Preprint: immune aging in beagles follows different trajectories in males and females, with rapamycin, canagliflozin, and caloric restriction tested in a separate young cohort
Preprint: immune aging in beagles follows different trajectories in males and females, with rapamycin, canagliflozin, and caloric restriction tested in a separate young cohort
On September 15, a group from the Southern University of Science and Technology in Shenzhen and collaborators posted a bioRxiv preprint: in 80 intact (non-neutered) laboratory beagles aged 1 to 11 years, the age-related remodeling of the immune system turned out to depend strongly on sex. In a separate group of 24 young beagles, the same authors compared early immune signatures of three geroprotectors over 90 days: rapamycin, canagliflozin, and caloric restriction.
Dogs are considered a convenient model for human aging: they share the living environment and age-related diseases of their owners, yet age several times faster, so the effect of an intervention becomes visible in years rather than decades. However, nearly all companion dogs are neutered, and sex hormones are among the principal regulators of immune cell function; in such a cohort, natural sex differences are blurred. The authors assembled a rare sample of intact laboratory beagles and tracked how blood parameters and cytokines change from age 1 to 11 separately in males and females.
White blood cell counts declined with age in roughly the same way in both sexes, but in the oldest, geriatric group some parameters rose again, indicating that blood aging does not follow a straight line. Far sharper divergence appeared in cytokines, the proteins immune cells use to signal inflammation: in males, 9 out of 40 cytokines changed significantly with age, most rising toward old age and falling again in deep old age; in females, only two of the same 40 shifted. The same sex dependence seen in cytokines also appeared in several red blood cell parameters, hemoglobin among them, while total white blood cell count showed no such pattern. The classical model of immunosenescence describes it as a single linear process, uniform across individuals; in these data it effectively split into two distinct curves depending on sex. In humans, immune aging has likewise turned out to be more heritable in men than in women.
Since immune aging diverged so markedly by sex, the authors tested whether the same holds for drugs: a separate group of 24 young beagles received one of three compounds for 90 days. Rapamycin, the most reproducible geroprotector in mice and already being tested in middle-aged dogs in the TRIAD trial, produced the broadest response: white blood cell and neutrophil counts rose, GM-CSF, IL-10, MCP-1, and TNF-α decreased, but four other cytokines increased. The immune system was being remodeled in both directions simultaneously, with some inflammatory signals dampened and others amplified.
Canagliflozin, a diabetes drug, was chosen deliberately: in mouse experiments it extended lifespan in males by 14% but had no effect in females, making it a ready-made probe for sex differences. In males, body weight began to drop in the first month; in females, only in the second. The blood and cytokine response was weaker than with rapamycin, although each group contained only three dogs per sex, so the conclusion about a sex-specific effect remains preliminary. Caloric restriction reduced body weight but produced no detectable change in blood parameters or cytokines over 90 days: in young healthy animals, the immune signature of dietary restriction apparently takes years rather than months to emerge. Caloric restriction extends lifespan even without such a signature, as shown in the classic study of Labrador Retrievers in which one dog in each pair received a quarter less food than the other for its entire life and ultimately lived longer.
The authors themselves describe these 90-day shifts as an early signature for future geroprotector trials in dogs that account for sex: what works in males may go undetected in females, and the reverse may be equally true.