Lurking within your body, from your liver to your brain, are zombie-like entities known as senescent cells. These cells no longer divide or function as they once did, yet they resist death and release a plethora of harmful biological signals that can impair cognition or weaken the immune system. Worryingly, their numbers increase as you age.
For over a decade, researchers have been exploring ways to selectively destroy these cells using various drugs. In a groundbreaking study (1), researchers from the Mayo Clinic and the Scripps Research Institute found that a combination of the small molecule drugs dasatinib and quercetin killed senescent cells in aged mice. The treatment reduced frailty and improved their endurance. This discovery paved the way for a new field of medicine called senolytics.
Recent findings from animal studies and human clinical trials have further advanced this field. Researchers are employing genetic tools to reprogram and eliminate senescent cells in mice and monkeys. Others are engineering senolytic immune cells. Currently, about 20 clinical trials are testing new and repurposed drugs with potential senolytic properties, aiming to combat age-related conditions like Alzheimer’s, lung disease, and chronic kidney disease.
The Origin of Senescent Cells
Senescent cells were first identified in 1961 by biologists Leonard Hayflick and Paul Moorhead, who discovered that human cells in a lab dish would divide no more than about 50 times before either dying or entering a state of cell senescence (2). While it takes weeks for dividing cells to become senescent in the lab, the duration of this process in the body and the lifespan of senescent cells remain unknown.
The Role of Senescent Cells
Senescence can arise from factors like physical injury, malnourishment, or DNA damage from UV light. Senescent cells avoid apoptosis to perform a service: releasing inflammatory signals that prompt the immune system to clear out damaged cells. This process helps tissues regenerate and repair until the immune system weakens with age, leading to a buildup of senescent cells that cause excessive inflammation. This accumulation is linked to diseases like osteoporosis, diabetes, heart disease, kidney disease, and Alzheimer’s.
Strategies for Senolytic Therapies
A key strategy in senolytics is designing drugs that make senescent cells susceptible to apoptosis. Usually, these cells survive by producing anti-death proteins. Blocking these proteins with drugs can induce cell death. For example, a biotech company called Unity has developed a drug called foselutoclax, which blocks BCL-xL, a key anti-death protein in senescent cells. Injecting this drug into the eyes of diabetic mice selectively killed senescent cells in the retinal blood vessels, reducing leakiness by about 50% and improving vision. In a phase II trial, human participants treated with foselutoclax could read more letters on an optician’s chart compared to those given a placebo (3).
Exploring Existing Drugs
Other scientists are testing existing drugs for their senolytic properties. These include the kinase inhibitor dasatinib, as well as plant-derived chemicals such as quercetin and fisetin. In rodent studies, these drugs have been shown to clear senescent cells and to reduce inflammation (4,5).
Immune System-Based Approaches
Researchers are also harnessing the immune system to kill senescent cells. Some are using genetically engineered chimeric antigen receptor (CAR) T cells, currently approved for treating blood cancers, to target and kill senescent cells. Earlier this year, cell biologist Corina Amor and her team identified a protein marker, uPAR, on senescent cells in older mice. They created CAR T cells designed to kill senescent cells with this marker, which improved the mice’s metabolic health and exercise capacity without causing toxicity (6,7).
The Future of Senolytics
The challenge of specificity in targeting senescent cells is shared by all senolytic approaches and researchers are only beginning to uncover the diversity of senescent cells and possible surface markers. There are several efforts underway to map senescence markers in humans – hopefully, improved markers will lead to better senolytics and the prevention or treatment of age-related diseases.
Suppliers of senescence products
Genetex
Abbexa
EnoGene
References
- Zhu, Y. et al. Aging Cell 14, 644–658 (2015). Pubmed
- Hayflick, L. & Moorhead, P. S. Exp. Cell Res. 25, 585–621 (1961). Pubmed
- Crespo-Garcia, S. et al. Nature Med. 30, 443–454 (2024). Pubmed
- Yousefzadeh, M. J. et al. EBioMedicine 36, 18–28 (2018). Pubmed
- Zhang, P. et al. Nature Neurosci. 22, 719–728 (2019). Pubmed
- Amor, C. et al. Nature Aging 4, 336–349 (2024). Pubmed
- Eskiocak, O. et al. Preprint at bioRxiv https://doi.org/10.1101/2024.03.19.585779 (2024).
Image References
Images from the National Institute of Aging: https://www.nia.nih.gov/news/does-cellular-senescence-hold-secrets-healthier-aging