Kick Cellular Senescence to the Curb: Activating Senescent Cell Surveillance System May Help Fight Obesity and Age-Related Disease

“Zombie Cells That Forgot to Die” — although this may sound like the premise of a new low-budget sci-fi movie, these ‘walking dead’ cells are a regular occurrence in the human body, with more accumulating from older age, stress, or chronic disease. Also known as senescent cells, these dysfunctional zombie-like cells undergo irreversible growth arrest but remain in the body, leaving a trail of inflammatory cellular debris in their wake. 

Although many studies have tested the use of senolytics — drugs or chemicals that remove senescent cells from the body — these compounds tend not to have specific targets, leading to accidental clearance of non-senescent cells and increasing the risk of toxic side effects. A new paper authored by Arora and colleagues aimed to circumvent this issue by boosting our body’s internal ability to clear senescent cells, rather than relying on an outside compound to do the job. Published recently in the journal Med, this UC San Francisco-based research team uses a fat-based molecule to activate a specific type of immune cell called invariant natural killer T cells (iNKT), providing a targeted approach to clearing out senescent cells. 

As iNKT cells have a natural ability to sense DNA damage, they can sniff out senescent cells and eliminate them, providing us with an internal senescence surveillance system. However, iNKT cells decline in both quantity and quality with age, allowing senescent cells to accumulate more rapidly and contribute to disease. With this groundbreaking study, Arora and colleagues show how stimulating this natural defense system can clear senescent cells without the potential side effects of senolytic drugs — and with it, opening new doors for immunotherapy-based treatment of both aging and age-related chronic diseases.

Seeking Cellular Senescence Surveillance

Besides their natural occurrence in the body, iNKT cells also have two characteristics that appealed to Arora and colleagues for their use in clearing senescent cells. First, iNKT cells all have the same unique receptor — this means that they can be specifically targeted and activated without triggering other cells’ activation. As corresponding author Anil Bhushan, Ph.D., puts it, "Using iNKT-targeted therapy can piggyback on their exquisite, built-in specificity." The second beneficial attribute of iNKT cells is that they are short-lived, leading them to return to dormancy after a period of activity. This ensures that they don’t kill off cells in an indefinite and unchecked manner.

To start, Arora and colleagues looked for specific tissues that exhibited an accumulation of senescent cells, finding an abundance of the zombie-like cells in the fat cells of mice. As obesity can also trigger a decline in iNKT activity that is similar to what occurs with older age, the research team used a model of obese mice to test senescent cell clearance, using a lipid-based compound called alpha-galactosylceramide (αGalCer) to activate the iNKT cells. 

iNKT cells act as an internal surveillance system for finding and eliminating senescent cells.

Killing Off Zombie Cells to Kickstart Health

The UCSF team treated obese mice with αGalCer to see if iNKT cell activation could regulate their senescent cell accumulation. As expected, mice with diet-induced obesity displayed significantly more senescent cells in their fat tissue than lean mice. After treatment with αGalCer, these senescent cells were effectively depleted, indicating that this lipid compound boosts iNKT cell activity and their senescence-surveillance abilities.

The obese mice treated with iNKT-activating αGalCer also had significantly improved metabolic markers, including better glucose tolerance, lower fasting glucose, and improved insulin sensitivity. This indicates that not only does iNKT activation clear senescent cells, but it also may prove therapeutic for metabolic-related diseases, including obesity and type 2 diabetes. 

Lastly, Arora and colleagues tested iNKT activation in mice with idiopathic pulmonary fibrosis (IPF), a chronic and fatal disease that causes scarring and dysfunction of the lungs. They found that activating iNKT cells in these mice successfully eliminated their senescent cell accumulation, reduced fibrosis in the lungs, and improved their survival rates. As IPF has a poor prognosis, with the average survival being only a few years, the ability to increase lifespan through senescent cell clearance could prove invaluable to the 100,000 people afflicted with this disease worldwide.

Thinking About the Future of iNKT-ing

The unique specificity of iNKT cell activation by the lipid-based molecule αGalCer introduces a novel approach for clearing cellular senescence. With these results, Arora and colleagues pave the way for using new immunotherapies to treat age-related diseases related to senescent cell buildup — and possibly for treating aging itself. Preliminary clinical studies have found that αGalCer is a well-tolerated treatment with minimal side effects, providing a safer option than many senolytic cocktail treatments currently being tested in longevity research. 

However, we’ll have to wait and see if these impressive results translate to humans. Senior author Dr. Bhushan has recently co-founded a company called Deciduous Therapeutics, with the hopes to begin clinical trials involving iNKT activation in the next few years and translate these preliminary findings into real-life therapies for people with age- or senescence-related diseases. As summarized by the authors, “Our results provide the first evidence that iNKT cells can eliminate senescent cells in these two distinct models [obesity and IPF] where tissue dysfunction is dependent on the accumulation of senescent cells.” 

References: 

Arora S, Thompson PJ, Wang Y, Bhattacharyya A, Apostolopoulou H, et al. Invariant natural killer T cells coordinate removal of senescent cells. Med (2021). https://doi.org/10.1016/j.medj.2021.04.014