Senolytic Agents

Senolytic agents are a promising class of drugs designed to selectively eliminate senescent cells (SnCs), which are cells that have stopped dividing but remain metabolically active and secrete harmful factors. These agents aim to address age-related diseases and functional decline by targeting cellular senescence, a key contributor to aging.

The Role of Cellular Senescence in Aging

Cellular senescence is characterised by irreversible cell cycle arrest, resistance to apoptosis, increased metabolic activity, and a senescence-associated secretory phenotype (SASP). The SASP involves the secretion of pro-inflammatory molecules that cause chronic inflammation and tissue dysfunction. Senescent cells accumulate with age and contribute to various age-related conditions, including metabolic dysfunction, osteoporosis, neurodegenerative diseases, and cardiovascular issues.

Mechanisms and Development of Senolytics

Senolytics work by inducing apoptosis in senescent cells, often by targeting anti-apoptotic pathways that these cells rely on for survival. For example, dasatinib and quercetin, one of the first identified senolytic combinations, target kinase pathways and PI3Ks/serpins. Other senolytics include navitoclax, a BCL-2 family inhibitor, and fisetin, a naturally occurring flavonoid.

Many senolytics are repurposed cancer therapies, while others are specifically designed or derived from natural compounds. The development of senolytics has expanded to include inhibitors of various survival pathways, addressing the heterogeneity of senescent cells.

Potential Applications and Challenges

Senolytics have shown potential in preclinical studies for treating age-related diseases such as pulmonary fibrosis, diabetic kidney disease, and osteoarthritis. They may also enhance immune function in older individuals by clearing senescent immune cells.

However, challenges remain, including the risk of off-target effects, tissue atrophy, and the potential loss of beneficial senescent cell functions, such as wound healing and tumor suppression. Additionally, the lack of specific markers for senescent cells complicates precise targeting.

Future Directions

Ongoing research focuses on optimising senolytics through medicinal chemistry, prodrug development, and PROTAC technology. Clinical trials are investigating senolytics for various conditions, with early results showing promise in reducing senescence markers. Large-scale, rigorous trials are needed to confirm efficacy and safety, particularly in human subjects.

Senolytic agents represent a groundbreaking approach to combating aging and age-related diseases, offering hope for extending healthy lifespans and improving quality of life in old age.