Leader: Fabrizio d'Adda di Fagagna (CNR); Other collaborator(s):
Whether telomere shortening and damage play relevant roles in natural aging is unclear. It is also possible that telomere shortening and damage may impact differently in different tissues and organs. Genetic inactivation of telomerase genes accellerates mouse aging and recapitulates some features of human aging and diseases. We plan to study the impact of telomere shortening in telomerase knockout mice and compare it to aging of wild-type mice. This will involve the study of the consequences of telomere dysfunction (telomeric DNA damage response activation and markers of cellular senescence) as detected by imaging techniques of relevant cellular markers and extensive transcriptomic analyses.
Brief description of the activities and of the intermediate results: We are thoroughly investigating the impact of telomere dysfunction by determining the engagment of DNA damage Response (DDR) pathways in vivo by immunohistochemical analyses in different tissues of telomerase KO mice. It is emerging that gH2AX and pKAP1 are activated in several tissues as analysed by immunohistochemistry. We are quantifying these signals in order to reach quantitative conclusions.
We have determined the impact of telomere dysfunction in two main organs: lungs and the hematopoietic systems. RNAseq analyses revealed extensive rewiring, leading to an accelerated aging phenotype – indeed several misregulated gene-expression pathways overlap with those altered in natural aging. These included proinflammatory pathways and more generally those associated with cellular senescence. Importantly, their analyses revealed a gene expression signature that to an extent overlaps with human degenerative conditions, indicating evolutionary conserved pathways and common potentially actionable targets. Our observation that the hematopoietic and immune system is also significantly compromised, as demonstrated by functional assays measuring hematopoietic stem cells fitness, provide further evidence to the notion that an impaired immune system may further aggravate aging conditions.
Dissemination:
40 invited oral presentations including 5 Keynote Lectures at international conferences and invited seminars.
We have continued our characterization of the impact of telomere dysfunction in human conditions modeled in transgenic mice with shortened telomeres. The computational analysis of the different quantitative parameters measured in these mice has revealed consistency among the changes observed and a coherent response to treatments.
Presently most efforts are dedicated to the assembly of a manuscript describing our findings.
Guidelines for minimal information on cellular senescence experimentation in vivo
Mikolaj Ogrodni∙ Juan Carlos Acosta∙ Peter D. Adams ∙ Fabrizio d’Adda di Fagagna ∙ Darren J. Baker ∙ Cleo L. Bishop ∙ Tamir Chandra ∙ Manuel Collado ∙ Jesus Gil ∙ Vassilis Gorgoulis ∙ Florian Gruber ∙ Eiji Har ∙ Pidder Jansen-Dürr ∙ Diana Jurk ∙ Sundeep Khosla ∙ James L. Kirkland ∙ Valery Krizhanovsky30 ∙ Tohru Minamino31,32 ∙ Laura J. Niedernhofer33 ∙ João F. Passos ∙ Nadja A.R. Ring∙ Heinz Redl ∙ Paul D. Robbins ∙ Francis Rodier∙ Karin Scharffetter-Kochanek ∙ John M. Sedivy ∙ Ewa Sikora ∙ Kenneth Witwer ∙ Thomas von Zglinicki ∙ Maximina H. Yun, Johannes Grillari Marco Demaria
Cell. 2024 Aug 8;187(16):4150-4175. https://www.cell.com/cell/fulltext/S0092-8674(24)00640-8
In memoriam Judy Campisi: spreading cellular senescence
Fabrizio d’Adda di Fagagna
Nature Reviews Molecular Cell Biology volume 25, page 950 (202)
https://www.nature.com/articles/s41580-024-00736-w
Judith Campisi (1948–2024)
Christopher D. Wiley, Eiji Hara & Fabrizio d’Adda di Fagagna
Nature Aging https://www.nature.com/articles/s43587-024-00603-5