The accumulation of damaged/senescent cells in the body with time is a hall mark of aging. These cells are believed to play a key role in the onset and/or progression of various aging-associated diseases. More generally, the decreased regenerative ability of transplanted stem cells in older recipients may also be partly attributable to the presence of a high level of senescent cells.
Many factors produced by senescent cells – including proinflammatory cytokines, profibrotic molecules and damaging agents such as labile iron and reactive aldehydes – are known to disrupt the function of normal cells and cause organ function to decline. The hostile environment created by senescent cells is likely to impair the ability of transplanted stem cells to home in on target tissues, mature and restore tissue function. Therefore, prior removal of senescent cells will likely enhance the effectiveness of stem cell transplantation therapies.
In recent years, two major observations in the longevity field have been made:
- The use of senolytics to remove senescent cells significantly improved health and lifespan in mice and as might be expected, this approach enhanced the repopulation ability of endogenous stem cells1.
- Stem cell transplantation has demonstrated beneficial effects in reducing aging-associated functional decline in both mice and humans, and extended lifespans in mice2,3.
The SenoStem project will test the hypothesis that prior removal of senescent cells by senolytics will create a more favorable niche for stem cells to engraft, and thus enhance their regenerative effect in older recipients. The overall aim is to determine whether these two different lifespan-extending interventions can act synergistically.
The first phase of this project will be to carryout in vitro and in vivo studies in order to identify the most effective and safe senolytic from a list of established and in-house candidates.
The second phase of the project will assess the effectiveness of a combination therapy in which mice are treated with a lead senolytic identified in phase I, followed by transplantation of stem cells. We expect that the combination therapy will be more effective than either the senolytic or stem cell treatment alone.
- Chang J, et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat Med. 2016 Jan;22(1):78-83. doi: 10.1038/nm.4010. PMID: 26657143
- Kovina MV, et al. Extension of Maximal Lifespan and High Bone Marrow Chimerism After Nonmyeloablative Syngeneic Transplantation of Bone Marrow From Young to Old Mice. Front Genet. 2019 Apr 12;10:310. doi: 10.3389/fgene.2019.00310. PMID: 31031800
- Guderyon MJ, et al. Mobilization-based transplantation of young-donor hematopoietic stem cells extends lifespan in mice. Aging Cell. 2020 Mar;19(3):e13110. doi: 10.1111/acel.13110. PMID: 32012439
Abdelhadi Rebbaa, PhD
Elena Magay, PhD
Oliver Frost (PhD Student)