title: Dietary restriction ameliorates haematopoietic ageing independent of telomerase, whilst lack of telomerase and short telomeres exacerbates the ageing phenotype.
abstract: Ageing is associated with an overall decline in the functional capacity of tissues and stem cells, including haematopoietic stem and progenitor cells (HSPCs), as well as telomere dysfunction. Dietary restriction (DR) is a recognised anti-ageing intervention that extends lifespan and improves health in several organisms. To investigate the role of telomeres and telomerase in haematopoietic ageing, we compared the HSPC profile and clonogenic capacity of bone marrow cells from wild type with telomerase-deficient mice and the effect of DR on these parameters. Compared with young mice, aged wild type mice demonstrated a significant accumulation of HSPCs (1.3% vs 0.2%, P=0.002) and elevated numbers of granulocyte/macrophage colony forming units (CFU-GM, 26.4 vs 17.3, P=0.0037) consistent with myeloid "skewing" of haematopoiesis. DR was able to restrict the increase in HSPC number as well as the myeloid "skewing" in aged wild type mice. In order to analyse the influence of short telomeres on the ageing phenotype we examined mice lacking the RNA template for telomerase, TERC(-/-). Telomere shortening resulted in a similar bone marrow phenotype to that seen in aged mice, with significantly increased HSPC numbers and an increased formation of all myeloid colony types but at a younger age than wild type mice. However, an additional increase in erythroid colonies (BFU-E) was also evident. Mice lacking telomerase reverse transcriptase without shortened telomeres, TERT(-/-), also presented with augmented haematopoietic ageing which was ameliorated by DR, demonstrating that the effect of DR was not dependent on the presence of telomerase in HSPCs. We conclude that whilst shortened telomeres mimic some aspects of haematopoietic ageing, both shortened telomeres and the lack of telomerase produce specific phenotypes, some of which can be prevented by dietary restriction.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK.
authors.forename: Nouf
authors.initials: N
authors.lastname: Al-Ajmi
authors.affiliation: Institute of Ageing and Health, Campus for Ageing and Vitality, Newcastle University, NE4 5PL, UK.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Saretzki
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK. Electronic address: colin.miles@newcastle.ac.uk.
authors.forename: Colin
authors.initials: C
authors.lastname: Miles
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Central Parkway, Newcastle upon Tyne NE1 3BZ, UK. Electronic address: ioakim.spyridopoulos@newcastle.ac.uk.
authors.forename: Ioakim
authors.initials: I
authors.lastname: Spyridopoulos
mesh_terms: D000367:Age Factors; D000375:Aging / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D031204:Caloric Restriction; D002454:Cell Differentiation; D019070:Cell Lineage; D049109:Cell Proliferation; D016922:Cellular Senescence; D005838:Genotype; D006412:Hematopoietic Stem Cells / Q000201:enzymology*; D008297:Male; D018345:Mice, Knockout; D010641:Phenotype; D012313:RNA / Q000235:genetics; D019098:Telomerase / Q000172:deficiency* / Q000235:genetics; D016615:Telomere / Q000378:metabolism*; D059506:Telomere Shortening
chemical_list: C422952:telomerase RNA; D012313:RNA; D019098:Telomerase; C509187:Tert protein, mouse
keywords: Ageing; Bone marrow; Dietary restriction; Haematopoiesis; TERC; TERT; Telomerase