Immunotherapy rejuvenates the lungs and shows a new way to eliminate aged cells

One of the main drivers of aging is the accumulation of aged cells in tissues. For reasons not entirely understood, with age, the body accumulates senescent cells that do not die, and that benefit one of the suspected culprits behind the body’s deterioration over the years: inflammation. Now, a team led by Harvard University researcher David Lagares has found a possible way to reverse this process in the lungs, one of the organs whose cells deteriorate over time and can lead to diseases such as fibrosis, an incurable condition that primarily affects people over 65.

Lagares’ team has focused on the immune system’s inability to eliminate senescent lung cells in old age. The scientists have turned to immunotherapy, a cancer treatment that stimulates the immune system to regain its ability to detect and eliminate tumor cells.

In this case, they have focused on a treatment that re-educates a type of immune system cell with a rather unsettling name: natural killer cells. These cells, along with lymphocytes and other immune components, are responsible for detecting and eliminating damaged or aged cells in different tissues, which can lead to inflammation and disease. Aged lung cells cause fibrosis, a disease that affects approximately three million people worldwide, and whose basic mechanism is also linked to other conditions, such as rheumatoid arthritis, and even lung damage associated with poor recovery from COVID-19.

The study shows in mice that an experimental drug known as monalizumab re-educates natural killer cells to eliminate senescent cells that accumulate in the lungs. This approach has partially reversed fibrosis in the animals. It has also been shown in experiments with cells from fibrosis patients to eliminate the aged cells responsible for the disease. The results were published this Wednesday in the journal Science Translational Medicine.

Beyond pulmonary fibrosis, this work demonstrates a way to eliminate aged cells and restore the body’s natural regenerative mechanisms. It is a step toward therapies capable of directly intervening in the biological processes of aging, the authors emphasize.

Immunotherapy, which has made tumors that were once practically a death sentence curable, is based on so-called checkpoints, molecules that allow the immune system to identify and destroy tumor cells. David Lagares explains that this approach could be useful not only against pulmonary fibrosis. “Our data point to a central idea: where the immune system has stopped eliminating aged cells, the HLA-E/NKG2A checkpoint could be operating as an evasion mechanism. Blocking it with immunotherapy could restore the immune system’s ability, particularly that of natural killer cells, to eliminate senescent fibroblasts,” he reasons. “If this mechanism is as universal as our data suggest, monalizumab could represent more than just a treatment for pulmonary fibrosis: a therapeutic platform against the pathological aging of tissues. A new type of immunotherapy to rejuvenate organs,” he adds.

In addition to fibrosis, other conditions are triggered by the accumulation of aged cells that cause inflammation and damage. These include rheumatoid arthritis, scleroderma with pulmonary fibrosis, post-COVID fibrosis, COPD, and radiation-induced pulmonary fibrosis in cancer survivors.

Monalizumab is an antibody developed by two pharmaceutical companies, Innate Pharma and AstraZeneca, that is in clinical trials as an experimental therapy against several types of cancer. It works in the same way as PD-1 inhibitors in immunotherapy: by releasing the brake that prevents the immune system from attacking tumor cells.

Lagares’ team, which has no connection to the drug’s developers, is exploring ways to take the research to the next level with the aim of eventually making it available to patients.

Pura Muñoz, vice president of Altos Labs, a company that researches anti-aging treatments, offers her opinion on the study, in which she was not involved. “Current medications for pulmonary fibrosis only slow the disease. In this study, a reversal of pulmonary fibrosis is observed for the first time in experimental models. This research is important because it suggests that restarting the body’s own immune response could allow pulmonary fibrosis to go into remission in patients, and therefore improve their health,” she explains in an email.

“Since several age-related diseases that affect important tissues such as the heart, skeletal muscle, or kidneys involve cycles of damage and failed repair, inflammation, and the presence of senescent cells that promote fibrosis, this work could have implications for improving the functionality of other organs, beyond the lungs,” she ventures.

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