An aged immune system drives senescence and ageing of solid organs
Authors: Laura J Niedernhofer
Yi Zhu
Adam L Burrack
Jonathan I Kato
Rafael R Flores
Paul D Robbins
Tokio Sano
Ryan D O&#x27;Kelly
Michael P Bank
Robert W Brooks
Yuxiang Cui
Ingunn M Stromnes
Sara J McGowan
Christin E Burd
Johnny Huard
Yinsheng Wang
Collin A McGuckian
Nam V Vo
Qing Dong
Kyoo-A Lee
Zoe C Schmiechen
Dong Wang
Jenna Klug
Matthew J Yousefzadeh
Aiping Lu
Eric E Kelley
Sara E Lewis
Erin A Wade
Christy E Trussoni
Warren C Ladiges
Nicholas F LaRusso
Luise Angelini
Smitha P S Pillai
Journal: Nature (2021)
Discipline: Multidisciplinary
Keywords: immunosenescence; ageing; immune system; DNA repair; senescence
Affiliations: Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA., Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA., Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, MN, USA., Center for Immunology, University of Minnesota Medical School, Minneapolis, MN, USA., Department of Molecular Medicine, The Scripps Research Institute, Jupiter, FL, USA., Division of Gastroenterology, Center for Cell Signaling in Gastroenterology, Mayo Clinic, Rochester, MN, USA., Department of Chemistry, University of California Riverside, Riverside, CA, USA., Department of Orthopaedic Surgery, University of Pittsburgh, Pittsburgh, PA, USA., Department of Orthopedic Surgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA., Fred Hutchinson Cancer Research Center, Seattle, WA, USA., Department of Comparative Medicine, University of Washington, Seattle, WA, USA., Departments of Molecular Genetics and Cancer Biology and Genetics, The Ohio State University, Columbus, OH, USA., Department of Physiology & Pharmacology, West Virginia University, Morgantown, WV, USA., Institute on the Biology of Aging and Metabolism, University of Minnesota, Minneapolis, MN, USA. ., Department of Biochemistry, Molecular Biology and Biophysics, University of Minnesota, Minneapolis, MN, USA. .

Abstract:  Ageing of the immune system, or immunosenescence, contributes to the morbidity and mortality of the elderly1,2. To define the contribution of immune system ageing to organism ageing, here we selectively deleted Ercc1, which encodes a crucial DNA repair protein3,4, in mouse haematopoietic cells to increase the burden of endogenous DNA damage and thereby senescence5-7 in the immune system only. We show that Vav-iCre+/-;Ercc1-/fl mice were healthy into adulthood, then displayed premature onset of immunosenescence characterized by attrition and senescence of specific immune cell populations and impaired immune function, similar to changes that occur during ageing in wild-type mice8-10. Notably, non-lymphoid organs also showed increased senescence and damage, which suggests that senescent, aged immune cells can promote systemic ageing. The transplantation of splenocytes from Vav-iCre+/-;Ercc1-/fl or aged wild-type mice into young mice induced senescence in trans, whereas the transplantation of young immune cells attenuated senescence. The treatment of Vav-iCre+/-;Ercc1-/fl mice with rapamycin reduced markers of senescence in immune cells and improved immune function11,12. These data demonstrate that an aged, senescent immune system has a causal role in driving systemic ageing and therefore represents a key therapeutic target to extend healthy ageing. 

Retracted: No

PubPeer comments:
 This is a really interesting paper - I am wondering, however, why the authors, for instance in Figure 3, do not show the control Ercc1 (- fl)? In extended Figure 1, they just show that Ercc1 expression is not reduced in liver, kidney, and aorta of Vav-iCre Ercc1 - fl mice relative to Ercc1 (- fl). In my view this is not sufficient to extrapolate to the other organs in Fig 3. Also I would have liked to see markers of senescence in all of these organs in the Ercc1 (- fl) control. Or am I missing something? Would be happy to hear other people s thoughts on this. , 
 Maybe to further clarify: In Methods, the authors state: u201cThe cDNA for exons 8u201310 of Ercc1 along with a neomycin cassette all flanked by loxP sites was inserted into the Ercc1 locus in frame with exon 7 to create a floxed allele of Ercc1 (Supplementary Fig. 2a). Ercc1+ fl FVB N mice were crossed with C57BL 6J Vav-iCre+ u2212;Ercc1+ u2212 mice to create Vav-iCre+ u2212;Ercc1u2212 fl mice carrying one knockout and one floxed allele excised by codon improved Cre (iCre) recombinase in haematopoietic cells (Supplementary Fig. 2b). With the experimental mice being Vav-iCre(+ u2013);Ercc1(u2013 fl), this experimental design requires the following mouse genotypes as controls: One that the authors report: Vav-iCre(+ u2013) and one that the authors do not report which, however is even more important: Ercc1(u2013 fl) Given that in the Vav-iCre(+ u2013);Ercc1(u2013 fl) mice, all organs other than the hematopoietic system carry a knockout allele of Ercc1, it is crucial that these mice are compared to the Cre-negative mice carrying the same knockout allele. However, in figures 1, 2, and 3, the authors only show the Vav-iCre(+ u2013) control. This would mean that they compared the Vav-iCre(+ u2013) control u2013 which according to the nomenclature would carry one allele of Cre but have a normal ERCC1 genotype u2013 to the experimental mice which carry one ERCC1 knockout at baseline already. Hence, any difference seen between the Vav-iCre(+ u2013) control and the Vav-iCre(+ u2013);Ercc1(u2013 fl) mice could be due to the ERCC1 knockout at baseline, independent of whether ERCC1 is knocked out in hematopoietic cells or not. I may be missing an important point. But if this is true, then this is extremely careless experimental design, which makes many of the results meaningless and many of the conclusions drawn by the authors false. Given that expert editors and reviewers scrutinized this manuscript, I have a hard time believing this, though. But even if this is merely incomplete reporting of experimental details, I am concerned because it encourages researchers to not carefully control and document their animal experiments. Can the authors please fully disclose the genotypes of the controls used?. ,