Zoledronic acid, a medication known for reducing fracture risk, has shown potential benefits beyond skeletal health. Some studies indicate that it can decrease mortality in humans and extend both lifespan and health span in animals. These additional effects may be attributed to its actions on senescent cells, which accumulate with ageing and contribute to various age-related conditions.
To investigate this further, the researchers conducted in vitro senescence assays using human lung fibroblasts and DNA repair-deficient mouse embryonic fibroblasts. The results revealed that zoledronic acid effectively killed senescent cells while having minimal impact on non-senescent cells. Encouraged by these findings, they proceeded to an animal study involving aged mice. The mice were treated with zoledronic acid or a control substance for 8 weeks. The researchers observed that zoledronic acid significantly reduced the levels of senescence-associated secretory phenotype (SASP) factors circulating in the mice, including CCL7, IL-1β, TNFRSF1A, and TGFβ1. Moreover, the grip strength of the mice improved, indicating enhanced physical function.
To delve deeper into the mechanisms of action, the researchers analysed publicly available RNAseq data and identified downregulation of senescence/SASP genes in CD115+ pre-osteoclastic cells isolated from mice treated with zoledronic acid. They further utilised single-cell proteomic analysis (cytometry by time of flight [CyTOF]) and found that zoledronic acid significantly reduced the number of these pre-osteoclastic cells and decreased the levels of p16, p21, and SASP markers without affecting other immune cell populations.
Collectively, the findings demonstrate that zoledronic acid exhibits senolytic effects in vitro, effectively eliminating senescent cells, and modulates senescence/SASP biomarkers in vivo. These results highlight the potential of zoledronic acid and other bisphosphonate derivatives as senotherapeutic agents. The study suggests the importance of conducting further research to explore the senotherapeutic efficacy of zoledronic acid and its potential applications in treating age-related conditions.
Investigating the effects of zoledronic acid on ageing markers: In-depth analysis in cellular and animal models
Here are our key takeaways from the article: In vitro and in vivo effects of zoledronic acid on senescence and senescence-associated secretory phenotype markers
Potential benefits: Zoledronic acid beyond fracture risk reduction
Zoledronic acid is a drug commonly prescribed to treat osteoporosis, a condition characterised by weak and brittle bones. However, recent studies indicate that this medication may have additional advantages beyond just preventing fractures. Researchers have found that zoledronic acid could potentially have positive effects on overall health and longevity. In experiments conducted on animals and humans, it has been associated with decreased mortality rates, extended lifespan, and improved health span (the period of life spent in good health).
Mechanisms: Senolytic and senomorphic effects of zoledronic acid
Ageing is a natural process that increases the risk of developing various health problems. As we age, we become more susceptible to issues like muscle loss, heart disease, cognitive disorders, and arthritis. These problems are often linked to the process of ageing itself. Scientists believe that by understanding the underlying mechanisms of ageing, such as cellular senescence (a state where cells become aged and dysfunctional), it might be possible to delay or even alleviate these age-related diseases.
Lab experiments: Zoledronic acid’s impact on senescent cells
Zoledronic acid has been found to possess the ability to kill senescent cells or inhibit the secretion of certain substances released by these cells. Senescent cells are cells that have entered a state of ageing and are no longer functioning optimally. They can produce harmful factors known as the senescence-associated secretory phenotype (SASP) that contribute to inflammation and the development of age-related diseases. In laboratory experiments conducted on human and mouse cells, zoledronic acid effectively targeted and eliminated senescent cells while sparing healthy cells.
Aged mice: Effects of zoledronic acid on SASP factors and grip strength
In studies involving aged mice, the administration of zoledronic acid resulted in several positive outcomes. It led to a decrease in the levels of circulating SASP factors, which are the harmful substances released by senescent cells. This reduction in SASP factors is beneficial because it helps reduce inflammation and its associated damage. Additionally, the treatment improved grip strength, which is an indicator of muscle function and overall vitality. Furthermore, zoledronic acid downregulated senescence/SASP genes in a type of bone cell called pre-osteoclastic cells.
Targeted cells: Zoledronic acid’s specific effects on CSF1R-expressing cells
Zoledronic acid specifically targeted a particular type of immune cell called myeloid cells that express a protein called CSF1R (also known as CD115+). By targeting these cells, the drug was able to reduce the expression of senescence/SASP markers, further suppressing the harmful effects of senescent cells. Moreover, in laboratory experiments, zoledronic acid also demonstrated senolytic effects on senescent mesenchymal cells, which are a different type of cell involved in tissue repair and maintenance.
Based on these findings, scientists believe that zoledronic acid possesses senolytic effects, meaning it can eliminate senescent cells, and it can modulate senescence/SASP biomarkers. This suggests that it has the potential to be used as a senotherapeutic (a therapy targeting ageing-related processes) for age-related diseases. However, further research is still needed to explore its effects in different tissues and populations to fully understand its potential benefits.
Reference: Samakkarnthai P, Saul D, Zhang L, Aversa Z, Doolittle ML, Sfeir JG, Kaur J, Atkinson EJ, Edwards JR, Russell GG, Pignolo RJ, Kirkland JL, Tchkonia T, et al, . In vitro and in vivo effects of zoledronic acid on senescence and senescence-associated secretory phenotype markers. Aging (Albany NY). 2023 May 7; 15:3331-3355 . https://doi.org/10.18632/aging.204701