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aging
multiple
diseases
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risk
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pathology makes
sense except in
the light of
aging”
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Elimination of
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• Inflammation
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p53
Mdm2 Cyclin
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Rb
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(assisted cell suicide)...
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HIGH burden of
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senescent
growing
SAβG
human fibroblasts
(IMR90)
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• PBS
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83rd ICREA Colloquium 'Ageing as a treatable condition. The two faces of cellular senescence in tissue repair and in multi...
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83rd ICREA Colloquium 'Ageing as a treatable condition. The two faces of cellular senescence in tissue repair and in multiple diseases' by Manuel Serrano

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Title: The two faces of cellular senescence in tissue repair and in multiple diseases

A major advance in the field of ageing research has been the demonstration that senescent cells play a key role in aging and, even more importantly, the discovery of small pharmacological compounds that can kill senescent cells within the organism resulting in improved health. Upon tissue damage or stress, a substantial fraction of cells respond by adopting a cellular state known as “senescence”. Regardless of their initial cell identity, senescent cells share key properties; namely, global chromatin remodelling, robust proliferation blockade, and a massive pro-inflammatory secretome. The initial biological purpose of senescent cells is to orchestrate tissue repair, ultimately leading to their own disposal by the immune system and to their replacement by new, functional cells. This is the favorable, beneficial, face of cellular senescence. However, in certain contexts that are generally associated with chronic damage, degenerative processes, or organismal ageing, tissue repair is inefficient and senescent cells are not cleared. Indeed, senescent cells accumulate in many human pathologies including various fibrotic diseases, atherosclerosis, and neurodegenerative diseases. This is the detrimental, pathological, face of cellular senescence. Importantly, the last few years have witnessed the identification of small compounds that preferentially kill senescent cells, termed senolytic drugs. Such senolytic treatments in mice show an unprecedented therapeutic effect on the aforementioned diseases including lung fibrosis, atherosclerosis, and neurodegenerative diseases. I will present our contributions to the understanding of cellular senescence both in tissue repair and in pathological contexts.

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83rd ICREA Colloquium 'Ageing as a treatable condition. The two faces of cellular senescence in tissue repair and in multiple diseases' by Manuel Serrano

  1. 1. aging multiple diseases Aging: high-risk of multi-morbidity risk
  2. 2. “Nothing in pathology makes sense except in the light of aging”
  3. 3. The hallmarks of aging Carlos Lopez-Otin, Maria Blasco, Linda Partridge, Manuel Serrano, Guido Kroemer Genomic instability Telomere attrition Epigenetic alterations Loss of proteostasis Deregulated nutrient-sensing Mitochondrial dysfunction Cellular senescence Loss of regenerative potential Intercellular communication Cell 2013
  4. 4. Apoptosis Senescence Damage Elimination of damaged cells • Elimination of damaged cells • Inflammation • Regeneration/repair
  5. 5. elimination of damaged cells PUMA, p21 ARF p53 Mdm2 Cyclin CDK p16, p15 Rb E2F p21, p27 senescence (assisted cell suicide) • arrest • rich secretome apoptosis (cell suicide) minimal inflammatory response inflammatory & ECM remodelling response damage Palbociclib (Pfizer)
  6. 6. clearanceinflammation regenerationplasticitydamage developmental cues Damage – Repair – Cancer - Aging senescence • Tumor Regression  Xue et al. (Lowe), Nature 2007  Ventura et al. (Jacks), Nature 2007 • Tissue Regeneration  Krizhanovsky et al. (Lowe), Cell 2008  Demaria et al. (Campisi), Dev. Cell 2014 • Embryonic Development  Munoz-Espin et al. (Serrano), Cell 2013  Storer et al. (Keyes), Cell 2013 • Organ Regeneration (amputated limb in salamander)  Yun et al. (Brockes), eLife 2015
  7. 7. clearanceinflammation regenerationplasticitydamage developmental cues fibrotic diseases aging persistent damage pathological context aging maladaptive senescence Damage – Repair – Cancer - Aging senescence
  8. 8. Munoz-Espin & Serrano Nat Rev Mol Cell Biol, 2014 The growing list of human pathologies associated to senescence tissue dysfunction senescence chronic inflammation fibrosis
  9. 9. Human IPFMouse lung 2 days after damage Lysosomal β-galactosidase
  10. 10. Oct. 6, 2018Oct. 26, 2017
  11. 11. Senolytic therapeutics time damage LOW burden of senescent cells YOUNG, HEALTHY AGED, DISEASED HIGH burden of senescent cells REJUVENATED, HEALTHY LOW burden of senescent cells SENOLYSIS normal cells senolytics senescent cells
  12. 12. Nature Reviews Drug Discovery, advanced online publication (July 2017) Navitoclax Senolytic therapeutics Childs et al., 2017 senolyticsPulmonary fibrosis Kidney fibrosis Fatty liver Atherosclerosis Osteoarthritis Alzheimer Diab. retinopathy Progerias So far only tested in mice
  13. 13. GalNP: a versatile vehicle to deliver drugs into senescent cells Ramon Martinez´s team, UPV, Valencia MSN scaffold diameter: 100 nm 50 nm diameter: 2.5 nm loading gating galacto-oligosaccharides: ~6-mer oligosaccharides linked to each pore: ~3 estimated number of pores: ~1,500 GalNP 50 nm β-galactosidase Exacerbated lyso-endosomal traffic (exocytosis & endocytosis) High lysosomal content (β-galactosidase)
  14. 14. GalNP, our most advanced senolytic: validation in cell-based assays senescent growing SAβG human fibroblasts (IMR90) Cargo: rhodamine fluorescence
  15. 15. GalNP, our most advanced senolytic: validation in mice (pulmonary fibrosis) PBS Bleo SAβG Intratracheal: • PBS • Bleomycin day 14day 0 6h post-injection Bleomycin-induced Pulmonary Fibrosis 0 1 2 3 4 5 6 7 1 2 PBS Bleomycin * (n=6) (n=7) Averageradiance (p/s/cm2/srx106) - -+ + PBS Bleo Injection (i.v.) of the nanoparticles GalNP(rho)control
  16. 16. anti-senescence nanotherapy (18 days) fibrosis fibrosis GalNP, our most advanced senolytic: validation in mice (pulmonary fibrosis) Muñoz-Espín et al., EMBO Mol Med 2018
  17. 17. Senescence: too good to be true? One common cause One common biology One common therapy AGED, DISEASED REJUVENATED, HEALTHY SENOLYTIC AGENTS
  18. 18. Researchers: Mar Garcia Technician: Maribel Muñoz Postdoctoral: Federico Pietrocola Cian Lynch Gianluca Varetti Mate Maus Kathleen Meyer Marta Kovatcheva Predoctoral: Dafni Chondronasiou Miguel Rovira Noelia Alcazar Raquel Bernad Selim Chaib Elena Menendez

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