Senolytics are a class of molecules under investigation for their ability to selectively eliminate aging cells from the body. Researchers are exploring if these agents can improve human health by targeting cells that accumulate with age. The goal is to develop compounds that could potentially delay, prevent, alleviate, or reverse age-related diseases.
The Function of Senescent Cells
Cells that stop dividing but do not die are known as senescent cells, often called “zombie cells.” These cells accumulate with age and in response to stress or damage, resisting the body’s natural process of programmed cell death, or apoptosis. While senescence can initially serve a protective role, such as preventing damaged cells from becoming cancerous or aiding in wound healing, their prolonged presence can cause harm.
The negative impact of senescent cells stems from their release of molecules called the Senescence-Associated Secretory Phenotype (SASP). This SASP includes pro-inflammatory cytokines, chemokines, and other factors that create a harmful environment in surrounding tissues. This chronic inflammation can disrupt tissue function, accelerate aging processes, and contribute to various age-related conditions, including those affecting the skin by breaking down collagen and reducing elasticity.
Mechanism of Senolytic Action
Senolytics function by selectively inducing apoptosis in senescent cells while generally sparing healthy cells. Senescent cells uniquely develop resistance to apoptosis, partly due to their inflammatory SASP. They achieve this resistance by upregulating specific pro-survival pathways, which healthy cells do not rely on to the same extent.
These pro-survival pathways include networks related to PI3K/AKT, p53/p21, dependence receptor/tyrosine kinases, and BCL-2/BCL-Xl. Senolytics are designed to temporarily disable these pathways, rendering senescent cells vulnerable to their own pro-apoptotic environment. By targeting these vulnerabilities, senolytics can trigger the self-destruction of these “zombie cells” without broadly affecting the body’s healthy cellular population.
Known Senolytic Compounds
Several compounds have been identified and studied for their senolytic properties. These agents vary in their origin and the specific pro-survival pathways they target within senescent cells. The aim is to find compounds that selectively eliminate these cells with minimal impact on healthy tissues.
One of the most widely studied senolytic combinations is Dasatinib plus Quercetin (D+Q). Dasatinib is a synthetic tyrosine kinase inhibitor, approved for clinical use since 2006. Quercetin is a natural flavonoid found in various fruits and vegetables. When used together, D+Q clears senescent cells more efficiently than either compound alone by targeting multiple survival pathways.
Fisetin is another natural senolytic, belonging to the flavonoid group of polyphenols. It is found in strawberries, apples, onions, and cucumbers. Fisetin has demonstrated senolytic activity in laboratory and animal studies, inducing apoptotic cell death in senescent cells.
Luteolin is also a natural flavonoid that has shown potential in modulating inflammatory processes. It has been investigated for its ability to decrease adverse photobiological effects. While its senolytic activity may vary, it is recognized for its capacity to reduce the accumulation of senescent cells and lessen the release of SASP.
Current Research and Health Implications
Current scientific investigation into senolytics is primarily in preclinical animal models, particularly mice. These studies have shown promising results, including improvements in cardiac function, reduced dementia, fewer cataracts, and decreased muscle loss, with some studies suggesting an extension of lifespan by as much as 27 percent. However, results from animal studies do not always translate directly to humans.
Human trials of senolytics are still in early stages, often focused on specific age-related diseases rather than general anti-aging. Conditions under investigation include idiopathic pulmonary fibrosis, diabetic kidney disease, osteoarthritis, and COVID-19. For instance, an early pilot study involving 14 patients with idiopathic pulmonary fibrosis showed some improvements in physical function after receiving senolytics, though this study lacked a control group.
Observed side effects in human studies have generally been mild to moderate. These have included temporary respiratory symptoms like cough and shortness of breath, as well as gastrointestinal discomfort or heartburn. Researchers caution against using senolytic agents outside of clinical trials until more is known about their effects and potential side effects in humans.