Senolytics Restore Bone Healing Capacity in Older Age

Scientists find that old mice treated with the senolytics dasatinib plus quercetin (D+Q) heal from bone fractures like young mice.

Key Points:

Senescent cells – cells that underlie many age-related diseases – populate in response to bone fracture in aged mice.
Senolytic treatment – which eliminates senescent cells – leads to accelerated healing at the wound site.
Treatment with senolytics restores the stem cell and bone growth squandered by senescent cells.

In the case of tissues like bone and muscle, our bodies have the remarkable capability of regenerating. But when it comes to aging, this capability is limited. And while our risk of severe bone fracture increases with age, our ability to heal decreases. Now, based on a new study published in The Journal of Clinical Investigation, it is now becoming more clear that senescent cells (stress-induced, growth-arrested cells that accumulate with aging) hinder this healing process.

Liu and colleagues from the University of Rochester in collaboration with researchers in China compared the bone healing time of young and old mice in response to limb fractures. They found that aged mice had more senescent cells within the healing fracture. However, these senescent cells were reduced in number by D+Q treatment. D+Q treatment also increased the stiffness, strength, and toughness of the healing aged bone. Additionally, senescent cells were shown to reduce bone growth, which could be restored by D+Q treatment. Furthermore, stem cells responsible for bone regeneration were hindered in aged mice but could be recovered by D+Q.

“Senolytic drugs represent a promising therapy for enhancing fracture repair in the elderly by eliminating SCs, which delay fracture repair by expressing TGF-β1, which we have identified as a molecular inhibitor of repair,” the investigators wrote.

Senolytics Enhance Fracture Healing

Liu and colleagues found that aged, 20-month-old mice (about 65 years old in human years) had more senescent cells than younger, 4-month-old mice (about 26 in human years) in healing bone tissue. Treating the mice with D+Q enhanced fracture healing and reduced the activation of senescent genes in the callus (a bony bridge formed over the fracture during recovery). The treatment helped increase cartilage, new bone area, and bone strength in the old mice.

(Liu, et al., 2022 | *The Journal of Clinical Investigation*) **D+Q Reduces Senescent Cells and Enhances Bone Healing.** Young mice treated with senolytics (Young-D+Q – magenta triangles) were mostly unaffected by the treatment, while aged mice treated with senolytics (Aged-D+Q – red circles) saw significantly decreased senescent cells (p16) and increased bone stiffness, bone strength, and bone toughness compared to untreated aged mice (Aged-V – blue circles).

Stem cells can multiply (proliferate) and transform into numerous cell types. They are necessary for generating and repairing muscle and bone tissue. Liu and colleagues found that senescent cells in the callus of aged mice prevent the proliferation of stem cells. They showed that senescent cells reduce bone growth, but could be restored by D+Q treatment. Furthermore, the reduction in stem cells observed in aged bone was recovered by D+Q treatment. These findings demonstrate that D+Q aids in the bone fracture repair process by eliminating senescent cells and recovering stem cell proliferation, allowing for bone regeneration.

(Liu, et al., 2022 | *The Journal of Clinical Investigation*) **D+Q Restores Bone Growth and Recovers Stem Cells.** E) The left image shows callus containing petri dishes: One dish with no treatment (Veh), one containing hydrogen peroxide (H₂O₂) to induce senescent cells, and one containing H₂O₂ and treated with D+Q (H₂O₂+ D+Q). The right graph shows that D+Q restored the reduction in bone growth caused by H₂O₂/senescent cells. G) Stem cells were reduced in untreated aged bone (blue), but recovered by D+Q treatment (red).

Senolytics for Wound Healing in the Elderly

Liu and his fellow scientists show how short-term use of D+Q may help facilitate fracture healing in the elderly by decreasing senescent cells. A previous study showed improved fracture healing in young adult mice in response to D+Q treatment. Overall, the research is mounting in favor of senolytics for improving bone health, including fracture healing, to the point that there is currently a clinical trial evaluating the use of D+Q, or fisetin, another senolytic in 120 aged females (NCT04313634).

It seems as though in addition to possible benefits in other areas of aging, senolytics may hold the answer to enhancing fracture healing in aged adults. While quercetin and fisetin are available as supplements, or parts of anti-aging supplements, in many health food stores and online, dasatinib is only available as a prescription for chemotherapy.