What are Senolytics?

16/11/2023

The relationship between senescence and aging
Targeting senescent cells
The benefits of senolytics
References
Further reading

Senolytics, a class of drugs designed to specifically target senescent cells—those that have ceased cell division—are gaining recognition for their potential to address various age-related health issues.

*Image Credit: LeviaUA/Shutterstock.com*

These cells may stop dividing due to environmental or internal conditions and serve as a protective measure when DNA becomes dysregulated to prevent cancer or facilitate tissue repair. However, senescent cells can become problematic as they often exhibit increased anti-apoptotic pathways, heightened metabolic activity, and undergo numerous epigenetic changes upon ceasing cell division.

Furthermore, they may adopt a secretory phenotype, releasing pro-inflammatory cytokines, chemokines that attract immune cells, metalloproteinases that degrade local tissue, and other agents that induce blood clotting and fibrosis.

The relationship between senescence and aging

Senescence is closely associated with the aging process. The gradual accumulation of DNA damage over a lifetime limits the ability of cells to repair themselves. This leads to a higher incidence of diseases and a progressive decline in the function of organs such as the heart, lungs, brain, eyes, and others as individuals age. Senescence is thought to be directly or indirectly linked to many fundamental aging processes that contribute to mortality.

Targeting senescent cells

Senescent cells have been implicated in causing inflammation, DNA damage, protein aggregation, fibrosis, lipotoxicity, mitochondrial dysfunction, immune cell dysfunction, and the production of reactive oxygen species. However, senescence also serves as a defense mechanism against cancer by halting cell division before uncontrolled growth occurs.

In some cases, senescent cells can even have a beneficial effect on surrounding cells and tissue by promoting stem cell differentiation into the appropriate cell type. Nonetheless, studies have shown that removing senescent cells from cancer-prone mice has an overall beneficial effect by reducing the occurrence of tumors limiting the number of secreting cells with a detrimental influence.

Unlike classical chemotherapy, which relies on the rapid division of cancer cells for efficacy, senolytic drugs target non-dividing senescent cells. These drugs interfere with the anti-apoptotic pathways of senescent cells, allowing the cells to undergo apoptosis.

Prominent examples of senolytics include tyrosine kinase inhibitors like dasatinib and quercetin. Dasatinib promotes apoptosis by inhibiting Src kinase, which would otherwise bind to receptors generating an anti-apoptotic signal.

Quercetin, on the other hand, acts as an antioxidant and anti-inflammatory agent. Both compounds exhibit specific anti-senescent cell effects, with varying efficacy depending on the source of senescence and the degree of genetic degradation.

Additionally, both compounds have demonstrated the ability to reduce senescent cell abundance in middle-aged mice by 30-70%, with similar results observed in human 3D tissue cultures.

The benefits of senolytics

Reducing the abundance of senescent cells in middle-aged and elderly mouse models has revealed various health benefits. These include enhanced cardiac and vascular function, improved insulin sensitivity, reduced vessel calcification, increased vessel sensitivity to neurotransmitters like acetylcholine, and relief from various age and obesity-related symptoms.

Senolytic treatment has also shown promise in addressing neurological and psychological dysfunction, reducing brain inflammation and anxiety in obese mice, and alleviating Alzheimer's disease-associated changes in the brain.

Mouse models have indicated improvements in age-related conditions like osteoporosis and arthritis through senolytic treatment. Senolytics have suppressed bone resorption and increased bone formation in age-related osteoporosis while elevating glycosaminoglycan levels in the vertebrae has aided in addressing arthritis.

Physical function in mice, assessed through daily activity, treadmill performance, and grip strength, has also improved with senolytic treatment in naturally aged mice and younger mice implanted with large numbers of senescent cells. Moreover, senolytics have extended the lifespan of aged mice by up to 35% and significantly reduced deaths resulting from age-associated cancer.

Clinical trials of senolytics in humans are in their early stages, but preliminary findings show improvements in mobility and strength for idiopathic pulmonary fibrosis patients. Several more studies focusing on individuals with specific age-related conditions are underway or in the planning stages. If these drugs prove as safe and effective in humans as they are in mice, they may become a valuable tool for addressing age-related health issues.

References

Kirkland & Tchkonia (2020) Senolytic drugs: from discovery to translation. Journal of Internal Medicine.
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7405395/
Justice et al. (2019) Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. EBiomedicine.
https://pubmed.ncbi.nlm.nih.gov/30616998/
Baar et al. (2017) Targeted Apoptosis of Senescent Cells Restores Tissue Homeostasis in Response to Chemotoxicity and Aging. Cell, 169(1).
https://pubmed.ncbi.nlm.nih.gov/28340339/

Erwotex.net

What are Senolytics?

The relationship between senescence and aging

Targeting senescent cells

The benefits of senolytics

References

Further Reading

Michael Greenwood