Investigate stem cell replenishment following senolytic treatment
Lead Research Organisation:
Loughborough University
Department Name: Wolfson Sch of Mech, Elec & Manufac Eng
Abstract
Aim: investigate stem cell replenishment following senolytic treatment
Background: two advanced methods are reported to extend median and maximal life span
-- elimination of senescent cells ( , )
-- stem cell (SC) transplantation ( , )
The interplay of these methods has yet to be investigated:
Transplanted SC might mitigate senolytic toxicity.
Navitoclax (ABT-273) is the most established senolytic with proven efficacy. While there are no many published comparative studies, internal data suggest superior efficacy compared to other senolytics.
Navitoclax has significant haematological toxicity, including thrombocytopenia , grade III transaminitis and gastrointestinal bleeds .
In fact, it is possible that Navitoclax is specifically damaging to SC by targeting intracellular bcl-2, which is highly prevalent in haematopoietic SC .
Various SC modalities for the observed regenerative benefits of SC transplants have been proposed. SC may have a direct functional effect by repopulating the SC niche, and/or a paracrine 'bystander' effect which includes immune modulation, reduction of inflammation and interference in cytotoxic signalling , .
Removing senescent cells from the SC niche might promote SC proliferation and aid engraftment of transplanted SC.
Resident senescent cells in the SC niche are suspected to limit the activity of non-senescent SC. Mobilisation of haematopoietic SC in aged mice emptied the HSC niche, allowing for an improved engraftment of transplanted SC, leading to a 12.2% increase in median lifespan, reduced frailty and mortality .
Overview: A PhD student (Loughborough) under supervision by myself and senior SENS personnel will oversee and conduct three research phases: (1) selecting a mouse senescence model; (2) establish a suitable dosing combination of senolytics and SC; (3) investigate lifespan effects of stem cell +senolytic treatment in aged mice.
The Project will contribute to in vivo and educational capacity building at SENSRF and establish a proof of concept for the potential use of senolytics in regenerative and rejuvenation medicine.
Background: two advanced methods are reported to extend median and maximal life span
-- elimination of senescent cells ( , )
-- stem cell (SC) transplantation ( , )
The interplay of these methods has yet to be investigated:
Transplanted SC might mitigate senolytic toxicity.
Navitoclax (ABT-273) is the most established senolytic with proven efficacy. While there are no many published comparative studies, internal data suggest superior efficacy compared to other senolytics.
Navitoclax has significant haematological toxicity, including thrombocytopenia , grade III transaminitis and gastrointestinal bleeds .
In fact, it is possible that Navitoclax is specifically damaging to SC by targeting intracellular bcl-2, which is highly prevalent in haematopoietic SC .
Various SC modalities for the observed regenerative benefits of SC transplants have been proposed. SC may have a direct functional effect by repopulating the SC niche, and/or a paracrine 'bystander' effect which includes immune modulation, reduction of inflammation and interference in cytotoxic signalling , .
Removing senescent cells from the SC niche might promote SC proliferation and aid engraftment of transplanted SC.
Resident senescent cells in the SC niche are suspected to limit the activity of non-senescent SC. Mobilisation of haematopoietic SC in aged mice emptied the HSC niche, allowing for an improved engraftment of transplanted SC, leading to a 12.2% increase in median lifespan, reduced frailty and mortality .
Overview: A PhD student (Loughborough) under supervision by myself and senior SENS personnel will oversee and conduct three research phases: (1) selecting a mouse senescence model; (2) establish a suitable dosing combination of senolytics and SC; (3) investigate lifespan effects of stem cell +senolytic treatment in aged mice.
The Project will contribute to in vivo and educational capacity building at SENSRF and establish a proof of concept for the potential use of senolytics in regenerative and rejuvenation medicine.
Studentship Projects
| Project Reference | Relationship | Related To | Start | End | Student Name |
|---|---|---|---|---|---|
| EP/R513088/1 | 01/10/2018 | 30/09/2023 | |||
| 2610407 | Studentship | EP/R513088/1 | 01/10/2021 | 31/03/2025 | Oliver Frost |
| EP/T518098/1 | 01/10/2020 | 30/09/2025 | |||
| 2610407 | Studentship | EP/T518098/1 | 01/10/2021 | 31/03/2025 | Oliver Frost |