Fight Aging!

PD-L1 and PD-L2 are components of immune checkpoints, widely expressed in tissues throughout the body. They act by binding to the PD-1 receptor on immune cells to suppress immune activation, and are part of the panoply of biochemical interactions that provide self-tolerance to prevent the immune system from inappropriately attacking healthy cells. Autoimmunity is a breakdown of these mechanisms. Cancerous cells abuse the strategies by which normal somatic cells are shielded from immune cell attention, and thus most research into immune checkpoints has taken place in the cancer research community. Inhibition of checkpoint interactions to unleash the immune system now forms the foundation for a number of cancer therapies, albeit that most work has focused on PD-1 and PD-L1 rather than on PD-L2.

In today's open access paper, researchers show that PD-L2 is generated by senescent cells in aged tissues, allowing these cells to shield themselves from the immune system. In youth senescent cells are generated constantly, in response to stress, damage, or cells reaching the Hayflick limit on replication. Senescent cells secrete inflammatory signals that attract the immune system, and are promptly destroyed after serving this purpose. Senescence helps reduce cancer risk, and is involved in the coordination of wound healing. Clearance of senescent cells becomes inefficient with age, however, and a growing population of lingering senescent cells contributes to chronic inflammation. It seems that PD-L2 contributes to this growing burden of senescent cells in later life.

PD-L2 inhibition seems a plausible basis for senolytic therapies that allow the immune system to destroy senescent cells. It seems likely that many of the same caveats apply here as for the use of checkpoint inhibitors in cancer therapy. Broad checkpoint inhibition can cause meaningful damage to normal tissues, as immune checkpoints do serve a useful, necessary purpose in the regulation of immune activity. Checkpoint inhibition is one of the many classes of therapy that can become a great deal safer, more effective, and more useful when narrowly targeted to specific cells. There are now ways to do this for senescent cells, such as PROTACs that only activate inside senescent cells, so it will be interesting to see what emerges from this line of research.

Blocking a Protein May Reduce Buildup of Harmful Aging Cells

A team has identified a protein that may hide aging cells from the body's immune system, allowing them to build up and contribute to age-related health problems. The findings suggest that the protein, called PD-L2, could serve as a target for treatments designed to remove harmful aging cells or as a blood marker that helps researchers track them. These harmful aging cells, called senescent cells, become damaged and stop dividing but do not die. The cells remain in tissues and release substances that promote inflammation and interfere with the function of nearby cells. Their buildup has been linked to age-related health problems.

Investigators found that in laboratory mice, removing or blocking PD-L2 reduced the number of aging cells and levels of the inflammatory substances they produce. The mice were better able to process sugar and could grip objects with greater strength. Investigators also found that human aging cells produced more PD-L2 than younger cells, and levels of the protein increased in some human tissues with age. "If we can find a way to block this protein, we may be able to help the immune system get rid of these cells and potentially improve health problems linked with aging."

Blocking PD-L2 prevents senescent cell accumulation and age-related dysfunction

Senescent cells, which are normally cleared by the immune system but accumulate with age, contribute to multiple disorders including metabolic dysfunction and impaired fitness. While immune checkpoint inhibitors have been well studied in cancer, the role of programmed cell death ligand 2 (PD-L2) in non-cancerous, age-associated cellular senescence remains unclear. We found that PD-L2 is upregulated in isolated senescent human cells and during aging, and senolytics can remove age-associated, highly PD-L2-expressing senescent cells. Old PD-L2 knockout mice accumulate fewer senescent cells than old wild-type mice, and their insulin sensitivity and grip strength are greater. Anti-PD-L2 therapy restored insulin sensitivity in aged wild-type mice. PD-L2 acts as an immune checkpoint on senescent cells, allowing them to evade immune clearance and promoting their persistence during aging. Targeting PD-L2 in senescent cells may be a strategy for alleviating the age-related dysfunction associated with cellular senescence.