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Local senolysis in aged mice only partially replicates the benefits of systemic senolysis
Joshua N Farr1,2,3, Dominik Saul1,2, Madison L Doolittle1,2
1Robert and Arlene Kogod Center on Aging.
Abstract:
Clearance of senescent cells (SnCs) can prevent several age-related pathologies, including bone loss. However, the local versus systemic roles of SnCs in mediating tissue dysfunction remain unclear. Thus, we developed a mouse model (p16-LOX-ATTAC) that allowed for inducible SnC elimination (senolysis) in a cell-specific manner and compared the effects of local versus systemic senolysis during aging using bone as a prototype tissue. Specific removal of Sn osteocytes prevented age-related bone loss at the spine, but not the femur, by improving bone formation without affecting osteoclasts or marrow adipocytes. By contrast, systemic senolysis prevented bone loss at the spine and femur and not only improved bone formation, but also reduced osteoclast and marrow adipocyte numbers. Transplantation of SnCs into the peritoneal cavity of young mice caused bone loss and also induced senescence in distant host osteocytes. Collectively, our findings provide proof-of-concept evidence that local senolysis has health benefits in the context of aging, but, importantly, that local senolysis only partially replicates the benefits of systemic senolysis. Furthermore, we establish that SnCs, through their senescence-associated secretory phenotype (SASP), lead to senescence in distant cells. Therefore, our study indicates that optimizing senolytic drugs may require systemic instead of local SnC targeting to extend healthy aging.
Insights
Clearing senescent cells (SnCs) locally benefits aging bone, but systemic senolysis offers broader advantages. Targeting SnCs throughout the body may be key to extending healthy aging by mitigating age-related bone loss.
Area of Science:
- Gerontology
- Cell Biology
- Biomedical Science
Background:
- Senescent cells (SnCs) accumulate with age and contribute to age-related diseases.
- The distinct roles of local versus systemic SnCs in tissue aging are not fully understood.
- Bone loss is a common age-related pathology potentially influenced by SnCs.
Purpose of the Study:
- To investigate the local versus systemic effects of senolysis on age-related bone loss.
- To determine if targeting SnCs in specific tissues or systemically yields different health benefits.
- To elucidate the mechanisms by which SnCs impact distant tissues.
Main Methods:
- Development of a novel inducible mouse model (p16-LOX-ATTAC) for cell-specific senolysis.
- Comparison of local senolysis in osteocytes versus systemic senolysis in aging mice.
- Assessment of bone parameters, including bone formation, osteoclasts, and marrow adipocytes.
- Transplantation experiments to evaluate the impact of SnCs on distant host cells.
Main Results:
- Local senolysis of osteocytes prevented spine bone loss but not femur bone loss, improving bone formation.
- Systemic senolysis prevented bone loss in both spine and femur, enhancing bone formation and reducing osteoclasts and marrow adiposity.
- Transplanted SnCs induced bone loss and distant osteocyte senescence in young mice.
- SnCs, via their senescence-associated secretory phenotype (SASP), induce senescence in remote cells.
Conclusions:
- Local senolysis provides partial benefits for aging bone, highlighting the importance of SnC targeting.
- Systemic senolysis offers more comprehensive benefits, suggesting broader therapeutic potential for age-related bone loss.
- SnCs can induce senescence in distant tissues, emphasizing the systemic nature of aging processes.
- Optimizing senolytic therapies for healthy aging may necessitate systemic rather than local SnC targeting.
