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Killing wisely: precision senolytics in the age of frailty
Valentin J A Barthet1, Scott W Lowe2,3
1Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, New York 10065, USA.
Abstract:
Cellular senescence plays a dual role in tissue biology by promoting tumor suppression and wound healing when transient but driving inflammation, fibrosis, and age-related disease when persistent. The growing recognition that senescent cell clearance can reverse these pathologies has catalyzed efforts to develop therapeutics that preferentially kill senescent cells (also known as "senolytics"). However, clinical translation from bench to bedside remains challenging due to senescent state heterogeneity, limited biomarkers, off-target toxicities, and the frailty of aged patients. Small molecule senolytics, although promising, often lack defined mechanisms of action and pose safety concerns that may constrain their use in older adults. Emerging precision approaches, including those that exploit surface markers and leverage engineered immune therapies, offer a rational and potentially more selective path forward. Here we highlight recent advances in senescence profiling and targeted clearance strategies, emphasizing the need for therapies designed with both biological complexity and the needs of aging populations in mind.
Insights
Clearing senescent cells can reverse age-related diseases. New precision therapies offer safer, targeted senolytics, addressing challenges in clinical translation for aging populations.
Area of Science:
- Cellular biology
- Gerontology
- Immunology
Background:
- Cellular senescence has dual roles: beneficial (tumor suppression, wound healing) and detrimental (inflammation, fibrosis, age-related diseases) when persistent.
- Persistent senescent cells contribute to various age-related pathologies.
- Senescent cell clearance is a therapeutic target for reversing these conditions.
Purpose of the Study:
- To review recent advances in understanding and targeting cellular senescence.
- To highlight challenges and emerging strategies for developing senolytic therapies.
- To emphasize the need for therapies tailored to biological complexity and aging individuals.
Main Methods:
- Review of current literature on senescence profiling and clearance strategies.
- Analysis of challenges in clinical translation of senolytics.
- Discussion of emerging precision approaches, including surface marker exploitation and engineered immune therapies.
Main Results:
- Senescent cell clearance shows potential to reverse age-related pathologies.
- Clinical translation of senolytics faces hurdles: heterogeneity, biomarkers, toxicity, and patient frailty.
- Small molecule senolytics have limitations regarding mechanism and safety in older adults.
Conclusions:
- Emerging precision therapies, like those using surface markers and immune strategies, offer a more targeted approach.
- Future senolytic therapies must account for senescence complexity and the specific needs of aging populations.
- Further research is needed to develop safe and effective senolytics for clinical use.
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