” (a measure of physiological aging, and thus the risk of aging-associated diseases and death for older ages).10 These clocks have been extensively validat- ed in humans, and epigenetic deviation from the age- average profile for one’s chronological age has been shown to predict various hallmarks of physiological aging including immunosenescence, diseases from cancer to heart disease to Alzheimer’s disease, frailty, and, grimly, time to death. Your clock-predicted biological age is determined by factors such as smoking status, diet, body mass index, exercise, and sleep. For C57Bl/6 mice, CpG sites within three genes have been shown to serve as markers of chronological aging,11 with accelerated changes in methylation in DBA/2 mice coinciding with their reduced longevity. Here, the authors show similar accelerated aging in the congenic mice with the DBA/2 chromosome 11 locus in the C57Bl/6 background. Thus, the DBA/2 version of this locus is sufficient to promote epigenetic aging. While hypothetical, this could be more than an association - given roles for PTTG1 in chromo- some cohesin, a known regulator of higher-order chro- matin organization and gene expression profiles12 impor- tant for stem cell and differentiation programs, differen- tial expression of PTTG1 could lead to changes in these programs and thus the tissue maintenance which is criti- cal for staying young.
Let’s consider our original question - why do we get old? - at an even higher level. Natural selection only acts
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haematologica | 2020; 105(2)