Blocking RANKL, a signal that tells cells to break down bone, extended lifespan in mice with a genetic model of accelerated aging

Blocking RANKL, a signal that tells cells to break down bone, extended lifespan in mice with a genetic model of accelerated aging

On August 9, Aging Cell published a study of mice with a genetic model of accelerated aging. These mice lack ZMPSTE24, an enzyme involved in the maturation of the protein prelamin A. They rapidly lose bone mass, develop muscle weakness, and have shorter lives. The authors suppressed RANKL in two ways. Both interventions improved bone and muscle health and extended the animals' lives.

Bone tissue is continuously remodeled. Osteocytes, cells embedded within bone, release RANKL, a protein signal that activates osteoclasts, the cells that break down old bone. Other cells then build new bone. Mice with ZMPSTE24 deficiency rapidly lose bone mass and develop muscle weakness. Fibrosis also accumulates in their muscles. This scar tissue interferes with muscle contraction. The mice also have shorter lives.

The authors selectively disabled RANKL in the osteocytes of these mice. Imaging showed better preservation of bone structure in the lower leg and vertebrae. The mice had greater grip strength, ran longer on a treadmill before reaching exhaustion, and had less fibrosis in the quadriceps.

In the genetic experiment, median lifespan increased from 230 to 276 days. When the authors analyzed the results by sex, the increase in lifespan was especially apparent in females.

In the second experiment, the researchers suppressed RANKL with an antibody. Starting at eight weeks of age, 33 mice received the antibody twice a week. A control group of 31 animals received an antibody that does not act on RANKL. The RANKL antibody again improved measures of bone health, reduced muscle fibrosis, and extended the animals' lives.