Zoledronate altered aging-related markers in the blood of women and the tissues of old mice
Zoledronate altered aging-related markers in the blood of women and the tissues of old mice
Zoledronate has been used for decades to prevent bone loss. In a new study, researchers measured changes in the blood of women, in the heart, liver, and intestine of old mice, and in human cells. They examined how the drug might affect cells outside the skeleton.
Bisphosphonates inhibit osteoclasts, the cells that break down bone tissue. Zoledronate was long considered a drug that acts almost entirely within the skeleton. However, clinical trials and patient observations raised another question: does it reach other tissues and alter processes associated with aging?
On 15 July, a study by a University of Oxford team reported evidence at three levels. The researchers examined plasma, the liquid component of blood, from 36 women over 65 years of age who had osteopenia, which is reduced bone density. At 18 and 36 months after an infusion of 5 mg zoledronate, about 400 of the five thousand measured proteins had changed. Some of these changes involved proteins associated with DNA damage, mitochondrial dysfunction, and inflammatory substances released by senescent cells.
Plasma provides evidence of the drug's activity, not a count of senescent cells. A recent review of human trials made a similar distinction: inflammatory proteins in the blood usually change more noticeably than direct markers of senescent cell accumulation in tissue. This human part of the study therefore identifies a measurable signal, but it does not show whether the body became younger.
The researchers gave zoledronate to six old mice for two months, then compared their organs with those of untreated mice of the same age and young animals. Gene activity changed in the heart, liver, and intestine, while estimates of cellular composition shifted toward the profile seen in young mice. The study connects the signal observed in human blood with specific tissues in which it can be investigated further.
The search for a mechanism led to heart cells. Labeled zoledronate entered heart, liver, and kidney cells. Low concentrations of zoledronate reduced cellular senescence after DNA damage. The researchers identified a pathway involving PHB2, a protein that helps maintain mitochondrial stability, and MEF2A, a regulator of heart cell function. When the researchers disabled MEF2A, the protective effect of zoledronate almost disappeared.
After a standard infusion, zoledronate rapidly binds to bone, and the kidneys then clear the remaining drug. In cell experiments, the effect appeared at a low, constant concentration that this dosing regimen does not reliably produce outside the skeleton. The next trial should assess zoledronate delivery to tissues, its safety, and its effects on organ function in humans. The current study provides specific cells, proteins, and measurement methods for that work.