Nature: Immunotherapy may fight aging!

There is a group of "old but immortal" cells in our body, namely senescence cells that have a unique phenotype, i.e. they are not productive but also refuse to "give way", not only preventing tissue regeneration, but also releasing various pro-inflammatory factors that may lead to chronic inflammation. There is a discipline that explores the "treatment of aging" by removing senescent cells with drugs called senolytics.

Senescent cells accumulate in the organism as we age. But why doesn't our body actively remove them?

A recent paper published in the journal Nature proposes an answer. Researchers from the University of Tokyo found that it turns out that senescent cells actually actively express PD-L1 as a way to escape the desperate pursuit of T cells. When aging mice were treated with anti-PD-1 antibodies, the researchers found that their aging phenotype was surprisingly significantly improved.

For a long time, scientists have speculated about senescent cells refusing to "retire". Previous research has found that genetically induced senescent stem cells can be killed by activated T and NK cells, implying that the immune system is to blame. After all, the immune system is already in charge of monitoring cells that are "out-of-range", and cancer cells have learned to avoid immune cells via immune checkpoints, a formula that appears to be very applicable to senescent cells.

Researchers labeled mice with the fluorescent protein p16, a marker of senescent cells, and analyzed it, finding that senescent mice had significantly more senescent cells and a higher percentage of senescent cells expressing PD-L1 in 24-26 month-old senescent mice and 2-month-old young mice.

Further investigation revealed that PD-L1 expression was slightly increased in senescent cells as a result of transcriptional regulator changes. Furthermore, PD-L1-expressing senescent cells had lower levels of rennin-like protease, trypsin-like protease, and cysteine-like protease, indicating that PD-L1 degradation was also reduced. Originally, the pro-inflammatory factors secreted by senescent cells and their intrinsic antigen presentation are signals for T cells to come to work, but with PD-L1 in the mix, it is no wonder that they are "immortal".

Since senescent cells express PD-L1, can immunotherapy also play a part in removing senescent cells?

Aging mice exhibit significant aging phenomena such as age-dependent increase in alveolar volume, increased hepatic lipids, decreased grip strength, and decreased locomotor activity. When researchers treated 17.5-month-old senescent mice with anti-PD-1 antibodies, they found significant improvements in these manifestations, while no such phenomena were observed in 3-month-old young mice.

Senescent cells play an important role in the pathogenesis of nonalcoholic steatohepatitis (NASH), so the researchers also tried anti-PD-1 antibodies on NASH mice. These mice were fed a choline-deficient, L-amino acid-based high-fat diet (CDA-HFD), which quickly induced NASH in the mice, with significant increases in liver lipid droplets and fibrosis, as well as elevated serum glutamate transaminase (ALT), aspartate transaminase (AST), and lactate dehydrogenase (LDH) levels.

Mice treated with an anti-PD-1 antibody improved in all indicators, including body weight and total cholesterol levels, with surprisingly similar effects to the senolytics drug ABT263, and even slightly better effects on liver steatosis. This suggests that removing PD-L1-expressing senescent cells may increase LDL secretion in the liver and decrease lipid accumulation during NASH progression.

However, it is important to note that immunotherapy must have some long-term safety concerns, such as triggering autoimmune diseases. Removal of senescent cells may also pose risks. To avoid such issues, treatment protocols must be continually optimized, with a good balance of immune clearance, inflammatory tolerance, and tissue repair.