An immune sentinel that briefly loses vigilance, then goes back to hunting down senescent cells. That is one way to describe what happens in the bodies of mice after a short course of an antibody against GD3. At 18 months, when the animals had already accumulated age-related changes, they received this antibody for three months. It binds to the GD3 molecule on the surface of senescent cells, which helps them hide from the immune system. After the course, the sentinel sees the offenders again and eliminates them.
The effect turned out to be astonishingly long-lasting. In males, 75th-percentile survival rose by 105%, and frailty remained reduced for more than a year after treatment ended. Death from non-cancer causes was delayed by about 200 days. In females, median survival barely changed, but death from tumors was delayed by almost 200 days, even though the frequency and spectrum of tumors did not change. This means the immune system became better at holding back tumor growth, but not at preventing tumors from arising.
Before this work, it was unknown whether a short course of immunotherapy against GD3 in middle age could provide long-term protection against age-related diseases, and how the effect differs between males and females. Now it is clear that a three-month course improves health and survival, protecting males from non-cancer deaths through innate immunity and females from cancer deaths through adaptive immunity. Comparison with a control group and with the classical senolytic D+Q, along with observation until natural death and correlation of survival with histology and the transcriptome, made this possible to establish. Even today, this is a rationale for preclinical trials of anti-GD3 as a prevention of age-related pathologies, especially with sex taken into account.
The sentinel is back on duty. A short intervention in the immune system in middle age changes the trajectory of aging, but differently in males and females. Perhaps in the future other immune checkpoints will emerge that can be temporarily blocked to restore the body's ability to clear out senescent cells.
In female mice, after anti-GD3 was stopped, GD3 levels in the lungs returned to baseline, while in males they remained reduced, as if immune memory persists longer in males.
In Douglas Adams's novel The Hitchhiker's Guide to the Galaxy, people seek a way to extend life but encounter unexpected side effects. Here the idea is similar: a short intervention in the immune system in middle age changes the trajectory of aging, but differently in men and women.
Not published on arXiv. Here are its page, the PDF and the formalization: you can check it yourself, not only read our account.