Aging of Protein Complexes
Dr. Alessandro Ori
Associated Group Leader
Our group is interested in studying how age and environmental factors affect our organs at the molecular level.
The Building Blocks of Our Body
The group of Dr. Alessandro Ori is associated to the FLI as a cooperation group between Genentech, South San Francisco CA, USA and the FLI.
The Research Group “Aging of Protein Complexes” is interested in studying how age and environmental factors affect our organs at the molecular level. The group employs ultra-sensitive approaches allowing the quantification of thousands of proteins in tissues as well as in rare cell populations.
The group’s goal is to identify, in an unbiased way, functionally relevant alterations of the proteome that will enable the researchers to understand the mechanisms of organ deterioration that impact on healthy lifespan.
By studying the molecular changes that occur between young and old animals, we aim to understand what makes old organs more prone to failure and disease.
Mechanisms of Proteostasis Impairment in Aging and Neurodegeneration
The impairment of proteostasis and resulting aggregation of misfolded proteins are associated with age-related diseases such as neurodegenerative disorders. The group’s research focuses on (i) how aging perturbs major protein complexes involved in protein synthesis (ribosomes) and degradation (proteasomes), (ii) how protein localization and post-translational modifications influence protein function in aging, and (iii) the interplay between mutations linked to increased risk of neurodegeneration and the aging process.
CZI collaborative project on TDP-43 Mislocalization in Aging and Neurodegeneration led by Dr. Paulius Grigaravicius
References:
Di Fraia D*, Marino A*, Lee JH*, Kelmer Sacramento E, Baumgart M, Bagnoli S, Balla T, Schalk F, Kamrad S, Guan R, Caterino C, Giannuzzi C, Tomaz da Silva P, Sahu AK, Gut H, Siano G, Tiessen M, Terzibasi-Tozzini E, Fornasiero EF, Gagneur J, Englert C, Patil KR, Correia-Melo C, Nedialkova DD, Frydman J#, Cellerino A#, Ori A#. Altered translation elongation contributes to key hallmarks of aging in the killifish brain. Science. 2025 Jul 31;389(6759):eadk3079. doi: 10.1126/science.adk3079. Epub 2025 Jul 31. PMID: 40743332.
Marino A*, Di Fraia D*, Panfilova D, Sahu AK, Minetti A, Omrani O, Cirri E, Ori A. Aging and diet alter the protein ubiquitylation landscape in the mouse brain. Nat Commun. 2025 Jun 6;16(1):5266. doi: 10.1038/s41467-025-60542-6. PMID: 40480969; PMCID: PMC12144301.
Kelmer Sacramento E*, Kirkpatrick JM*, Mazzetto M, Baumgart M, Bartolome A, Di Sanzo S, Caterino C, Sanguanini M, Papaevgeniou N, Lefaki M, Childs D, Bagnoli S, Terzibasi Tozzini E, Di Fraia D, Romanov N, Sudmant PH, Huber W, Chondrogianni N, Vendruscolo M, Cellerino A#, Ori A#. Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation. Mol Syst Biol. 2020 Jun;16(6):e9596. doi: 10.15252/msb.20209596. PMID: 32558274; PMCID: PMC7301280. Cover.
Mapping the composition of lysosomes
Lysosomes are multifunctional organelles that play a central role in autophagy and therefore in protein quality control and aggregate clearance. In addition, lysosomes are involved in intracellular signaling and regulating cellular homeostasis in response to changes in nutrient availability via the mTORC1 complex, a key modulator of aging. The Ori group, together with collaborators from Stanford University, uses proteomics to study the composition of lysosomes across different brain cell types and in models of neurological disorders.
NCL foundation funded project on Batten disease led by Dr. Julia Heiby.
References:
Ghoochani A*, Heiby JC*, Rawat ES, Medoh UN, Di Fraia D, Dong W, Gastou M, Nyame K, Laqtom NN, Gomez-Ospina N, Ori A#, Abu-Remaileh M#. Cell-Type Resolved Protein Atlas of Brain Lysosomes Identifies SLC45A1-Associated Disease as a Lysosomal Disorder. bioRxiv [Preprint]. 2024 Oct 14:2024.10.14.618295. doi: 10.1101/2024.10.14.618295. PMID: 39464040; PMCID: PMC11507716. Accepted at Cell.
Wyant GA, Abu-Remaileh M, Frenkel EM, Laqtom NN, Dharamdasani V, Lewis CA, Chan SH, Heinze I, Ori A#, Sabatini DM#. NUFIP1 is a ribosome receptor for starvation-induced ribophagy. Science. 2018 May 18;360(6390):751-758. doi: 10.1126/science.aar2663. Epub 2018 Apr 26. PMID: 29700228; PMCID: PMC6020066
Stem Cell Aging
Adult (somatic) stem cells play a crucial role in maintaining and regenerating organs. However, their function and number decrease during aging. A particular focus of the group is to understand molecular mechanisms that lead to the regenerative capacity loss of these cells. Focusing on the intestinal epithelium and skeletal muscle, the group examines proteome profiles of stem cells and surrounding tissue across age groups following injury and evaluates the consequences of anti-aging interventions such as dietary restriction.
References:
Minetti A*, Omrani O*, Brenner C, Cansiz F, Imada S, Rösler J, Khawaled S, Allies G, Meckelmann SW, Gebert N, Heinze I, Rahnis N, Lu J, Spengler K, Rasa M, Cirri E, Heller R, Yilmaz Ö, Tasdogan A, Neri F#., Ori A#. Polyamines sustain epithelial regeneration in aged intestines by modulating protein homeostasis. Nat Cell Biol. 2025 Nov 24. doi: 10.1038/s41556-025-01804-9. Epub ahead of print. PMID: 41286441.
Gebert N, Cheng CW, Kirkpatrick JM, Di Fraia D, Yun J, Schädel P, Pace S, Garside GB, Werz O, Rudolph KL, Jasper H, Yilmaz ÖH, Ori A. Region-Specific Proteome Changes of the Intestinal Epithelium during Aging and Dietary Restriction. Cell Rep. 2020 Apr 28;31(4):107565. doi: 10.1016/j.celrep.2020.107565. PMID: 32348758; PMCID: PMC7446723.
Schüler SC, Kirkpatrick JM, Schmidt M, Santinha D, Koch P, Di Sanzo S, Cirri E, Hemberg M, Ori A#., von Maltzahn J#.. Extensive remodeling of the extracellular matrix during aging contributes to age-dependent impairments of muscle stem cell functionality. Cell Rep. 2021 Jun 8;35(10):109223. doi: 10.1016/j.celrep.2021.109223. PMID: 34107247.
